Review Article Evidences of Herbal Medicine-Derived...
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Review Article Evidences of Herbal Medicine-Derived Natural Products Effects in Inflammatory Lung Diseases Fernanda Paula R. Santana, 1 Nathalia M. Pinheiro, 2 Márcia Isabel B. Mernak, 1 Renato F. Righetti, 2 Mílton A. Martins, 2 João H. G. Lago, 1 Fernanda D. T. Q. dos Santos Lopes, 2 Iolanda F. L. C. Tibério, 2 and Carla M. Prado 3 1 Instituto de Ciˆ encias Ambientais, Qu´ ımicas e Farmacˆ euticas, Federal University of S˜ ao Paulo, Diadema–SP 09972-270, Brazil 2 School of Medicine, University of S˜ ao Paulo, S˜ ao Paulo–SP 01246903, Brazil 3 Instituto de Sa´ ude e Sociedade, Federal University of S˜ ao Paulo, Santos–SP 11015-020, Brazil Correspondence should be addressed to Carla M. Prado; [email protected] Received 18 March 2016; Accepted 7 June 2016 Academic Editor: Chang-Shik Yin Copyright © 2016 Fernanda Paula R. Santana et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pulmonary inflammation is a hallmark of many respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory syndrome distress (ARDS). Most of these diseases are treated with anti-inflammatory therapy in order to prevent or to reduce the pulmonary inflammation. Herbal medicine-derived natural products have been used in folk medicine and scientific studies to evaluate the value of these compounds have grown in recent years. Many substances derived from plants have the biological effects in vitro and in vivo, such as flavonoids, alkaloids, and terpenoids. Among the biological activities of natural products derived from plants can be pointed out the anti-inflammatory, antiviral, antiplatelet, antitumor anti- allergic activities, and antioxidant. Although many reports have evaluated the effects of these compounds in experimental models, studies evaluating clinical trials are scarce in the literature. is review aims to emphasize the effects of these different natural products in pulmonary diseases in experimental models and in humans and pointing out some possible mechanisms of action. 1. Introduction Pulmonary diseases rate has been increasing and it is related to causes of death for decades. Among the pulmonary diseases, chronic obstructive pulmonary diseases (COPD), asthma, and acute respiratory distress syndrome (ARDS) are the most common and are linked to high mortality and/or high morbidity rates [1–3]. ese pulmonary diseases have in common the pulmonary inflammation which could be acute or chronic and the orchestration of a lot of inflammatory mediators [4]. Inflammation is a cellular response that can occur in the lung induced by external or internal agents. Although it is an important response in the organism, the chronic inflam- mation could damage the lung. Lung inflammation involves the activation of inflammatory cells, such as macrophages, lymphocytes, neutrophils, and eosinophils, which is a source of different kinds of inflammatory mediators such as his- tamine, tumor necrosis factor (TNF-), interleukins, IL-1, IL-4, IL-5, and IL-6, prostaglandins, leukotrienes, and nitric oxide. e release of these inflammatory mediators is related to the signals and symptoms observed in pulmonary diseases such as loss of lung function, airway hyperresponsiveness and obstruction, airway edema, mucus hypersecretion, and lung remodeling [3, 4]. e treatment of the respiratory disorders oſten involves the use of anti-inflammatory therapies and it is required not only to counteract lung inflammation but also to avoid the remodeling process and the destruction of lung tissue preventing a decrement in lung function that is observed in many patients [5]. Additionally, pulmonary diseases such as emphysema and ARDS do not have proper treatments yet, requiring more studies in alternative therapy [6, 7]. Hindawi Publishing Corporation Mediators of Inflammation Volume 2016, Article ID 2348968, 14 pages http://dx.doi.org/10.1155/2016/2348968
Transcript of Review Article Evidences of Herbal Medicine-Derived...
Review ArticleEvidences of Herbal Medicine-Derived Natural ProductsEffects in Inflammatory Lung Diseases
Fernanda Paula R Santana1 Nathalia M Pinheiro2
Maacutercia Isabel B Mernak1 Renato F Righetti2 Miacutelton A Martins2 Joatildeo H G Lago1
Fernanda D T Q dos Santos Lopes2 Iolanda F L C Tibeacuterio2 and Carla M Prado3
1 Instituto de Ciencias Ambientais Quımicas e Farmaceuticas Federal University of Sao Paulo DiademandashSP 09972-270 Brazil2School of Medicine University of Sao Paulo Sao PaulondashSP 01246903 Brazil3Instituto de Saude e Sociedade Federal University of Sao Paulo SantosndashSP 11015-020 Brazil
Correspondence should be addressed to Carla M Prado carlapradounifespbr
Received 18 March 2016 Accepted 7 June 2016
Academic Editor Chang-Shik Yin
Copyright copy 2016 Fernanda Paula R Santana et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited
Pulmonary inflammation is a hallmark of many respiratory diseases such as asthma chronic obstructive pulmonary disease(COPD) and acute respiratory syndrome distress (ARDS) Most of these diseases are treated with anti-inflammatory therapy inorder to prevent or to reduce the pulmonary inflammation Herbal medicine-derived natural products have been used in folkmedicine and scientific studies to evaluate the value of these compounds have grown in recent years Many substances derivedfrom plants have the biological effects in vitro and in vivo such as flavonoids alkaloids and terpenoids Among the biologicalactivities of natural products derived from plants can be pointed out the anti-inflammatory antiviral antiplatelet antitumor anti-allergic activities and antioxidant Although many reports have evaluated the effects of these compounds in experimental modelsstudies evaluating clinical trials are scarce in the literature This review aims to emphasize the effects of these different naturalproducts in pulmonary diseases in experimental models and in humans and pointing out some possible mechanisms of action
1 Introduction
Pulmonary diseases rate has been increasing and it is relatedto causes of death for decades Among the pulmonarydiseases chronic obstructive pulmonary diseases (COPD)asthma and acute respiratory distress syndrome (ARDS) arethe most common and are linked to high mortality andorhigh morbidity rates [1ndash3]These pulmonary diseases have incommon the pulmonary inflammation which could be acuteor chronic and the orchestration of a lot of inflammatorymediators [4]
Inflammation is a cellular response that can occur in thelung induced by external or internal agents Although it isan important response in the organism the chronic inflam-mation could damage the lung Lung inflammation involvesthe activation of inflammatory cells such as macrophageslymphocytes neutrophils and eosinophils which is a source
of different kinds of inflammatory mediators such as his-tamine tumor necrosis factor (TNF-120572) interleukins IL-1120573IL-4 IL-5 and IL-6 prostaglandins leukotrienes and nitricoxide The release of these inflammatory mediators is relatedto the signals and symptoms observed in pulmonary diseasessuch as loss of lung function airway hyperresponsiveness andobstruction airway edema mucus hypersecretion and lungremodeling [3 4]
The treatment of the respiratory disorders often involvesthe use of anti-inflammatory therapies and it is requirednot only to counteract lung inflammation but also to avoidthe remodeling process and the destruction of lung tissuepreventing a decrement in lung function that is observed inmany patients [5] Additionally pulmonary diseases such asemphysema and ARDS do not have proper treatments yetrequiring more studies in alternative therapy [6 7]
Hindawi Publishing CorporationMediators of InflammationVolume 2016 Article ID 2348968 14 pageshttpdxdoiorg10115520162348968
2 Mediators of Inflammation
Herbs have been used in folk medicine since many yearsand the use of herbal-derived natural products as a thera-peutic tool has been increasing considerably [8ndash10] Howeverseveral herbal-derived natural compounds significantly affectcellular mechanisms and evidence of the benefic effects ofherbal-derived natural products in inflammatory pulmonarydiseases has been increasing [8]The use of these compoundsmust be based on scientific evidence The structures of thevarious products cited in this review are presented in Figure 1Herein we review the anti-inflammatory activity of herbal-derived natural products with respect to three pulmonarydiseases namely asthma emphysema and ARDS (Table 1)
2 Evidence of Herbal-Derived NaturalProducts in ARDS
ARDS is characterized by acute pulmonary inflammationprimary characterized by neutrophil infiltration interstitialedema and hypoxemia is often accompanied by aggressivefibrosis and is still one of the leading causes of death withinan intensive care unit [11ndash13]
The acute phase of ARDS is characterized by local inflam-mation and systemic response [14] Experimental and clinicalstudies have sought to elucidate the complex mechanismsinvolved in the pathogenesis of secondary injury Severalmechanisms remain little understood however knowing thefunctions of cytokines and inflammatory mediators involvedin the process helps us to clarify the process of injury andrepair in ARDS
Some specific cells are able to secrete some solubleprotein called cytokines which have the ability to modify thebehavior of other cells [15] TNF-120572 and interleukin 1 beta and8 (IL-1 120573 and IL-8) [15] cytokines classified as proinflam-matory [14] are included among the cytokines involved inacute phase of ARDS
Patients with ARDS more than 72 hours usually evolveinto the late phase of ARDS which is characterized by havingdiffuse alveolar damage that is sometimes irreversible [16]Although mortality has been reduced due to the improvedcontrol of ventilation no effective pharmacological treatmentfor the disease is available until now
Many experimental studies seek evidence in naturalsubstances to help in treating this disease however noevidence of the use of herbal medicine in patients with ARDSwas found Several studies demonstrated that plants canhave effects on cell migration anti-inflammatory cytokinesmetalloproteinase oxidative stress and the downregulationof several transcription factors making as a potential ther-apeutic use in ARDS Currently the phytochemical groupssurveyed more with anti-inflammatory and antimicrobialactions are the flavonoids alkaloids and glycosides [17ndash19]
Eriodictyol (1) a flavonoid isolated from the Chineseherb Dracocephalum rupestre has long been established asan antioxidant and anti-inflammatory agent Zhu et al [20]investigated the effects of eriodictyol on lipopolysaccharide-(LPS-) induced acute lung injury (ALI) in mice and havedemonstrated that eriodictyol alleviates the LPS-inducedlung injury in mice by regulating the transcription factor
nuclear factor erythroid-2-related factor 2 (Nrf2) pathwayand inhibiting the expression of inflammatory cytokines inmacrophages
Kuo et al [21] showed that pretreatment with flavonoidsluteolin (2) reduced pulmonary hemorrhage and neu-trophilic inflammation as well as interstitial edema Thecontrol of pulmonary inflammation was due to the reductionof cytokines such as TNF-120572 KC and ICAM-1 content in thebronchoalveolar lavage fluid (BALF)The control of oxidativedamage and lipid peroxidation was attributed to reducedactivity of catalase and superoxide dismutase activity Themechanism involved is related to the effects of luteolin in theinhibition of NF-120581B and the MAPK activity
Quercetin (3) is also evaluated in a LPS-induced exper-imental ALI and it reduced the release of proinflammatorycytokines in the BALF such as TNF-120572 IL1-120573 and IL-6 by a heme oxygenase-1(HO-1) dependent pathway [22]Other authors also demonstrated that quercetin is effectivein reducing serum cytokines TNF-120572 IL1-120573 IL-6 and nitricoxide (NO) and the mechanism involves an increase in IL-10 secretion an anti-inflammatory cytokine [23] In additionto these cytoprotective effects quercetin also decreased theratio of lung weight to body weight and MMP-9 activity [2223] Quercetin also reduced lung permeability the numberof macrophages and neutrophils and the myeloperoxidaseactivityWang et al [23] also showed that quercetin is effectivein reducing COX-2 iNOS expression HMGB1 and p65-nuclear factor kappa B (NF-120581B) [23]
Kaempferol (4) naturally occurring flavonoid whenevaluated in ALI models induced by LPS appeared effectivein reducing pulmonary edema as well as the bleeding andthickness of the alveolar wall The kaempferol also reducedthe inflammatory cells and total protein in the BALF andcytokines including TNF-120572 IL-1120573 and IL-6 Despite theincrease in superoxide dismutase activity the mechanism ofaction is through the control of signaling pathways MAPKand NF-120581B [24]
