10. Bakan ND, Ozkan G, Camsari G, Gur A, Bayram M, Acikmese B,

Cetinkaya E. Silicosis in denim sandblasters. Chest (In press)

11. Centers for Disease Control and Prevention. Silicosis mortality, pre-

vention, and control-United States, 1968–2002. MMWR Morb Mortal

Wkly Rep 2005;54:401–405.

12. Maxfield R, Alo C, Reilly MJ, Rosenman K, Kalinowski D, Stanbury

M, Valiante DJ, Jones B, Randolph S, Socie E, et al. Surveillance

for silicosis, 1993–Illinois, Michigan, New Jersey, North Carolina,

Ohio, Texas, and Wisconsin. MMWR CDC Surveill Summ 1997;46:

13–28.

Copyrightª 2011 by the American Thoracic Society

DOI: 10.1164/rccm.201108-1440ED

Vitamin D and Asthma: Another Dimension

In this issue of the Journal, Gupta and colleagues (pp. 1342–1349)add to the ever-enlarging body of literature reporting associa-tions between vitamin D status (as reflected by serum 25(OH)Dconcentrations) and measures of asthma severity and control(1). In a well-characterized clinical cohort of children with ei-ther moderate or severe (treatment-resistant) asthma, they in-vestigated associations between serum 25(OH)D and lungfunction, asthma control, exacerbations, and medication history.As might be expected in light of prior reports, the investigatorsfound an inverse relationship between 25(OH)D and asthmaseverity, exacerbations, and inhaled glucocorticoid requirement,and a positive relationship between 25(OH)D and both lungfunction and asthma control. These findings validate, using dataobtained directly from patients with severe asthma, otherreports in which vitamin D status is associated with asthmaseverity in children (2–4). The authors take their findings a stepfurther, however, by also providing us with data regarding vita-min D and aspects of airway pathology.

Per established protocol, fiberoptic bronchoscopy was per-formed during the clinical evaluation of a subset of the childrenwith severe asthma. Using endobronchial biopsy specimens fromthese patients, the investigators were able to quantify measuresof tissue inflammation and airway remodeling in the context ofvitamin D status. While there was not a relationship between 25(OH)D and tissue eosinophils, neutrophils, or mast cells, therewas a significant and inverse correlation between 25(OH)D andthe volume fraction of airway smooth muscle (ASM), indepen-dent of differences in myocyte proliferation. This increase inASM volume associated with lower vitamin D levels was ob-served independent of other pathological findings of airwayremodeling. While the authors point out the limitations of theirdataset, and while there are challenges inherent in disentanglingthe confounding roles of variables such as environment, race/ethnicity, atopy, and concurrent treatment in a study of this sizeand design, these observations open another dimension in clin-ical investigation of the vitamin D–asthma association.

Much of the existing literature in pediatric asthma has focusedon vitamin D either as a potential modulator of immune func-tion, for example by reducing exacerbation risk (5), or as a mod-ifier of sensitivity to glucocorticoids (4). But there have alsobeen reports that reduced serum 25(OH)D is unfavorably asso-ciated with measures of airflow, bronchodilator responsiveness,and airway hyperresponsiveness, and the findings in this manu-script suggest that these observations are mediated in part bychanges in ASM structure and/or function. In some of thereported clinical studies, vitamin D–associated alterations inlung function occur in the absence of concurrent increases inmarkers of atopy or airway inflammation, for example, totalIgE, skin prick test reactivity, or circulating eosinophils (3).Thus, although current concepts regarding airway remodelingwould suggest that increases in ASM cell growth, proliferation,or migration occur in the setting of ongoing tissue inflammationand in step with other changes such as subepithelial fibrosis,basement membrane thickening, and angiogenesis (6), the

clinical literature in this area would suggest that the decouplingof ASM volume from inflammation reported herein may not beentirely unexpected. Indeed, the authors speculate that their dataprovide in vivo validation of in vitro experiments indicating thatvitamin D has direct inhibitory effects on airway smooth muscleproliferation, independent of any effects on airway inflammation(7, 8). Although much remains to be clarified regarding themechanisms by which vitamin D alters ASM in vivo, given thatthis work was conducted in a pediatric population, it is interestingto view these data in light of the recent report of Zosky andcolleagues, in which physiologic and histologic assessments inmice demonstrated a link between vitamin D deficiency and de-velopmental alterations in lung structure and function (9).

A number of mechanisms could underpin the inverse rela-tionship between vitamin D levels and ASM hypertrophy de-scribed in this study at the molecular level. The vitamin Dreceptor (VDR), a nuclear receptor whose cognate ligand is vi-tamin D, may repress the activity of prohypertrophic signalingpathways that are active in the asthmatic airway. Supporting thisnotion, vitamin D prevents the induction of a–smooth muscleactin expression in renal myofibroblasts by TGF (10), which hasbeen implicated in promoting both ASM hypertrophy and myo-fibroblast activation in asthma. Vitamin D also plays a criticalrole in calcium homeostasis and signaling in many tissues, rais-ing the possibility that vitamin D may limit prohypertrophicsignaling associated with