The dried root Paeonia lactiflora has been used as amedicinal herb in traditional Chinese medicine for cen-turies The glucosides of peony (TGP) the waterethanolextract of the dried Paeonia lactiflora contain more than15 components including paeoniflorin (5) albiflorin (6)oxypaeoniflorin (7) benzoylpaeoniflorin (8) oxybenzoyl-paeoniflorin (9) paeoniflorigenone (10) lactiflorin (11) gal-loylpaeoniflorin (12) paeonin (13) paeonolide (14) andpaeonol (15) Using a model of LPS-induced ALI He andDai [25] demonstrated that TGP markedly suppressed LPS-induced NO production and inducible nitric oxide synthase(iNOS) expression peritoneal macrophages from rats Inaddition the production of reactive oxygen species fromLPS-stimulatedmacrophages was inhibited Kim andHa [26]showed that paeoniflorin (5) the principle component ofTGP was effective in inhibiting theNO and PGE2 productioninduced by LPS in stimulated macrophages Further exper-iments showed that paeoniflorin inhibited LPS-stimulatedTNF-120572 and interleukin- (IL-) 1120573 release and promoted anincrease in IL-10 production [27]
Mitraphylline (16) is the major pentacyclic oxindolicalkaloid presented inUncaria tomentosa and has traditionally
Mediators of Inflammation 3
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Figure 1 Continued
4 Mediators of Inflammation
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Figure 1 Natural products (1ndash45) from plants with effects in inflammatory lung diseases
been used to treat inflammatory diseases [28] However thespecific role ofmitraphylline in inflammation is still not clearSome studies provided its ability to inhibit proinflammatorycytokines such as TNF-120572 through NF-120581B-dependent mech-anism TNF-120572 primes neutrophils and modulates phagocyticand oxidative burst activities in inflammatory processes [29]Recently Montserrat-de la Paz et al [30] investigated theeffects on mitraphylline in LPS-activated human primaryneutrophils including activation of surface markers by FACSand the expression of inflammatory cytokines The treat-ment with mitraphylline reduced the activated neutrophilsCD16(+)CD62L(minus) and the expression and secretion ofproinflammatory cytokines (TNF-120572 IL-6 or IL-8) to thelevels obtained in basal control condition
Asperuloside (17) an iridoid glycoside found in HerbaPaederiae is a product from traditional Chinese herbalmedicine Qiu et al [31] investigated the protective effectsof asperuloside on inflammatory responses in a LPS-inducedALI model This compound was able to downregulate TNF-120572 IL-1120573 and IL-6 levels both in vitro and in vivo Addition-ally the treatment with asperuloside also reduced the lung
wet-to-dry weight histological alterations and myeloperoxi-dase activity in this model The mechanism involved in theeffects of asperuloside is related to the phosphorylation ofthe inhibitor of NF-120581B (I120581B120572) extracellular signal-relatedkinases 1 and 2 (ERK12) and c-Jun N-terminal kinase (JNK)and p38 mitogen-activated protein kinase (p38MAPK) inLPS-induced lung inflammation These results indicate thatasperuloside exerts its anti-inflammatory effect in correlationwith the inhibition of proinflammatory mediators throughsuppressing NF-120581B translocation and MAPK phosphoryla-tion
The rhizome of Picrorhiza scrophulariiflora has beendescribed as part of Asian traditional medicine for thetreatment of rather a broad range of diseases [32] includingtumors and liver infections Picroside II (18) is known asa major constituent of this plant [33] and it was reportedthat the herb has immunomodulatory and anti-inflamma-tory functions The ethanol extract of P scrophulariiflorasuppresses redox-sensitive inflammation [34] while crudeextract of P scrophulariiflora reduces the classical pathway ofcomplement activation the production of ROS by activated
Mediators of Inflammation 5
Table 1 Herbal-derived natural compounds effects in lung inflammation and diseases
Inflammatory mediators Effects in ReferenceNatural products
Eriodictyol (1)Regulation of Nrf2 pathway and inhibiting the expression ofinflammatory cytokines TNF-120572 IL-6 IL-1120573 and in BALF andserum
ALI model [20]
Luteolin (2) Reduction of TNF-120572 KC ICAM-1 SOD activations of MAPKand NF-120581B pathways and neutrophils inflammation ALI model [21]
Quercetin (3)Reduction of TNF-120572 IL1-120573 IL-5 and IL-6 in BALF NO COX-2iNOS expression HMGB1 and p65NF-120581B Increase IL-10secretion
ALI modelasthma model [22 23 67]
Kaempferol (4) Reduction of inflammatory cells activation of MAPK and NF-120581Bpathways ALI model [24]
Mitraphylline (16) Reduction of IL-1120572 IL-1120573 IL-17 TNF-120572 IL-6 and IL-8 ALI model [29 30]Asperuloside (17) Reduction of TNF-120572 IL-1120573 and IL-6 levels ALI model [31]
Eugenol (19) Inhibition of superoxide radicals from xanthine oxidase systemand the generation of hydroxyl radical ALI model [39]
Sakuranetin (30)Reduction of eosinophils TNF-120572 IL-5 IL-1120573 M-CSF andRANTES and inhibition of NF-120581B in lung MMP-9-positive andMMP-12-positive cells and increased TIMP-1 expression
Asthma modelelastase model [62 88]
Kuwanon G (31) Reduction of IL-4 IL-5 and IL-13 in the sera and BALF Asthma model [63]Naringin (37) Reduction of IL-4 IL-5 IL-13 and INF-120575 levels Asthma model [70 71]
Apigenin (38) Reduction of eosinophil infiltration in lung tissue and IL-6TNF-120572 and IL-17A levels Asthma model [72]
Extracts of plants
Astragalus membranaceus Reduction of eosinophils and lymphocyte infiltration ModulateTh12 immune balance and activates PPAR Asthma model [69]
Boerhavia procumbens Reduction in the infiltration of eosinophils and lymphocytes inlungs Asthma model [65]
Ocimum gratissimum Reduction in the infiltration of eosinophils and IL-4 expression Asthma model [66]Punica granatum Reduction of eosinophils and cytokines IL-1120573 and IL-5 Asthma model [75]
Siegesbeckia glabrescens Reduction of the expression of iNOS and COX-2 cytokine IL-4IL-5 and IL-13 Asthma model [78]
Herbal formula PM014 Reduction of neutrophils macrophages and lymphocytes in BALFTNF-120572 and IL-6 levels Elastase model [89]
Callicarpa japonica Reduction of neutrophil infiltration cytokines IL-6 and TNF-120572and the oxidative stress
Cigarette smokemodel [90]
neutrophils and the proliferation of T lymphocytes [35] Nohet al [36] using a model of RAW 2647 cells and also an invivomodel of LPS-induced ALI showed that Picroside II waseffective in suppressing neutrophilic lung inflammation andthat the possible anti-inflammatory effect of Picroside II wasat least in part associated with TGF-120573 signaling
The phenylpropanoid eugenol (19) is a substance presentin essential oils of various plants and it is part of a phenolicgroup with a recognized antioxidant capacity [37] Eugenolcan prevent lipid peroxidation [38] and also inhibit theformation of superoxide radicals from xanthine oxidasesystem and the generation of hydroxyl radical [39 40] Therelationship between oxidative stress and inflammation inARDS is not completely understood however it is fact thatthe reduction of oxidative stress culminates with reductionin inflammatory mediators release by inflammatory cells[41] Murakami et al [42] showed that eugenol inhibitsthe transcription of NF-120581B and COX-2 stimulated by LPS
According with these findings Huang et al [43] showedthat animals which received eugenol have reduction inproinflammatory cytokines and inflammatory cells in BALFdue to an antioxidative effect of this product and by inhibitionof the transcription of NF-120581B in lung homogenate
As reported in the literature [44 45] the crude extractsfrom fruits and leaves of Morinda citrifolia have been usedin traditional medicine for the treatment of inflammationand pulmonary diseases These effects could be associatedwith the presence of several antioxidant natural productssuch as iridoid glycosides (deacetylasperulosidic acid 20and asperulosidic acid 21) and flavonoids (quercetin-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside22 and kaempferol-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside 23) Additionally turmeric (Curcumalonga) and ginger (Zingiber officinale) displayed an importanteffect in inflammation including lung and pulmonary whichcould be due the presence of curcumin (24) [46 47]
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 Mediators of Inflammation
Herbs have been used in folk medicine since many yearsand the use of herbal-derived natural products as a thera-peutic tool has been increasing considerably [8ndash10] Howeverseveral herbal-derived natural compounds significantly affectcellular mechanisms and evidence of the benefic effects ofherbal-derived natural products in inflammatory pulmonarydiseases has been increasing [8]The use of these compoundsmust be based on scientific evidence The structures of thevarious products cited in this review are presented in Figure 1Herein we review the anti-inflammatory activity of herbal-derived natural products with respect to three pulmonarydiseases namely asthma emphysema and ARDS (Table 1)
2 Evidence of Herbal-Derived NaturalProducts in ARDS
ARDS is characterized by acute pulmonary inflammationprimary characterized by neutrophil infiltration interstitialedema and hypoxemia is often accompanied by aggressivefibrosis and is still one of the leading causes of death withinan intensive care unit [11ndash13]
The acute phase of ARDS is characterized by local inflam-mation and systemic response [14] Experimental and clinicalstudies have sought to elucidate the complex mechanismsinvolved in the pathogenesis of secondary injury Severalmechanisms remain little understood however knowing thefunctions of cytokines and inflammatory mediators involvedin the process helps us to clarify the process of injury andrepair in ARDS
Some specific cells are able to secrete some solubleprotein called cytokines which have the ability to modify thebehavior of other cells [15] TNF-120572 and interleukin 1 beta and8 (IL-1 120573 and IL-8) [15] cytokines classified as proinflam-matory [14] are included among the cytokines involved inacute phase of ARDS
Patients with ARDS more than 72 hours usually evolveinto the late phase of ARDS which is characterized by havingdiffuse alveolar damage that is sometimes irreversible [16]Although mortality has been reduced due to the improvedcontrol of ventilation no effective pharmacological treatmentfor the disease is available until now
Many experimental studies seek evidence in naturalsubstances to help in treating this disease however noevidence of the use of herbal medicine in patients with ARDSwas found Several studies demonstrated that plants canhave effects on cell migration anti-inflammatory cytokinesmetalloproteinase oxidative stress and the downregulationof several transcription factors making as a potential ther-apeutic use in ARDS Currently the phytochemical groupssurveyed more with anti-inflammatory and antimicrobialactions are the flavonoids alkaloids and glycosides [17ndash19]
Eriodictyol (1) a flavonoid isolated from the Chineseherb Dracocephalum rupestre has long been established asan antioxidant and anti-inflammatory agent Zhu et al [20]investigated the effects of eriodictyol on lipopolysaccharide-(LPS-) induced acute lung injury (ALI) in mice and havedemonstrated that eriodictyol alleviates the LPS-inducedlung injury in mice by regulating the transcription factor
nuclear factor erythroid-2-related factor 2 (Nrf2) pathwayand inhibiting the expression of inflammatory cytokines inmacrophages
Kuo et al [21] showed that pretreatment with flavonoidsluteolin (2) reduced pulmonary hemorrhage and neu-trophilic inflammation as well as interstitial edema Thecontrol of pulmonary inflammation was due to the reductionof cytokines such as TNF-120572 KC and ICAM-1 content in thebronchoalveolar lavage fluid (BALF)The control of oxidativedamage and lipid peroxidation was attributed to reducedactivity of catalase and superoxide dismutase activity Themechanism involved is related to the effects of luteolin in theinhibition of NF-120581B and the MAPK activity
Quercetin (3) is also evaluated in a LPS-induced exper-imental ALI and it reduced the release of proinflammatorycytokines in the BALF such as TNF-120572 IL1-120573 and IL-6 by a heme oxygenase-1(HO-1) dependent pathway [22]Other authors also demonstrated that quercetin is effectivein reducing serum cytokines TNF-120572 IL1-120573 IL-6 and nitricoxide (NO) and the mechanism involves an increase in IL-10 secretion an anti-inflammatory cytokine [23] In additionto these cytoprotective effects quercetin also decreased theratio of lung weight to body weight and MMP-9 activity [2223] Quercetin also reduced lung permeability the numberof macrophages and neutrophils and the myeloperoxidaseactivityWang et al [23] also showed that quercetin is effectivein reducing COX-2 iNOS expression HMGB1 and p65-nuclear factor kappa B (NF-120581B) [23]
Kaempferol (4) naturally occurring flavonoid whenevaluated in ALI models induced by LPS appeared effectivein reducing pulmonary edema as well as the bleeding andthickness of the alveolar wall The kaempferol also reducedthe inflammatory cells and total protein in the BALF andcytokines including TNF-120572 IL-1120573 and IL-6 Despite theincrease in superoxide dismutase activity the mechanism ofaction is through the control of signaling pathways MAPKand NF-120581B [24]
The dried root Paeonia lactiflora has been used as amedicinal herb in traditional Chinese medicine for cen-turies The glucosides of peony (TGP) the waterethanolextract of the dried Paeonia lactiflora contain more than15 components including paeoniflorin (5) albiflorin (6)oxypaeoniflorin (7) benzoylpaeoniflorin (8) oxybenzoyl-paeoniflorin (9) paeoniflorigenone (10) lactiflorin (11) gal-loylpaeoniflorin (12) paeonin (13) paeonolide (14) andpaeonol (15) Using a model of LPS-induced ALI He andDai [25] demonstrated that TGP markedly suppressed LPS-induced NO production and inducible nitric oxide synthase(iNOS) expression peritoneal macrophages from rats Inaddition the production of reactive oxygen species fromLPS-stimulatedmacrophages was inhibited Kim andHa [26]showed that paeoniflorin (5) the principle component ofTGP was effective in inhibiting theNO and PGE2 productioninduced by LPS in stimulated macrophages Further exper-iments showed that paeoniflorin inhibited LPS-stimulatedTNF-120572 and interleukin- (IL-) 1120573 release and promoted anincrease in IL-10 production [27]
Mitraphylline (16) is the major pentacyclic oxindolicalkaloid presented inUncaria tomentosa and has traditionally
Mediators of Inflammation 3
OHO
OH O
OHOH
OHO
OH O
OHOH
21
OHO
OH O
OHOH
OH
OHO
OH O
OH
OH
3 4
HOHO
HOO
OH
O O
OH
OOO
O
O
O
O
HO
OHOHHO
HO
5 6
OOHO
HOHO
OH
O
OO
OHO
OH O OH
H O OO
HO
O OHHOOH
O O
78
OOHO
OHO
OH
O
OO
O
OH
H
HO
O
OO O OHO
OO
O
OO
OHOHO
HO
O
O9
1011
O
OO
O
H
OH
OO
O
O
HO
OHHO
OHHO
HO
OO
O OO
O
OO
HOOH H
H H
OHOH
12
13
O O
O
O
OHOHHO
OO
OHHO
HO
O
HO
O
NH
NO
OOO
HH
H
14 15 16
OO OH
O
OO
O
O
OH
OHOH
H
H
OO
O
HOO
O
O
H
HO
OHOH
OH
HO
OH
17
18HO
O OOH
OH
OH
O
OHOHO H
HHOH
OH
O
HO O
O
O
HO
O Glc20
19 21
OHO
OH OO
OH
OH
OHOOH
OHO
O
OHHOHO
OHO
OH OO
OH
OHOOH
OHO
O
OHHOHO
22
23
O OH
OHO
OOH
O
OHOH
HOOH
OH
24 25
O
OHOH
HOOH
OH
OH
O
OOH
HOOH
OH
O OH
OHOH
26
27
O
OOH
HOOH
OH
O OH
OHOH
OH
28
HO
OH
OH
29
OO
OH O
OH
30
Figure 1 Continued
4 Mediators of Inflammation
OHO
OH O
OHHOOH
HO
O
OHHO
31
OHO
OH O
OH
O
OH
OHOH
OH
OH
N C O
NCO
32
33
O
O O OHOH
OH
OHHO
OO
HO
OH O
34
35
O
OH
OH
O
OH
O
OH
OHH
OH
O
OOH
OOO
O
OH
HOHO
OHOHHO
OH
36 37
O
OOH
HO
OH
O
OOH
HO
O
O
OH
38
39
O
OOH
O
OH
O
OHO
OOH
HO
OH
O
OH
40 41
O
OOH
O
O
O
OH
O
OOH
O
OH
O
OHOHHO
HO
42
43
O
OOH
HO
OH
O
O
OHO
OHOH
OH
HO
O
OO
MeO
HO
44
45
Figure 1 Natural products (1ndash45) from plants with effects in inflammatory lung diseases
been used to treat inflammatory diseases [28] However thespecific role ofmitraphylline in inflammation is still not clearSome studies provided its ability to inhibit proinflammatorycytokines such as TNF-120572 through NF-120581B-dependent mech-anism TNF-120572 primes neutrophils and modulates phagocyticand oxidative burst activities in inflammatory processes [29]Recently Montserrat-de la Paz et al [30] investigated theeffects on mitraphylline in LPS-activated human primaryneutrophils including activation of surface markers by FACSand the expression of inflammatory cytokines The treat-ment with mitraphylline reduced the activated neutrophilsCD16(+)CD62L(minus) and the expression and secretion ofproinflammatory cytokines (TNF-120572 IL-6 or IL-8) to thelevels obtained in basal control condition
Asperuloside (17) an iridoid glycoside found in HerbaPaederiae is a product from traditional Chinese herbalmedicine Qiu et al [31] investigated the protective effectsof asperuloside on inflammatory responses in a LPS-inducedALI model This compound was able to downregulate TNF-120572 IL-1120573 and IL-6 levels both in vitro and in vivo Addition-ally the treatment with asperuloside also reduced the lung
wet-to-dry weight histological alterations and myeloperoxi-dase activity in this model The mechanism involved in theeffects of asperuloside is related to the phosphorylation ofthe inhibitor of NF-120581B (I120581B120572) extracellular signal-relatedkinases 1 and 2 (ERK12) and c-Jun N-terminal kinase (JNK)and p38 mitogen-activated protein kinase (p38MAPK) inLPS-induced lung inflammation These results indicate thatasperuloside exerts its anti-inflammatory effect in correlationwith the inhibition of proinflammatory mediators throughsuppressing NF-120581B translocation and MAPK phosphoryla-tion
The rhizome of Picrorhiza scrophulariiflora has beendescribed as part of Asian traditional medicine for thetreatment of rather a broad range of diseases [32] includingtumors and liver infections Picroside II (18) is known asa major constituent of this plant [33] and it was reportedthat the herb has immunomodulatory and anti-inflamma-tory functions The ethanol extract of P scrophulariiflorasuppresses redox-sensitive inflammation [34] while crudeextract of P scrophulariiflora reduces the classical pathway ofcomplement activation the production of ROS by activated
Mediators of Inflammation 5
Table 1 Herbal-derived natural compounds effects in lung inflammation and diseases
Inflammatory mediators Effects in ReferenceNatural products
Eriodictyol (1)Regulation of Nrf2 pathway and inhibiting the expression ofinflammatory cytokines TNF-120572 IL-6 IL-1120573 and in BALF andserum
ALI model [20]
Luteolin (2) Reduction of TNF-120572 KC ICAM-1 SOD activations of MAPKand NF-120581B pathways and neutrophils inflammation ALI model [21]
Quercetin (3)Reduction of TNF-120572 IL1-120573 IL-5 and IL-6 in BALF NO COX-2iNOS expression HMGB1 and p65NF-120581B Increase IL-10secretion
ALI modelasthma model [22 23 67]
Kaempferol (4) Reduction of inflammatory cells activation of MAPK and NF-120581Bpathways ALI model [24]
Mitraphylline (16) Reduction of IL-1120572 IL-1120573 IL-17 TNF-120572 IL-6 and IL-8 ALI model [29 30]Asperuloside (17) Reduction of TNF-120572 IL-1120573 and IL-6 levels ALI model [31]
Eugenol (19) Inhibition of superoxide radicals from xanthine oxidase systemand the generation of hydroxyl radical ALI model [39]
Sakuranetin (30)Reduction of eosinophils TNF-120572 IL-5 IL-1120573 M-CSF andRANTES and inhibition of NF-120581B in lung MMP-9-positive andMMP-12-positive cells and increased TIMP-1 expression
Asthma modelelastase model [62 88]
Kuwanon G (31) Reduction of IL-4 IL-5 and IL-13 in the sera and BALF Asthma model [63]Naringin (37) Reduction of IL-4 IL-5 IL-13 and INF-120575 levels Asthma model [70 71]
Apigenin (38) Reduction of eosinophil infiltration in lung tissue and IL-6TNF-120572 and IL-17A levels Asthma model [72]
Extracts of plants
Astragalus membranaceus Reduction of eosinophils and lymphocyte infiltration ModulateTh12 immune balance and activates PPAR Asthma model [69]
Boerhavia procumbens Reduction in the infiltration of eosinophils and lymphocytes inlungs Asthma model [65]
Ocimum gratissimum Reduction in the infiltration of eosinophils and IL-4 expression Asthma model [66]Punica granatum Reduction of eosinophils and cytokines IL-1120573 and IL-5 Asthma model [75]
Siegesbeckia glabrescens Reduction of the expression of iNOS and COX-2 cytokine IL-4IL-5 and IL-13 Asthma model [78]
Herbal formula PM014 Reduction of neutrophils macrophages and lymphocytes in BALFTNF-120572 and IL-6 levels Elastase model [89]
Callicarpa japonica Reduction of neutrophil infiltration cytokines IL-6 and TNF-120572and the oxidative stress
Cigarette smokemodel [90]
neutrophils and the proliferation of T lymphocytes [35] Nohet al [36] using a model of RAW 2647 cells and also an invivomodel of LPS-induced ALI showed that Picroside II waseffective in suppressing neutrophilic lung inflammation andthat the possible anti-inflammatory effect of Picroside II wasat least in part associated with TGF-120573 signaling
The phenylpropanoid eugenol (19) is a substance presentin essential oils of various plants and it is part of a phenolicgroup with a recognized antioxidant capacity [37] Eugenolcan prevent lipid peroxidation [38] and also inhibit theformation of superoxide radicals from xanthine oxidasesystem and the generation of hydroxyl radical [39 40] Therelationship between oxidative stress and inflammation inARDS is not completely understood however it is fact thatthe reduction of oxidative stress culminates with reductionin inflammatory mediators release by inflammatory cells[41] Murakami et al [42] showed that eugenol inhibitsthe transcription of NF-120581B and COX-2 stimulated by LPS
According with these findings Huang et al [43] showedthat animals which received eugenol have reduction inproinflammatory cytokines and inflammatory cells in BALFdue to an antioxidative effect of this product and by inhibitionof the transcription of NF-120581B in lung homogenate
As reported in the literature [44 45] the crude extractsfrom fruits and leaves of Morinda citrifolia have been usedin traditional medicine for the treatment of inflammationand pulmonary diseases These effects could be associatedwith the presence of several antioxidant natural productssuch as iridoid glycosides (deacetylasperulosidic acid 20and asperulosidic acid 21) and flavonoids (quercetin-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside22 and kaempferol-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside 23) Additionally turmeric (Curcumalonga) and ginger (Zingiber officinale) displayed an importanteffect in inflammation including lung and pulmonary whichcould be due the presence of curcumin (24) [46 47]
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 3
OHO
OH O
OHOH
OHO
OH O
OHOH
21
OHO
OH O
OHOH
OH
OHO
OH O
OH
OH
3 4
HOHO
HOO
OH
O O
OH
OOO
O
O
O
O
HO
OHOHHO
HO
5 6
OOHO
HOHO
OH
O
OO
OHO
OH O OH
H O OO
HO
O OHHOOH
O O
78
OOHO
OHO
OH
O
OO
O
OH
H
HO
O
OO O OHO
OO
O
OO
OHOHO
HO
O
O9
1011
O
OO
O
H
OH
OO
O
O
HO
OHHO
OHHO
HO
OO
O OO
O
OO
HOOH H
H H
OHOH
12
13
O O
O
O
OHOHHO
OO
OHHO
HO
O
HO
O
NH
NO
OOO
HH
H
14 15 16
OO OH
O
OO
O
O
OH
OHOH
H
H
OO
O
HOO
O
O
H
HO
OHOH
OH
HO
OH
17
18HO
O OOH
OH
OH
O
OHOHO H
HHOH
OH
O
HO O
O
O
HO
O Glc20
19 21
OHO
OH OO
OH
OH
OHOOH
OHO
O
OHHOHO
OHO
OH OO
OH
OHOOH
OHO
O
OHHOHO
22
23
O OH
OHO
OOH
O
OHOH
HOOH
OH
24 25
O
OHOH
HOOH
OH
OH
O
OOH
HOOH
OH
O OH
OHOH
26
27
O
OOH
HOOH
OH
O OH
OHOH
OH
28
HO
OH
OH
29
OO
OH O
OH
30
Figure 1 Continued
4 Mediators of Inflammation
OHO
OH O
OHHOOH
HO
O
OHHO
31
OHO
OH O
OH
O
OH
OHOH
OH
OH
N C O
NCO
32
33
O
O O OHOH
OH
OHHO
OO
HO
OH O
34
35
O
OH
OH
O
OH
O
OH
OHH
OH
O
OOH
OOO
O
OH
HOHO
OHOHHO
OH
36 37
O
OOH
HO
OH
O
OOH
HO
O
O
OH
38
39
O
OOH
O
OH
O
OHO
OOH
HO
OH
O
OH
40 41
O
OOH
O
O
O
OH
O
OOH
O
OH
O
OHOHHO
HO
42
43
O
OOH
HO
OH
O
O
OHO
OHOH
OH
HO
O
OO
MeO
HO
44
45
Figure 1 Natural products (1ndash45) from plants with effects in inflammatory lung diseases
been used to treat inflammatory diseases [28] However thespecific role ofmitraphylline in inflammation is still not clearSome studies provided its ability to inhibit proinflammatorycytokines such as TNF-120572 through NF-120581B-dependent mech-anism TNF-120572 primes neutrophils and modulates phagocyticand oxidative burst activities in inflammatory processes [29]Recently Montserrat-de la Paz et al [30] investigated theeffects on mitraphylline in LPS-activated human primaryneutrophils including activation of surface markers by FACSand the expression of inflammatory cytokines The treat-ment with mitraphylline reduced the activated neutrophilsCD16(+)CD62L(minus) and the expression and secretion ofproinflammatory cytokines (TNF-120572 IL-6 or IL-8) to thelevels obtained in basal control condition
Asperuloside (17) an iridoid glycoside found in HerbaPaederiae is a product from traditional Chinese herbalmedicine Qiu et al [31] investigated the protective effectsof asperuloside on inflammatory responses in a LPS-inducedALI model This compound was able to downregulate TNF-120572 IL-1120573 and IL-6 levels both in vitro and in vivo Addition-ally the treatment with asperuloside also reduced the lung
wet-to-dry weight histological alterations and myeloperoxi-dase activity in this model The mechanism involved in theeffects of asperuloside is related to the phosphorylation ofthe inhibitor of NF-120581B (I120581B120572) extracellular signal-relatedkinases 1 and 2 (ERK12) and c-Jun N-terminal kinase (JNK)and p38 mitogen-activated protein kinase (p38MAPK) inLPS-induced lung inflammation These results indicate thatasperuloside exerts its anti-inflammatory effect in correlationwith the inhibition of proinflammatory mediators throughsuppressing NF-120581B translocation and MAPK phosphoryla-tion
The rhizome of Picrorhiza scrophulariiflora has beendescribed as part of Asian traditional medicine for thetreatment of rather a broad range of diseases [32] includingtumors and liver infections Picroside II (18) is known asa major constituent of this plant [33] and it was reportedthat the herb has immunomodulatory and anti-inflamma-tory functions The ethanol extract of P scrophulariiflorasuppresses redox-sensitive inflammation [34] while crudeextract of P scrophulariiflora reduces the classical pathway ofcomplement activation the production of ROS by activated
Mediators of Inflammation 5
Table 1 Herbal-derived natural compounds effects in lung inflammation and diseases
Inflammatory mediators Effects in ReferenceNatural products
Eriodictyol (1)Regulation of Nrf2 pathway and inhibiting the expression ofinflammatory cytokines TNF-120572 IL-6 IL-1120573 and in BALF andserum
ALI model [20]
Luteolin (2) Reduction of TNF-120572 KC ICAM-1 SOD activations of MAPKand NF-120581B pathways and neutrophils inflammation ALI model [21]
Quercetin (3)Reduction of TNF-120572 IL1-120573 IL-5 and IL-6 in BALF NO COX-2iNOS expression HMGB1 and p65NF-120581B Increase IL-10secretion
ALI modelasthma model [22 23 67]
Kaempferol (4) Reduction of inflammatory cells activation of MAPK and NF-120581Bpathways ALI model [24]
Mitraphylline (16) Reduction of IL-1120572 IL-1120573 IL-17 TNF-120572 IL-6 and IL-8 ALI model [29 30]Asperuloside (17) Reduction of TNF-120572 IL-1120573 and IL-6 levels ALI model [31]
Eugenol (19) Inhibition of superoxide radicals from xanthine oxidase systemand the generation of hydroxyl radical ALI model [39]
Sakuranetin (30)Reduction of eosinophils TNF-120572 IL-5 IL-1120573 M-CSF andRANTES and inhibition of NF-120581B in lung MMP-9-positive andMMP-12-positive cells and increased TIMP-1 expression
Asthma modelelastase model [62 88]
Kuwanon G (31) Reduction of IL-4 IL-5 and IL-13 in the sera and BALF Asthma model [63]Naringin (37) Reduction of IL-4 IL-5 IL-13 and INF-120575 levels Asthma model [70 71]
Apigenin (38) Reduction of eosinophil infiltration in lung tissue and IL-6TNF-120572 and IL-17A levels Asthma model [72]
Extracts of plants
Astragalus membranaceus Reduction of eosinophils and lymphocyte infiltration ModulateTh12 immune balance and activates PPAR Asthma model [69]
Boerhavia procumbens Reduction in the infiltration of eosinophils and lymphocytes inlungs Asthma model [65]
Ocimum gratissimum Reduction in the infiltration of eosinophils and IL-4 expression Asthma model [66]Punica granatum Reduction of eosinophils and cytokines IL-1120573 and IL-5 Asthma model [75]
Siegesbeckia glabrescens Reduction of the expression of iNOS and COX-2 cytokine IL-4IL-5 and IL-13 Asthma model [78]
Herbal formula PM014 Reduction of neutrophils macrophages and lymphocytes in BALFTNF-120572 and IL-6 levels Elastase model [89]
Callicarpa japonica Reduction of neutrophil infiltration cytokines IL-6 and TNF-120572and the oxidative stress
Cigarette smokemodel [90]
neutrophils and the proliferation of T lymphocytes [35] Nohet al [36] using a model of RAW 2647 cells and also an invivomodel of LPS-induced ALI showed that Picroside II waseffective in suppressing neutrophilic lung inflammation andthat the possible anti-inflammatory effect of Picroside II wasat least in part associated with TGF-120573 signaling
The phenylpropanoid eugenol (19) is a substance presentin essential oils of various plants and it is part of a phenolicgroup with a recognized antioxidant capacity [37] Eugenolcan prevent lipid peroxidation [38] and also inhibit theformation of superoxide radicals from xanthine oxidasesystem and the generation of hydroxyl radical [39 40] Therelationship between oxidative stress and inflammation inARDS is not completely understood however it is fact thatthe reduction of oxidative stress culminates with reductionin inflammatory mediators release by inflammatory cells[41] Murakami et al [42] showed that eugenol inhibitsthe transcription of NF-120581B and COX-2 stimulated by LPS
According with these findings Huang et al [43] showedthat animals which received eugenol have reduction inproinflammatory cytokines and inflammatory cells in BALFdue to an antioxidative effect of this product and by inhibitionof the transcription of NF-120581B in lung homogenate
As reported in the literature [44 45] the crude extractsfrom fruits and leaves of Morinda citrifolia have been usedin traditional medicine for the treatment of inflammationand pulmonary diseases These effects could be associatedwith the presence of several antioxidant natural productssuch as iridoid glycosides (deacetylasperulosidic acid 20and asperulosidic acid 21) and flavonoids (quercetin-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside22 and kaempferol-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside 23) Additionally turmeric (Curcumalonga) and ginger (Zingiber officinale) displayed an importanteffect in inflammation including lung and pulmonary whichcould be due the presence of curcumin (24) [46 47]
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 Mediators of Inflammation
OHO
OH O
OHHOOH
HO
O
OHHO
31
OHO
OH O
OH
O
OH
OHOH
OH
OH
N C O
NCO
32
33
O
O O OHOH
OH
OHHO
OO
HO
OH O
34
35
O
OH
OH
O
OH
O
OH
OHH
OH
O
OOH
OOO
O
OH
HOHO
OHOHHO
OH
36 37
O
OOH
HO
OH
O
OOH
HO
O
O
OH
38
39
O
OOH
O
OH
O
OHO
OOH
HO
OH
O
OH
40 41
O
OOH
O
O
O
OH
O
OOH
O
OH
O
OHOHHO
HO
42
43
O
OOH
HO
OH
O
O
OHO
OHOH
OH
HO
O
OO
MeO
HO
44
45
Figure 1 Natural products (1ndash45) from plants with effects in inflammatory lung diseases
been used to treat inflammatory diseases [28] However thespecific role ofmitraphylline in inflammation is still not clearSome studies provided its ability to inhibit proinflammatorycytokines such as TNF-120572 through NF-120581B-dependent mech-anism TNF-120572 primes neutrophils and modulates phagocyticand oxidative burst activities in inflammatory processes [29]Recently Montserrat-de la Paz et al [30] investigated theeffects on mitraphylline in LPS-activated human primaryneutrophils including activation of surface markers by FACSand the expression of inflammatory cytokines The treat-ment with mitraphylline reduced the activated neutrophilsCD16(+)CD62L(minus) and the expression and secretion ofproinflammatory cytokines (TNF-120572 IL-6 or IL-8) to thelevels obtained in basal control condition
Asperuloside (17) an iridoid glycoside found in HerbaPaederiae is a product from traditional Chinese herbalmedicine Qiu et al [31] investigated the protective effectsof asperuloside on inflammatory responses in a LPS-inducedALI model This compound was able to downregulate TNF-120572 IL-1120573 and IL-6 levels both in vitro and in vivo Addition-ally the treatment with asperuloside also reduced the lung
wet-to-dry weight histological alterations and myeloperoxi-dase activity in this model The mechanism involved in theeffects of asperuloside is related to the phosphorylation ofthe inhibitor of NF-120581B (I120581B120572) extracellular signal-relatedkinases 1 and 2 (ERK12) and c-Jun N-terminal kinase (JNK)and p38 mitogen-activated protein kinase (p38MAPK) inLPS-induced lung inflammation These results indicate thatasperuloside exerts its anti-inflammatory effect in correlationwith the inhibition of proinflammatory mediators throughsuppressing NF-120581B translocation and MAPK phosphoryla-tion
The rhizome of Picrorhiza scrophulariiflora has beendescribed as part of Asian traditional medicine for thetreatment of rather a broad range of diseases [32] includingtumors and liver infections Picroside II (18) is known asa major constituent of this plant [33] and it was reportedthat the herb has immunomodulatory and anti-inflamma-tory functions The ethanol extract of P scrophulariiflorasuppresses redox-sensitive inflammation [34] while crudeextract of P scrophulariiflora reduces the classical pathway ofcomplement activation the production of ROS by activated
Mediators of Inflammation 5
Table 1 Herbal-derived natural compounds effects in lung inflammation and diseases
Inflammatory mediators Effects in ReferenceNatural products
Eriodictyol (1)Regulation of Nrf2 pathway and inhibiting the expression ofinflammatory cytokines TNF-120572 IL-6 IL-1120573 and in BALF andserum
ALI model [20]
Luteolin (2) Reduction of TNF-120572 KC ICAM-1 SOD activations of MAPKand NF-120581B pathways and neutrophils inflammation ALI model [21]
Quercetin (3)Reduction of TNF-120572 IL1-120573 IL-5 and IL-6 in BALF NO COX-2iNOS expression HMGB1 and p65NF-120581B Increase IL-10secretion
ALI modelasthma model [22 23 67]
Kaempferol (4) Reduction of inflammatory cells activation of MAPK and NF-120581Bpathways ALI model [24]
Mitraphylline (16) Reduction of IL-1120572 IL-1120573 IL-17 TNF-120572 IL-6 and IL-8 ALI model [29 30]Asperuloside (17) Reduction of TNF-120572 IL-1120573 and IL-6 levels ALI model [31]
Eugenol (19) Inhibition of superoxide radicals from xanthine oxidase systemand the generation of hydroxyl radical ALI model [39]
Sakuranetin (30)Reduction of eosinophils TNF-120572 IL-5 IL-1120573 M-CSF andRANTES and inhibition of NF-120581B in lung MMP-9-positive andMMP-12-positive cells and increased TIMP-1 expression
Asthma modelelastase model [62 88]
Kuwanon G (31) Reduction of IL-4 IL-5 and IL-13 in the sera and BALF Asthma model [63]Naringin (37) Reduction of IL-4 IL-5 IL-13 and INF-120575 levels Asthma model [70 71]
Apigenin (38) Reduction of eosinophil infiltration in lung tissue and IL-6TNF-120572 and IL-17A levels Asthma model [72]
Extracts of plants
Astragalus membranaceus Reduction of eosinophils and lymphocyte infiltration ModulateTh12 immune balance and activates PPAR Asthma model [69]
Boerhavia procumbens Reduction in the infiltration of eosinophils and lymphocytes inlungs Asthma model [65]
Ocimum gratissimum Reduction in the infiltration of eosinophils and IL-4 expression Asthma model [66]Punica granatum Reduction of eosinophils and cytokines IL-1120573 and IL-5 Asthma model [75]
Siegesbeckia glabrescens Reduction of the expression of iNOS and COX-2 cytokine IL-4IL-5 and IL-13 Asthma model [78]
Herbal formula PM014 Reduction of neutrophils macrophages and lymphocytes in BALFTNF-120572 and IL-6 levels Elastase model [89]
Callicarpa japonica Reduction of neutrophil infiltration cytokines IL-6 and TNF-120572and the oxidative stress
Cigarette smokemodel [90]
neutrophils and the proliferation of T lymphocytes [35] Nohet al [36] using a model of RAW 2647 cells and also an invivomodel of LPS-induced ALI showed that Picroside II waseffective in suppressing neutrophilic lung inflammation andthat the possible anti-inflammatory effect of Picroside II wasat least in part associated with TGF-120573 signaling
The phenylpropanoid eugenol (19) is a substance presentin essential oils of various plants and it is part of a phenolicgroup with a recognized antioxidant capacity [37] Eugenolcan prevent lipid peroxidation [38] and also inhibit theformation of superoxide radicals from xanthine oxidasesystem and the generation of hydroxyl radical [39 40] Therelationship between oxidative stress and inflammation inARDS is not completely understood however it is fact thatthe reduction of oxidative stress culminates with reductionin inflammatory mediators release by inflammatory cells[41] Murakami et al [42] showed that eugenol inhibitsthe transcription of NF-120581B and COX-2 stimulated by LPS
According with these findings Huang et al [43] showedthat animals which received eugenol have reduction inproinflammatory cytokines and inflammatory cells in BALFdue to an antioxidative effect of this product and by inhibitionof the transcription of NF-120581B in lung homogenate
As reported in the literature [44 45] the crude extractsfrom fruits and leaves of Morinda citrifolia have been usedin traditional medicine for the treatment of inflammationand pulmonary diseases These effects could be associatedwith the presence of several antioxidant natural productssuch as iridoid glycosides (deacetylasperulosidic acid 20and asperulosidic acid 21) and flavonoids (quercetin-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside22 and kaempferol-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside 23) Additionally turmeric (Curcumalonga) and ginger (Zingiber officinale) displayed an importanteffect in inflammation including lung and pulmonary whichcould be due the presence of curcumin (24) [46 47]
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 5
Table 1 Herbal-derived natural compounds effects in lung inflammation and diseases
Inflammatory mediators Effects in ReferenceNatural products
Eriodictyol (1)Regulation of Nrf2 pathway and inhibiting the expression ofinflammatory cytokines TNF-120572 IL-6 IL-1120573 and in BALF andserum
ALI model [20]
Luteolin (2) Reduction of TNF-120572 KC ICAM-1 SOD activations of MAPKand NF-120581B pathways and neutrophils inflammation ALI model [21]
Quercetin (3)Reduction of TNF-120572 IL1-120573 IL-5 and IL-6 in BALF NO COX-2iNOS expression HMGB1 and p65NF-120581B Increase IL-10secretion
ALI modelasthma model [22 23 67]
Kaempferol (4) Reduction of inflammatory cells activation of MAPK and NF-120581Bpathways ALI model [24]
Mitraphylline (16) Reduction of IL-1120572 IL-1120573 IL-17 TNF-120572 IL-6 and IL-8 ALI model [29 30]Asperuloside (17) Reduction of TNF-120572 IL-1120573 and IL-6 levels ALI model [31]
Eugenol (19) Inhibition of superoxide radicals from xanthine oxidase systemand the generation of hydroxyl radical ALI model [39]
Sakuranetin (30)Reduction of eosinophils TNF-120572 IL-5 IL-1120573 M-CSF andRANTES and inhibition of NF-120581B in lung MMP-9-positive andMMP-12-positive cells and increased TIMP-1 expression
Asthma modelelastase model [62 88]
Kuwanon G (31) Reduction of IL-4 IL-5 and IL-13 in the sera and BALF Asthma model [63]Naringin (37) Reduction of IL-4 IL-5 IL-13 and INF-120575 levels Asthma model [70 71]
Apigenin (38) Reduction of eosinophil infiltration in lung tissue and IL-6TNF-120572 and IL-17A levels Asthma model [72]
Extracts of plants
Astragalus membranaceus Reduction of eosinophils and lymphocyte infiltration ModulateTh12 immune balance and activates PPAR Asthma model [69]
Boerhavia procumbens Reduction in the infiltration of eosinophils and lymphocytes inlungs Asthma model [65]
Ocimum gratissimum Reduction in the infiltration of eosinophils and IL-4 expression Asthma model [66]Punica granatum Reduction of eosinophils and cytokines IL-1120573 and IL-5 Asthma model [75]
Siegesbeckia glabrescens Reduction of the expression of iNOS and COX-2 cytokine IL-4IL-5 and IL-13 Asthma model [78]
Herbal formula PM014 Reduction of neutrophils macrophages and lymphocytes in BALFTNF-120572 and IL-6 levels Elastase model [89]
Callicarpa japonica Reduction of neutrophil infiltration cytokines IL-6 and TNF-120572and the oxidative stress
Cigarette smokemodel [90]
neutrophils and the proliferation of T lymphocytes [35] Nohet al [36] using a model of RAW 2647 cells and also an invivomodel of LPS-induced ALI showed that Picroside II waseffective in suppressing neutrophilic lung inflammation andthat the possible anti-inflammatory effect of Picroside II wasat least in part associated with TGF-120573 signaling
The phenylpropanoid eugenol (19) is a substance presentin essential oils of various plants and it is part of a phenolicgroup with a recognized antioxidant capacity [37] Eugenolcan prevent lipid peroxidation [38] and also inhibit theformation of superoxide radicals from xanthine oxidasesystem and the generation of hydroxyl radical [39 40] Therelationship between oxidative stress and inflammation inARDS is not completely understood however it is fact thatthe reduction of oxidative stress culminates with reductionin inflammatory mediators release by inflammatory cells[41] Murakami et al [42] showed that eugenol inhibitsthe transcription of NF-120581B and COX-2 stimulated by LPS
According with these findings Huang et al [43] showedthat animals which received eugenol have reduction inproinflammatory cytokines and inflammatory cells in BALFdue to an antioxidative effect of this product and by inhibitionof the transcription of NF-120581B in lung homogenate
As reported in the literature [44 45] the crude extractsfrom fruits and leaves of Morinda citrifolia have been usedin traditional medicine for the treatment of inflammationand pulmonary diseases These effects could be associatedwith the presence of several antioxidant natural productssuch as iridoid glycosides (deacetylasperulosidic acid 20and asperulosidic acid 21) and flavonoids (quercetin-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside22 and kaempferol-3-O-120572-L-rhamnopyranosyl-(1rarr6)-120573-D-glucopyranoside 23) Additionally turmeric (Curcumalonga) and ginger (Zingiber officinale) displayed an importanteffect in inflammation including lung and pulmonary whichcould be due the presence of curcumin (24) [46 47]
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 Mediators of Inflammation
The presence of different polyphenol derivatives in greentea (Camellia sinensis leaves) such as catechin (epicate-chin 25 epigallocatechin 26 epicatechin gallate 27 andepigallocatechin gallate 28) is associated with the potentchemopreventive agent against lung cancer formation inanimal studies [48] The reported mechanisms for activity ofgreen tea against cancer are antioxidation induction of phaseII enzymes inhibition of TNF-120572 expression and releaseinhibition of cell proliferation and induction of apoptosis
Finally considering that antioxidant derivatives could beassociated with anti-inflammatory effects and consequentlywith the lung diseases treatment the red wine could beconsidered an important source of bioactive compounds dueto accumulation of stilbenes especially resveratrol (29) Asreported [49 50] treatment using resveratrol inhibits lungcancer cell growth via induction of premature senescencethrough ROS-mediated DNA damage
Many other natural compounds have been effective in thereduction of proinflammatory cytokines both in BALF in thelung tissue and in serum [51ndash53] Despite evidence showingthat many natural substances were effective in controllingthe alterations observed in models of in ALI there is noevidence at least in our knowledge related to the effectsof herbal medicine in ARDS in humans There is still needfor more studies to better understanding the mechanismsinvolved and to elucidate the efficacy and the safety ofnatural compounds to a subsequent clinical application inpatients
3 Evidence of Herbal-Derived NaturalProducts in Bronchial Asthma
Asthma is a heterogeneous and complex chronic respiratorydisease associated with several phenotypes Generally thesymptoms of asthma are recurrent episodes of wheezingbreathlessness chest tightness and coughing particularly atnight or early in the morning that are typically associatedwith variable airflow obstruction [1] Approximately 10of the world population is affected by the disease varyingfrom 1 to 18 Clinically the patients present symptoms suchas wheeze dyspnea chest tightness and cough that varyover time and in intensity which is associated with airflowlimitation [1]
Asthma depends on the interaction of genetic and envi-ronmental factors featured by the activation of theTh2 profilecells eosinophils mast cells and neutrophils [54] Severalmediatorsmodulators are involved in asthma pathogenesisand in hyperresponsiveness such as Th2 cytokines (IL-5 IL-4 and IL-13) IL-17 leukotrienes nitric oxide Rho kinasecholinergic system and others that were clearly evaluated inhumans and animal models [1 55ndash59]
The long-term goals for asthma treatment are to achievecontrol of symptoms with low side effects of the medicationsand reduce the risk of exacerbations and of fixed airflowobstruction frequently associated with the remodeling pro-cess Corticosteroids are considered the gold-standard treat-ment for asthma including during an acute asthma attackThe corticosteroids are responsible for inhibiting numerous
anti-inflammatory pathways Inhaled or oral corticosteroidsare widely used acting as a powerful anti-inflammatory drug
Some patients (10 to 25) remain symptomatic despiteoptimal glucocorticosteroid therapy and there is evidence ofpersistent airway and distal lung inflammation and sufferingfrom the unwanted effects of high-prolonged corticoid ther-apy such as osteoporosis cataracts and diabetes In additioncorticosteroids do not act directly on pulmonary structuralchanges better regulating the different processes involvedin the pathophysiology of asthma [1 60 61] However thediscovery of new drugs for the control of the disease isessential in patients with severe corticosteroid-insensitiveasthma and also for the decrease of the collateral systemiceffects of steroid use
Several studies demonstrated anti-inflammatory effectsof flavonoids of different plants in experimental asthma treat-ment Toledo et al [62] investigated the effects of sakuranetin(30) a flavonoid from Baccharis retusa in an asthma modeland found that this flavonoid induces a reduction of the Th2cytokines such as IL-5 RANTES and Eotaxin in sensitizedmice Sakuranetin also reduced the number of inflammatorycells in the lung particularly eosinophils and IgE title inthe animals sensitized with ovalbumin and treated with thisflavonoid The effects of sakuranetin seem to be related tothe inhibition of NF-120581B in lung Reinforcing the effects offlavonoids in asthma Jung et al [63] demonstrated thatkuwanon G (31) a flavonoid isolated from root bark ofMorus alba L decreases the levels of IgE in ovalbumin-induced allergic asthma in mice Further considering theinflammatory mediators involved in asthma kuwanon Gsignificantly decreased the levels of IL-4 IL-5 and IL-13in the sera and in bronchoalveolar lavage of asthma miceChung et al [64] demonstrated using flavonoids kaempferol-3-O-rhamnoside (32) and kaempferol (4) a reduction ininflammatory cell numbers in BALF and also an inhibitionin the increase in Th2 cytokines (IL-4 IL-5 and IL-13) andTNF-120572 protein levels
The effects of herbal-derived natural compounds oneosinophilic infiltration in differentmurinemodels of asthmahave been previously demonstrated Using amethanol extractfrom Boerhavia procumbens Bokhari and Khan [65] demon-strated a reduction in the infiltration of eosinophils andlymphocytes in lungs of toluene diisocyanate (33) exposurein rats Costa et al [66] found that Ocimum gratissimum aplant rich in rosmarinic acid (34) and commonly used in folkmedicine in Brazil attenuates the eosinophilic airway inflam-mation and reduced mucus production and IL-4 expressionin an experimental model of respiratory allergy to Blomiatropicalis The administration of flavonoid quercetin (3) inovalbumin immunized mice suggested a reduction in thenumber of eosinophil in the BALF neutrophil in peripheralblood and the levels of IL-5 in lung homogenate [67]
The administration of wogonin (35) a flavone derivedfrom a plant called Scutellariae radix reduced the total IgEand ovalbumin specific IgE levels compared with the oval-bumin challenged group [68] Astragalus membranaceus atraditional Chinese herb decreases airway allergic responsesincluding specific IgE eosinophilia lymphocyte infiltrationand airway inflammation modulatesTh12 immune balance
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 7
and activates PPAR in amurine asthmamodel [69]This plantis composed essentially by saponins (huangqiyiesaponin C36) and flavonoids (quercetin 3 and kaempferol 4) whichare known anti-inflammatory metabolites
Naringin (37) a component isolated from the driedunripe or ripe fruit peel of Citrus grandis ldquotomentosardquo(Exocarpium Citri Grandis) reduced enhanced cough andairway hyperresponsiveness and inhibited the increases inthe leukocytes IL-4 IL-5 and IL-13 in BALF in a model ofasthma using guinea pigs [70] Further using the same com-ponent Guihua et al [71] also demonstrated an inhibitionof ovalbumin-induced increased airway resistance (Raw) andeosinophil infiltration as well as IL-4 and INF-120575 levels afternaringin administrationThe apigen (38) a related flavonoidalso inhibited OVA-induced increases in Raw and eosinophilinfiltration in lung tissue associated with a reduction in IL-6TNF-120572 and IL-17A levels [72]
Curcumin (24) a natural product isolated from theplant Curcuma longa improved the airway inflammationand reversed the increased levels of Notch signaling pathway(Notch12) receptors and the transcription factor GATA3in ovalbumin-sensitized mice [73] Other studies withintranasal curcumin administration demonstrated a protec-tive effect on the recruitment of inflammatory cells to theairways and in the remodeling features such as peribronchialand airway smoothmuscle thickening andmucus secretion inovalbumin-induced chronic asthma in a murine model [74]
de Oliveira et al [75] demonstrated the anti-inflamma-tory effects of Punica granatum which inhibited leukocytesrecruitment in BALF especially eosinophils and decreasedcytokines (IL-1120573 and IL-5) release in the lungs of OVA-sensitized BALBc mice This effect could be associatedwith the presence of different metabolites such as alkaloidsterpenoids and flavonoids
The remodeling process in asthmatics induces significantstructural changes in proximal and distal airways as wellas in the distal lung This process is associated with airwaysmooth muscle hypertrophy and hyperplasia mucous glandhyperplasia and increased thickness of the airway wall [5476 77] It is well known that inflammatory mediators suchas IL-4 and IL-13 as well as the persistence of chronicinflammation in airways are involved in the remodelingprocess so natural compounds that inhibit the inflamma-tory process in asthma may also prevent the remodelingprocess
Extracts of Siegesbeckia glabrescens a traditional medici-nal plant in Korea reducedmucus overproduction in airwaysin a asthmamurine model decreased the expression of iNOSand COX-2 reducing the number of inflammatory cells inBALF and the cytokine release (IL-4 IL-5 and IL-13) [78]Using an inhalator approach the treatment with Lavenderessential oil (Lvn) in a murine model of bronchial asthmareduced the airway resistance (Raw) and the number ofeosinophils recovered in BALF and also in peribronchial andperivascular tissues Furthermore Lvn reduced mucous cellhyperplasia and the mRNA expression of Muc5b withoutsignificantly changing the mRNA expression of Muc5ac [79]Chemically this plant showed to be composed by quercetinflavonoid derivatives such as 341015840-O-dimethylquercetin (39)
37-O-dimethylquercetin (40) 3-O-methylquercetin (41)and 3741015840-O-trimethylquercetin (42) [80]
Wang et al [81] contribute to the mechanisms involvedin the anti-inflammatory effects of Yupingfeng Pulvis inan asthma model which is related to a reduction of theproportion ofTh17 cells whereas the population of Treg cellsin BALF was increased inhibiting the pulmonary proinflam-matory cytokines release in treated animals
Several studies have associated the diet with the develop-ment of allergic diseases In this context low consumptionof fruits and vegetables rich in antioxidant substances isassociated with high risk of asthma and atopic diseasesdevelopment However the diet rich in antioxidants andlipids particularly during pregnancy and childhood is relatedto reducing the allergic diseases prevalence [82] In apopulation-based study the asthma incidence was lower athigher quercetin (3) and naringin (37) flavonoids intake fromthe diet [83] However Smith et al [35] showed that theconsumption of soy isoflavone such as genistin (43) andgenistein (44) did not improves asthma control in adolescentsand adults patients with poorly controlled asthma
Studying asthmatic patients Watson et al [84] investi-gated the effects of the purple passion fruit peel (PFP) extractand observed that patients who received oral administrationof purple passion fruit peel showed a reduction of wheezeand cough as well as shortness of breath An herbal knownas Umckaloabo with contains root extract of Pelargoniumsidoides seems to be effective in the treatment of acute res-piratory infections [85 86] Additionally Tahan and Yaman[87] demonstrated that Umckaloabo reduced asthma attackduring upper respiratory tract viral infections in asthmaticchildren which demonstrated a minor cough frequency andnasal congestion Collectively these data suggest that highintake of fruit and vegetables had a negative association withrisk of asthma
4 Evidence of Herbal-Derived NaturalProducts in COPD
Chronic obstructive pulmonary disease (COPD) is the majorcause of chronic respiratory morbidity and mortality andthe fifth cause of death worldwide [91 92] and it is char-acterized by a persistent airflow limitation associated withan enhanced chronic inflammatory response to noxiousparticles or gases [92] This inflammatory response usuallypromotes parenchymal destruction (resulting in emphysema)and small airways fibrosis [92] The incidence and severity ofchronic obstructive pulmonary disease (COPD) are growingaffecting between 100 and 150 million people worldwide [92]
COPD is characterized by persistent airflow limitationthat is usually progressive and is associated with an enhancedchronic inflammatory response to noxious particles or gasesin the airways and the lung [92] The inhalation of cigarettesmoke and other environmental pollutants stimulates thealveolar macrophages in the lung epithelial cells to generatereactive oxygen species and reactive nitrogen species [93] inexcess causing an imbalance in the system
The proteaseantiprotease imbalance is still recognized asthe main mechanism enrolled in emphysema development
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Behavioural Neurology
EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 Mediators of Inflammation
[94ndash97] The majority of studies in animal models haveattested the importance ofMMPs in parenchymal destructionin emphysema [98ndash100] especially the MMP-12 other pro-teases such as neutrophil elastase from the serine proteasesfamily are described in humans emphysema [101]
These proteases are produced by neutrophils macropha-ges and bronchial epithelial cells [102ndash104] In emphysemathere is an increase in neutrophils in sputum and airwayswhile macrophages are predominate in parenchyma and inbronchoalveolar lavage suggesting an importance of thesecells in distal airways [105 106] In this context elastasesecreted by neutrophils andmacrophagesmay play an impor-tant role in lung tissue destruction [107 108]
The proteolytic attack of extracellular matrix componentsof lung parenchyma by proteases induces alveolar wallsdestruction associated with a dynamic tissue repair andremodeling process involving a reorganization of extracellu-lar matrix (ECM) components [109] However biochemicaland histological studies have demonstrated that the remodel-ing of col I and III elastin and fibrillin results in loss of lungelasticity [110ndash112]
The COPDmanagement is divided into some approachessuch as the reduction of risk factors and therapeutic man-agement of stable disease and of the exacerbations Howeverno currently available treatments reduce the progression oreven adequately suppress the inflammation in small airwaysand lung parenchyma [92] Therefore we have to considerthe importance of new approaches in emphysema studiesespecially in concern with the new targets to avoid theprogression of the alveolar walls destruction and remodeling
There are a large number of protein families that are ableto inhibit serine cysteine andmetalloproteases [113] and themechanisms of inhibition could be attributed to the catalyticmechanisms of proteases action or a mechanism-unrelatedblockage of the specific active sites [113]
Animal models of emphysema have been used as featuresto better clarify the pathogenesis of such disease and themost used are the elastases and cigarette-induced modelsHowever both of them showed advantages and disadvantagesthat have been considered for each experimental approachAlthough the CS-induced model is suggested as the bestto reproduce the pathogenesis of humans emphysema theparenchymal destruction is mild even after long time ofexposure whereas the elastase instillations produce severeemphysema depending on the dose in short times [114ndash116]but so far it is not a model that resembles the physiology ofthis disease as in humans
Several antioxidant agents such as thiol moleculespolyphenols derived from natural products and other sub-stances such as curcumin resveratrol andquercetin havebeen evaluated in models of emphysema Considering thatthe physiopathology of COPD involves oxidative stress andprotease-antiprotease unbalance substances that affect theseaspects should be considered to be beneficial in COPDThere are studies showing the effects of protease inhibitorsagainst the emphysema development and progression inexperimental models [94 117 118]
In a previous study Lourenco et al [119] demonstratedin elastase-induced model that a treatment with a serine
protease inhibitor from the cattle tick (rBmTI-A) atten-uated emphysema in treated mice before and after theelastase intranasal instillation The rBmTI-A treatment wasresponsible to reverse the loss of elastic recoil the alveolarenlargement and the total inflammatory cells amount inbronchoalveolar lavage Indeed it was sufficient to reducethe density of positive cells formetalloprotease-12 suggestingthat this MMP could be a therapeutic target [119]
Wright et al [120] showed in guinea pigs acutely orchronically exposed to cigarette smoke that the treatmentwith a serine elastase inhibitor (ZD0892) decreased theinflammatory activity mediated in part by neutrophils witha reduction in parenchymal destruction [120] Also Kurakiet al [121] performed a prior treatment with an oral inhibitorfor neutrophil elastase (ONO-6818) before the induction ofacute lung injury and emphysema in rats by intratrachealadministration of human neutrophil elastase They observedthat theONO-6818 treatment inhibited lung hemorrhage andthe neutrophils increase at the acute phase and that in longterm it prevented HNE-induced emphysema
Takayama et al [118] performed a posttreatment with aneutrophil elastase inhibitor (NEI ONO-5046) after intesti-nal ischemia-reperfusion in rats and observed a reductionin neutrophil activation in pulmonary vessels and neutrophilinfiltration in the lungs preventing the lung injury develop-ment
Considering the herbal medicine few studies have eval-uated the effects of these compounds in emphysema More-over it is difficult to isolate the effects of these compoundsin the inhibition of elastase activity or in the inflammatorymediators In this context Sartor et al [122] showed thatthe flavonoid epigallocatechin gallate (28) is an inhibitorof leukocyte elastase Lee et al [89] showed that an herbalformula PM014 reduced inflammatory cells in BALF and thelevels of TNF-120572 and IL-6 in a model of elastase+LPS-inducedemphysema
More recently Lee et al [90] evaluated the effects ofCallicarpa japonica a traditionally herbal used in orien-tal countries to treat inflammatory diseases The obtainedresults indicated that Callicarpa japonica extracts reducedneutrophil infiltration the production of cytokines IL-6 andTNF-120572 and the oxidative stress in amodel of cigarette smokeAdditionally the authors found a reduction in the productionof mucus in lung tissue of cigarette smoke animals Themechanisms involvedwere evaluated in vitro andwere relatedto a reduction in the phosphorylation of ERK
Other traditional Chinese medicines have been usedto treat chronic obstructive pulmonary disease (COPD) inpatients [123 124] In this context Li et al [123] demonstratedthat the Bu-Fei Jian-Pi granules Bu-Fei Yi-Shen granules andYi-Qi Zi-Shen granules three common Chinese medicineshave beneficial effects onmeasured outcomes in stable COPDpatients over the 6-month treatment Moreover Li et al [124]demonstrated the benefic effects of the three Tiao-Bu Fei-Shen (Bu-Fei Jian-Pi Bu-Fei Yi-Shen and Yi-Qi Zi-Shengranules) in the reduction in the levels of IL-1120573 TNF-120572 p-NF-120581B p-I120581B120572 TGF-1205731 and Smad2 in COPD rats
Song et al [125] studied the Picroside C (45) isolatedfrom Pseudolysimachion rotundum and found that this
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 9
Possible effects of herbal-derived natural products in pulmonary inflammatory responses
AllergenInfection
Cigarette smokeTrauma
Inflammatory responseMigration of macrophages to airway epithelial and lung tissue
Acute inflammationVascular changes
Neutrophils recruitmentOther cytokines release(IL-6 IL-8 and TNF-120572)
Cytokines release(TNF-120572 IL-1120573 and IL-8)
Allergic inflammationEosinophils recruitmentMast cells recruitment
Cytokines releaseTh2 immune response(IL-4 IL-5 and IL-13)
Mucus production
Chronic inflammationMononuclear infiltrationMacrophages recruitment
Remodeling tissueTissue damageAngiogenesis
Evolution of inflammationof action of naturalproducts to reducepulmonary inflammation
lowastlowastPossible mechanism
NF-120581B activationlowastlowast
Oxidative stresslowastlowast
MAPK pathwaylowastlowast
Proteases-antiprotease imbalance lowastlowast
Figure 2 Possible mechanism involved in the effects of herbal-derived natural products on pulmonary inflammation in respiratory diseasesIt is believed that the natural products derived from plants inhibit the pulmonary inflammation by the inhibition of the transcription ofNF-120581B to the nucleus thus preventing the development of all the inflammatory processes triggered by allergen cigarette smoke virus orbacteria Therefore these products can reduce the inflammatory cytokines release and oxidative stress These effects together culminate withthe improvement of lung function and with the reduction of pulmonary inflammation
compound protects the neutrophil influx the production ofreactive oxygen species and the classical cytokines IL-6 andTNF-120572 as well as the elastase activity The author suggestedthat the mechanism involved is the inhibition of the NF-120581Bpathway which counteracts the lung inflammation
Our group also evaluated the effects of sakuranetin inmodel of elastase-induced emphysema We found that saku-ranetin (30) isolated from Baccharis retusa prevented thealveolar destruction in a model of elastase-induced emphy-sema Moreover the authors showed that this compoundreduced lung remodeling and the levels of TNF-120572 IL-1120573 andM-CSF in the BALFThemechanisms involved are associatedwith the inhibition of NF-120581B and oxidative stress in lung[88]
At least in our knowledge only the group of Mukaidaet al [126] has evaluated the effects of a natural compoundin COPD patients The authors tested the effects of a mixof six herbal compounds and found that elderly COPDpatients have reduced the intensity of the cough howeverother parameters were not evaluatedThese findings reinforcethe importance of oxidative stress and proteaseantiproteaseimbalance in emphysema development and suggest oxidativestress MMP-12 and neutrophil elastase as a future targets foremphysema therapy
5 Conclusions
In conclusion herbal medicine-derived natural productscan be considered as an alternative therapeutic potentialfor respiratory diseases since several compounds showedanti-inflammatory effects inhibition different inflammatorymediators involved in respiratory diseases such as asthmaARDS and COPDThe possible mechanisms involved in theeffects of natural products in pulmonary inflammation andrespiratory diseases are summarized in the Figure 2 Most ofthe studies are pointing out the effects of natural productson the inhibition of NF-120581B andMAPK pathways besides theantioxidant effects associated with these products Howeverthe clinical trials using these compounds are scarce in theliterature and the safety and efficacy should be confirmed forfurther studies
Competing Interests
The authors declare that they have no competing interests
Acknowledgments
The authors would like to thank the CNPq (3005462012-2 3044652012-7 and 4768772012-1) as well as FAPESP
10 Mediators of Inflammation
(201014831-3 201115817-7 and 200855359-5) for providingfinancial support and fellowships
References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
10 Mediators of Inflammation
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References
[1] E D Bateman S S Hurd P J Barnes et al ldquoGlobal strategyfor asthma management and prevention GINA executive sum-maryrdquo European Respiratory Journal vol 31 no 1 pp 143ndash1782008
[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000
[3] P J Barnes ldquoChronic obstructive pulmonary diseaserdquoThe NewEngland Journal of Medicine vol 343 no 4 pp 269ndash280 2000
[4] D M Murphy and P M OrsquoByrne ldquoRecent advances in thepathophysiology of asthmardquo Chest vol 137 no 6 pp 1417ndash14262010
[5] H H Kariyawasam M Aizen J Barkans D S Robinsonand A B Kay ldquoRemodeling and airway hyperresponsivenessbut not cellular inflammation persist after allergen challengein asthmardquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 896ndash904 2007
[6] J Villar J Blanco J M Anon et al ldquoThe ALIEN study inci-dence and outcome of acute respiratory distress syndrome inthe era of lung protective ventilationrdquo Intensive Care Medicinevol 37 no 12 pp 1932ndash1941 2011
[7] B R Celli N E Thomas J A Anderson et al ldquoEffect ofpharmacotherapy on rate of decline of lung function in chronicobstructive pulmonary disease results from the TORCH studyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol178 no 4 pp 332ndash338 2008
[8] C A Slader H K Reddel C R Jenkins C L Armour and S ZBosnic-Anticevich ldquoComplementary and alternative medicineuse in asthma who is using whatrdquo Respirology vol 11 no 4 pp373ndash387 2006
[9] C Janson S Chinn D Jarvis and P Burney ldquoPhysician-diagnosed asthma and drug utilization in the European Com-munity Respiratory Health Surveyrdquo European Respiratory Jour-nal vol 10 no 8 pp 1795ndash1802 1997
[10] DM Eisenberg R C KesslerM I Van Rompay et al ldquoPercep-tions about complementary therapies relative to conventionaltherapies among adults who use both results from a nationalsurveyrdquo Annals of Internal Medicine vol 135 no 5 pp 344ndash3512001
[11] C R Bernard ldquoAcute respiratory distress syndrome a historicalperspectiverdquo American Journal of Respiratory and Critical CareMedicine vol 172 no 7 pp 798ndash806 2005
[12] G J Bellingan ldquoThe pulmonary physician in critical care 6 thepathogenesis of ALIARDSrdquoThorax vol 57 no 6 pp 540ndash5462002
[13] K P Steinberg L D Hudson R B Goodman et al ldquoEfficacyand safety of corticosteroids for persistent acute respiratorydistress syndromerdquo The New England Journal of Medicine vol354 no 16 pp 1671ndash1684 2006
[14] A M W Petersen and B K Pedersen ldquoThe anti-inflammatoryeffect of exerciserdquo Journal of Applied Physiology vol 98 no 4pp 1154ndash1162 2005
[15] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995
[16] A W Thille A Esteban P Fernandez-Segoviano et al ldquoCom-parison of the berlin definition for acute respiratory distresssyndrome with autopsyrdquo American Journal of Respiratory andCritical Care Medicine vol 187 no 7 pp 761ndash767 2013
[17] S Pan S Zhou S Gao et al ldquoNew perspectives on howto discover drugs from herbal medicines CAMrsquos outstandingcontribution to modern therapeuticsrdquo Evidence-Based Comple-mentary and Alternative Medicine vol 2013 Article ID 62737525 pages 2013
[18] R J Nijveldt E VanNood D E C VanHoorn P G Boelens KVan Norren and P A M Van Leeuwen ldquoFlavonoids a reviewof probable mechanisms of action and potential applicationsrdquoAmerican Journal of Clinical Nutrition vol 74 no 4 pp 418ndash425 2001
[19] J HG Lago A C Toledo-ArrudaMMernak et al ldquoStructure-activity association of flavonoids in lung diseasesrdquo Moleculesvol 19 no 3 pp 3570ndash3595 2014
[20] G-F Zhu H-J Guo Y Huang C-T Wu and X-F ZhangldquoEriodictyol a plant flavonoid attenuates LPS-induced acutelung injury through its antioxidative and anti-inflammatoryactivityrdquo Experimental and Therapeutic Medicine vol 10 no 6pp 2259ndash2266 2015
[21] M-Y Kuo M-F Liao F-L Chen et al ldquoLuteolin attenuatesthe pulmonary inflammatory response involves abilities ofantioxidation and inhibition of MAPK and NF120581B pathwaysin mice with endotoxin-induced acute lung injuryrdquo Food andChemical Toxicology vol 49 no 10 pp 2660ndash2666 2011
[22] K Takashima M Matsushima K Hashimoto et al ldquoPro-tective effects of intratracheally administered quercetin onlipopolysaccharide-induced acute lung injuryrdquo RespiratoryResearch vol 15 article 150 2014
[23] L Wang J Chen B Wang et al ldquoProtective effect of quercetinon lipopolysaccharide-induced acute lung injury in mice byinhibiting inflammatory cell influxrdquo Experimental Biology andMedicine vol 239 no 12 pp 1653ndash1662 2014
[24] X Chen X Yang T Liu et al ldquoKaempferol regulates MAPKsand NF-120581B signaling pathways to attenuate LPS-induced acutelung injury in micerdquo International Immunopharmacology vol14 no 2 pp 209ndash216 2012
[25] D-Y He and S-M Dai ldquoAnti-inflammatory and immunomod-ulatory effects of Paeonia lactiflora Pall a traditional Chineseherbal medicinerdquo Frontiers in Pharmacology vol 2 article 102011
[26] I D Kim and B J Ha ldquoPaeoniflorin protects RAW 2647macrophages from LPS-induced cytotoxicity and genotoxicityrdquoToxicology in Vitro vol 23 no 6 pp 1014ndash1019 2009
[27] W Cao W Zhang J Liu et al ldquoPaeoniflorin improves survivalin LPS-challenged mice through the suppression of TNF-120572 and IL-1120573 release and augmentation of IL-10 productionrdquoInternational Immunopharmacology vol 11 no 2 pp 172ndash1782011
[28] J L Aguilar P Rojas A Marcelo et al ldquoAnti-inflammatoryactivity of two different extracts of Uncaria tomentosa (Rubi-aceae)rdquo Journal of Ethnopharmacology vol 81 no 2 pp 271ndash276 2002
[29] R Rojas-Duran G Gonzalez-Aspajo C Ruiz-Martel et alldquoAnti-inflammatory activity of Mitraphylline isolated fromUncaria tomentosa barkrdquo Journal of Ethnopharmacology vol143 no 3 pp 801ndash804 2012
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 11
[30] S Montserrat-de la Paz A Fernandez-Arche R de la Puerta etal ldquoMitraphylline inhibits lipopolysaccharide-mediated activa-tion of primary human neutrophilsrdquo Phytomedicine vol 23 no2 pp 141ndash148 2016
[31] J Qiu G Chi Q Wu Y Ren C Chen and H Feng ldquoPretreat-ment with the compound asperuloside decreases acute lunginjury via inhibiting MAPK and NF-120581B signaling in a murinemodelrdquo International Immunopharmacology vol 31 pp 109ndash115 2016
[32] N An D Wang T Zhu et al ldquoEffects of scrocaffeside A fromPicrorhiza Scrophulariiflora on immunocyte function in vitrordquoImmunopharmacology and Immunotoxicology vol 31 no 3 pp451ndash458 2009
[33] H Azaizeh B Saad K Khalil and O Said ldquoThe state of the artof traditional Arab herbal medicine in the eastern region of theMediterranean a reviewrdquo Evidence-Based Complementary andAlternative Medicine vol 3 no 2 pp 229ndash235 2006
[34] L J He M Liang F F Hou Z J Guo D Xie and X ZhangldquoEthanol extraction of Picrorhiza scrophulariiflora preventsrenal injury in experimental diabetes via anti-inflammationactionrdquo Journal of Endocrinology vol 200 no 3 pp 347ndash3552009
[35] L J Smith R Kalhan R AWise et al ldquoEffect of a soy isoflavonesupplement on lung function and clinical outcomes in patientswith poorly controlled asthmardquo JAMA vol 313 no 20 pp2033ndash2043 2015
[36] S Noh K-S Ahn S-R Oh K H Kim and M Joo ldquoNeu-trophilic lung inflammation suppressed by picroside II is asso-ciated with TGF-120573 signalingrdquo Evidence-Based Complementaryand Alternative Medicine vol 2015 Article ID 897272 11 pages2015
[37] M drsquoAvila Farias P S Oliveira F S P Dutra et al ldquoEugenolderivatives as potential anti-oxidants is phenolic hydroxylnecessary to obtain an effectrdquo Journal of Pharmacy and Phar-macology vol 66 no 5 pp 733ndash746 2014
[38] N Okada K Satoh T Atsumi et al ldquoRadical modulatingactivity and cytotoxic activity of synthesized eugenol-relatedcompoundsrdquoAnticancer Research vol 20 no 5 pp 2955ndash29602000
[39] M E Hidalgo C De La Rosa H Carrasco W Cardona CGallardo and L Espinoza ldquoAntioxidant capacity of eugenolderivativesrdquo Quimica Nova vol 32 no 6 pp 1467ndash1470 2009
[40] A Khan A Ahmad F Akhtar et al ldquoInduction of oxidativestress as a possible mechanism of the antifungal action of threephenylpropanoidsrdquo FEMS Yeast Research vol 11 no 1 pp 114ndash122 2011
[41] K Kim Y Li G Jin et al ldquoEffect of valproic acid on acute lunginjury in a rodent model of intestinal ischemia reperfusionrdquoResuscitation vol 83 no 2 pp 243ndash248 2012
[42] Y Murakami M Shoji A Hirata S Tanaka I Yokoeand S Fujisawa ldquoDehydrodiisoeugenol an isoeugenol dimerinhibits lipopolysaccharide-stimulated nuclear factor kappa Bactivation and cyclooxygenase-2 expression in macrophagesrdquoArchives of Biochemistry and Biophysics vol 434 no 2 pp 326ndash332 2005
[43] XHuang Y Liu Y Lu andCMa ldquoAnti-inflammatory effects ofeugenol on lipopolysaccharide-induced inflammatory reactionin acute lung injury via regulating inflammation and redoxstatusrdquo International Immunopharmacology vol 26 no 1 pp265ndash271 2015
[44] H-L Huang C-T Liu M-C Chou C-H Ko and C-KWang ldquoNoni (Morinda citrifolia L) fruit extracts improve colon
microflora and exert anti-inflammatory activities in caco-2cellsrdquo Journal ofMedicinal Food vol 18 no 6 pp 663ndash676 2015
[45] K Murata Y Abe M Futamura-Masuda A Uwaya F Isamiand H Matsuda ldquoActivation of cell-mediated immunity byMorinda citrifolia fruit extract and its constituentsrdquo NaturalProduct Communications vol 9 no 4 pp 445ndash450 2014
[46] S Ghosh S Banerjee and P C Sil ldquoThe beneficial role ofcurcumin on inflammation diabetes and neurodegenerativedisease a recent updaterdquo Food and Chemical Toxicology vol 83pp 111ndash124 2015
[47] Y He Y Yue X Zheng K Zhang S Chen and Z DuldquoCurcumin inflammation and chronic diseases how are theylinkedrdquoMolecules vol 20 no 5 pp 9183ndash9213 2015
[48] M S Butt R S AhmadM T SultanMM N Qayyum andANaz ldquoGreen tea and anticancer perspectives updates from lastdecaderdquo Critical Reviews in Food Science and Nutrition vol 55no 6 pp 792ndash805 2015
[49] S C Gupta R Kannappan S Reuter J H Kim and BB Aggarwal ldquoChemosensitization of tumors by resveratrolrdquoAnnals of the New York Academy of Sciences vol 1215 no 1 pp150ndash160 2011
[50] E Conte E Fagone M Fruciano E Gili M Iemmolo andC Vancheri ldquoAnti-inflammatory and antifibrotic effects ofresveratrol in the lungrdquo Histology and Histopathology vol 30no 5 pp 523ndash529 2015
[51] C-Y Sun C-Q Pei B-X Zang LWang andM Jin ldquoThe abil-ity of hydroxysafflor yellow a to attenuate lipopolysaccharide-induced pulmonary inflammatory injury inmicerdquo PhytotherapyResearch vol 24 no 12 pp 1788ndash1795 2010
[52] X Chu X Ci M Wei et al ldquoLicochalcone A inhibitslipopolysaccharide-induced inflammatory response in vitroand in vivordquo Journal of Agricultural and Food Chemistry vol60 no 15 pp 3947ndash3954 2012
[53] J Peng D Wei Z Fu et al ldquoPunicalagin ameliorateslipopolysaccharide-induced acute respiratory distress syn-drome in micerdquo Inflammation vol 38 no 2 pp 493ndash499 2015
[54] S S Possa E A Leick C M Prado M A Martins and I FL C Tiberio ldquoEosinophilic inflammation in allergic asthmardquoFrontiers in Pharmacology vol 4 article 46 2013
[55] C M Prado E A Leick-Maldonado D I Kasahara V LCapelozziMAMartins and I F L C Tiberio ldquoEffects of acuteand chronic nitric oxide inhibition in an experimental modelof chronic pulmonary allergic inflammation in guinea pigsrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 289 no 4 pp L677ndashL683 2005
[56] C M Prado E A Leick-Maldonado L Yano et al ldquoEffects ofnitric oxide synthases in chronic allergic airway inflammationand remodelingrdquo American Journal of Respiratory Cell andMolecular Biology vol 35 no 4 pp 457ndash465 2006
[57] S S Possa H T Charafeddine R F Righetti et al ldquoRho-kinase inhibition attenuates airway responsiveness inflamma-tionmatrix remodeling and oxidative stress activation inducedby chronic inflammationrdquo American Journal of PhysiologymdashLung Cellular and Molecular Physiology vol 303 no 11 ppL939ndashL952 2012
[58] A-G Besnard D Togbe I Couillin et al ldquoInflammasome-IL-1-Th17 response in allergic lung inflammationrdquo Journal ofMolecular Cell Biology vol 4 no 1 pp 3ndash10 2012
[59] R F Righetti P A da Silva Pigati S S Possa et al ldquoEffectsof Rho-kinase inhibition in lung tissue with chronic inflamma-tionrdquo Respiratory Physiology amp Neurobiology vol 192 pp 134ndash146 2014
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
12 Mediators of Inflammation
[60] P A Pigati R F Righetti S S Possa et al ldquoY-27632 is associatedwith corticosteroid-potentiated control of pulmonary remod-eling and inflammation in guinea pigs with chronic allergicinflammationrdquo BMC Pulmonary Medicine vol 15 article 852015
[61] F C R Souza N B Gobbato R G Maciel et al ldquoEffectsof corticosteroid montelukast and iNOS inhibition on distallung with chronic inflammationrdquo Respiratory Physiology andNeurobiology vol 185 no 2 pp 435ndash445 2013
[62] A C Toledo C P P Sakoda A Perini et al ldquoFlavononetreatment reverses airway inflammation and remodelling in anasthma murine modelrdquo British Journal of Pharmacology vol168 no 7 pp 1736ndash1749 2013
[63] H W Jung S Y Kang J S Kang A R Kim E-R Woo andY-K Park ldquoEffect of kuwanon G isolated from the root bark ofMorus alba on ovalbumin-induced allergic response in amousemodel of asthmardquo Phytotherapy Research vol 28 no 11 pp1713ndash1719 2014
[64] M J Chung R P Pandey JW Choi J K Sohng D J Choi andY I Park ldquoInhibitory effects of kaempferol-3-O-rhamnosideon ovalbumin-induced lung inflammation in a mouse modelof allergic asthmardquo International Immunopharmacology vol 25no 2 pp 302ndash310 2015
[65] J Bokhari and M R Khan ldquoEvaluation of anti-asthmaticand antioxidant potential of Boerhavia procumbens in toluenediisocyanate (TDI) treated ratsrdquo Journal of Ethnopharmacologyvol 172 pp 377ndash385 2015
[66] R S Costa T C B Carneiro A T Cerqueira-Lima etal ldquoOcimum gratissimum Linn and rosmarinic acid atten-uate eosinophilic airway inflammation in an experimentalmodel of respiratory allergy to Blomia tropicalisrdquo InternationalImmunopharmacology vol 13 no 1 pp 126ndash134 2012
[67] A P Rogerio A Kanashiro C Fontanari et al ldquoAnti-inflammatory activity of quercetin and isoquercitrin in experi-mental murine allergic asthmardquo Inflammation Research vol 56no 10 pp 402ndash408 2007
[68] E K Ryu T-H Kim E J Jang et al ldquoWogonin a plant flavonefrom Scutellariae radix attenuated ovalbumin-induced airwayinflammation in mouse model of asthma via the suppressionof IL-4STAT6 signalingrdquo Journal of Clinical Biochemistry andNutrition vol 57 no 2 pp 105ndash112 2015
[69] S-M Chen Y-S Tsai S-W Lee et al ldquoAstragalus mem-branaceus modulates Th12 immune balance and activatesPPAR120574 in a murine asthma modelrdquo Biochemistry and CellBiology vol 92 no 5 pp 397ndash405 2014
[70] H-Y Jiao W-W Su P-B Li et al ldquoTherapeutic effects ofnaringin in a guinea pig model of ovalbumin-induced cough-variant asthmardquo Pulmonary Pharmacology and Therapeuticsvol 33 pp 59ndash65 2015
[71] X Guihua L Shuyin G Jinliang and S Wang ldquoNaringinprotects ovalbumin-induced airway inflammation in a mousemodel of asthmardquo Inflammation vol 39 no 2 pp 891ndash899 2016
[72] J Li and B Zhang ldquoApigenin protects ovalbumin-inducedasthma through the regulation of Th17 cellsrdquo Fitoterapia vol91 pp 298ndash304 2013
[73] L ChongW Zhang Y Nie et al ldquoProtective effect of curcuminon acute airway inflammation of allergic asthma in micethrough Notch1-GATA3 signaling pathwayrdquo Inflammation vol37 no 5 pp 1476ndash1485 2014
[74] P S Chauhan Subhashini D Dash and R Singh ldquoIntranasalcurcumin attenuates airway remodeling in murine model of
chronic asthmardquo International Immunopharmacology vol 21no 1 pp 63ndash75 2014
[75] J F F de Oliveira D V Garreto M C P Da Silva et al ldquoTher-apeutic potential of biodegradable microparticles containingPunica granatumL (pomegranate) inmurinemodel of asthmardquoInflammation Research vol 62 no 11 pp 971ndash980 2013
[76] D D Cataldo M M Gueders N Rocks et al ldquoPathogenicrole of matrix metalloproteases and their inhibitors in asthmaand chronic obstructive pulmonary disease and therapeuticrelevance of matrix metalloproteases inhibitorsrdquo Cellular andMolecular Biology vol 49 no 6 pp 875ndash884 2003
[77] R Halwani S Al-Muhsen and Q Hamid ldquoAirway remodelingin asthmardquo Current Opinion in Pharmacology vol 10 no 3 pp236ndash245 2010
[78] C-M Jeon I-S Shin N-R Shin et al ldquoSiegesbeckiaglabrescens attenuates allergic airway inflammation in LPS-stimulated RAW 2647 cells and OVA induced asthma murinemodelrdquo International Immunopharmacology vol 22 no 2 pp414ndash419 2014
[79] T Ueno-Iio M Shibakura K Yokota et al ldquoLavender essentialoil inhalation suppresses allergic airway inflammation andmucous cell hyperplasia in a murine model of asthmardquo LifeSciences vol 108 no 2 pp 109ndash115 2014
[80] J Y Kim H J Lim and J-H Ryu ldquoIn vitro anti-inflammatoryactivity of 3-O-methyl-flavones isolated from SiegesbeckiaglabrescensrdquoBioorganic andMedicinal Chemistry Letters vol 18no 4 pp 1511ndash1514 2008
[81] Z Wang X Cai Z Pang et al ldquoYupingfeng pulvis regulatesthe balance of T cell subsets in asthma micerdquo Evidence-BasedComplementary and Alternative Medicine vol 2016 Article ID6916353 7 pages 2016
[82] G Devereux and A Seaton ldquoDiet as a risk factor for atopy andasthmardquo Journal of Allergy andClinical Immunology vol 115 no6 pp 1109ndash1118 2005
[83] P Knekt J Kumpulainen R Jarvinen et al ldquoFlavonoid intakeand risk of chronic diseasesrdquo The American Journal of ClinicalNutrition vol 76 no 3 pp 560ndash568 2002
[84] R R Watson S Zibadi H Rafatpanah et al ldquoOral administra-tion of the purple passion fruit peel extract reduces wheeze andcough and improves shortness of breath in adults with asthmardquoNutrition Research vol 28 no 3 pp 166ndash171 2008
[85] A Timmer J Gunther E Motschall G Rucker G Antesand W V Kern ldquoPelargonium sidoides extract for treatingacute respiratory tract infectionsrdquo The Cochrane Database ofSystematic Reviews vol 10 Article ID CD006323 2013
[86] T B Agbabiaka R Guo and E Ernst ldquoPelargonium sidoidesfor acute bronchitis a systematic review and meta-analysisrdquoPhytomedicine vol 15 no 5 pp 378ndash385 2008
[87] F Tahan and M Yaman ldquoCan the Pelargonium sidoides rootextract EPs 7630 prevent asthma attacks during viral infectionsof the upper respiratory tract in childrenrdquo Phytomedicine vol20 no 2 pp 148ndash150 2013
[88] L Taguchi N M Pinheiro C R Olivo et al ldquoA flavanonefrom Baccharis retusa (Asteraceae) prevents elastase-inducedemphysema in mice by regulating NF-120581B oxidative stress andmetalloproteinasesrdquo Respiratory Research vol 16 article 792015
[89] H Lee Y Kim H J Kim et al ldquoHerbal formula PM014attenuates lung inflammation in a murine model of chronicobstructive pulmonary diseaserdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 769830 10pages 2012
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Mediators of Inflammation 13
[90] J-W Lee N-R Shin J-W Park et al ldquoCallicarpa japonicaThunb attenuates cigarette smoke-induced neutrophil inflam-mation and mucus secretionrdquo Journal of Ethnopharmacologyvol 175 pp 1ndash8 2015
[91] C R Simpson J Hippisley-Cox and A Sheikh ldquoTrends inthe epidemiology of chronic obstructive pulmonary disease inEngland a national study of 51 804 patientsrdquo British Journal ofGeneral Practice vol 60 no 576 pp e277ndashe284 2010
[92] GOLD Global Strategy for the Diagnosis Management andPrevention of COPD 2015
[93] P Ernst and S Suissa ldquoSystemic effects of inhaled corticos-teroidsrdquo Current Opinion in Pulmonary Medicine vol 18 no 1pp 85ndash89 2012
[94] R A Stockley ldquoProteases and antiproteasesrdquo Novartis Founda-tion Symposium vol 234 pp 189ndash204 2001
[95] Y Takubo A Guerassimov H Ghezzo et al ldquo1205721-Antitrypsindetermines the pattern of emphysema and function in tobaccosmoke-exposed mice parallels with human diseaserdquo AmericanJournal of Respiratory and Critical Care Medicine vol 166 no12 part 1 pp 1596ndash1603 2002
[96] P J Barnes S D Shapiro and R A Pauwels ldquoChronic obstruc-tive pulmonary disease molecular and cellular mechanismsrdquoEuropean Respiratory Journal vol 22 no 4 pp 672ndash688 2003
[97] S Ito E P Ingenito K K Brewer et al ldquoMechanics nonlin-earity and failure strength of lung tissue in a mouse model ofemphysema possible role of collagen remodelingrdquo Journal ofApplied Physiology vol 98 no 2 pp 503ndash511 2005
[98] R D Hautamaki D K Kobayashi R M Senior and S DShapiro ldquoRequirement for macrophage elastase for cigarettesmoke-induced emphysema inmicerdquo Science vol 277 no 5334pp 2002ndash2004 1997
[99] G A Finlay L ROrsquoDriscoll K J Russell et al ldquoMatrixmetallo-proteinase expression and production by alveolar macrophagesin emphysemardquo American Journal of Respiratory and CriticalCare Medicine vol 156 no 1 pp 240ndash247 1997
[100] A Churg R Wang X Wang P-O Onnervik K Thim and JL Wright ldquoEffect of an MMP-9MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigsrdquoThorax vol 62 no 8 pp 706ndash713 2007
[101] S D Shapiro ldquoProteinases in chronic obstructive pulmonarydiseaserdquo Biochemical Society Transactions vol 30 no 2 pp 98ndash102 2002
[102] S T Holgate P M Lackie D E Davies W R Roche andA F Walls ldquoThe bronchial epithelium as a key regulator ofairway inflammation and remodelling in asthmardquo Clinical andExperimental Allergy vol 29 supplement 2 pp 90ndash95 1999
[103] R M Senior N L Connolly J D Cury H G Welgusand E J Campbell ldquoElastin degradation by human alveolarmacrophages A prominent role of metalloproteinase activityrdquoAmerican Review of Respiratory Disease vol 139 no 5 pp 1251ndash1256 1989
[104] S D Shapiro E J Campbell H G Welgus and R M SeniorldquoElastin degradation bymononuclear phagocytesrdquoAnnals of theNew York Academy of Sciences vol 624 pp 69ndash80 1991
[105] V M Keatings D J Evans B J OrsquoConnor and P J BarnesldquoCellular profiles in asthmatic airways a comparison of inducedsputum bronchial washings and bronchoalveolar lavage fluidrdquoThorax vol 52 no 4 pp 372ndash374 1997
[106] T R Martin G Raghu R J Maunder and S C SpringmeyerldquoThe effects of chronic bronchitis and chronic air-flow obstruc-tion on lung cell populations recovered by bronchoalveolar
lavagerdquo American Review of Respiratory Disease vol 132 no 2pp 254ndash260 1985
[107] P J Barnes ldquoThe cytokine network in asthma and chronicobstructive pulmonary diseaserdquo The Journal of Clinical Inves-tigation vol 118 no 11 pp 3546ndash3556 2008
[108] A Churg and J LWright ldquoProteases and emphysemardquo CurrentOpinion in PulmonaryMedicine vol 11 no 2 pp 153ndash159 2005
[109] T Abraham and J Hogg ldquoExtracellular matrix remodelingof lung alveolar walls in three dimensional space identifiedusing second harmonic generation and multiphoton excitationfluorescencerdquo Journal of Structural Biology vol 171 no 2 pp189ndash196 2010
[110] S Kononov K Brewer H Sakai et al ldquoRoles of mechanicalforces and collagen failure in the development of elastase-induced emphysemardquo American Journal of Respiratory andCritical Care Medicine vol 164 no 10 part 1 pp 1920ndash19262001
[111] B Suki and J H T Bates ldquoExtracellular matrix mechanicsin lung parenchymal diseasesrdquo Respiratory Physiology andNeurobiology vol 163 no 1ndash3 pp 33ndash43 2008
[112] M M J F Koenders R G Wismans B Starcher B C JHamel R P N Dekhuijzen and TH VanKuppevelt ldquoFibrillin-1 staining anomalies are associated with increased stainingfor TGF-120573 and elastic fibre degradation new clues to thepathogenesis of emphysemardquoThe Journal of Pathology vol 218no 4 pp 446ndash457 2009
[113] J Otlewski F Jelen M Zakrzewska and A Oleksy ldquoThe manyfaces of protease-protein inhibitor interactionrdquo EMBO Journalvol 24 no 7 pp 1303ndash1310 2005
[114] J L Wright M Cosio and A Churg ldquoAnimal models ofchronic obstructive pulmonary diseaserdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 295no 1 pp L1ndashL15 2008
[115] J Lieberman ldquoElastase collagenase emphysema and alpha1antitrypsin deficiencyrdquo Chest vol 70 no 1 pp 62ndash67 1976
[116] M Lesser M L Padilla and C Cardozo ldquoInduction of emphy-sema in hamsters by intratracheal instillation of cathepsin BrdquoAmerican Review of Respiratory Disease vol 145 no 3 pp 661ndash668 1992
[117] R M Senior and N R Anthonisen ldquoChronic obstructivepulmonary disease (COPD)rdquo American Journal of Respiratoryand Critical Care Medicine vol 157 no 4 part 2 pp S139ndashS1471998
[118] M Takayama M Ishibashi H Ishii T Kuraki T Nishida andM Yoshida ldquoEffects of neutrophil elastase inhibitor (ONO-5046) on lung injury after intestinal ischemia-reperfusionrdquoJournal of Applied Physiology vol 91 no 4 pp 1800ndash1807 2001
[119] J D Lourenco L P Neves C R Olivo et al ldquoA treatmentwith a protease inhibitor recombinant from the cattle tick(Rhipicephalus Boophilus microplus) ameliorates emphysema inmicerdquo PLoS ONE vol 9 no 6 article e98216 2014
[120] J L Wright S G Farmer and A Churg ldquoSynthetic serineelastase inhibitor reduces cigarette smoke-induced emphysemain guinea pigsrdquo American Journal of Respiratory and CriticalCare Medicine vol 166 no 7 pp 954ndash960 2002
[121] T Kuraki M Ishibashi M Takayama M Shiraishi and MYoshida ldquoA novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysemain ratsrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 4 pp 496ndash500 2002
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
14 Mediators of Inflammation
[122] L Sartor E Pezzato and S Garbisa ldquo(-)Epigallocatechin-3-gallate inhibits leukocyte elastase potential of the phyto-factorin hindering inflammation emphysema and invasionrdquo Journalof Leukocyte Biology vol 71 no 1 pp 73ndash79 2002
[123] S-Y Li J-S Li M-H Wang et al ldquoEffects of comprehensivetherapy based on traditional Chinese medicine patterns in sta-ble chronic obstructive pulmonary disease a four-center open-label randomized controlled studyrdquo BMC Complementary andAlternative Medicine vol 12 article 197 2012
[124] Y Li J-S Li W-W Li et al ldquoLong-term effects of threeTiao-Bu Fei-Shen therapies onNF-120581BTGF-1205731smad2 signalingin rats with chronic obstructive pulmonary diseaserdquo BMCComplementary and Alternative Medicine vol 14 article 1402014
[125] H-H Song I-S Shin S Y Woo et al ldquoPiscroside C a noveliridoid glycoside isolated from Pseudolysimachion rotundumvar subinegrum suppresses airway inflammation induced bycigarette smokerdquo Journal of Ethnopharmacology vol 170 pp20ndash27 2015
[126] K Mukaida N Hattori K Kondo et al ldquoA pilot study of themultiherbKampomedicine bakumondoto for cough in patientswith chronic obstructive pulmonary diseaserdquo Phytomedicinevol 18 no 8-9 pp 625ndash629 2011
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
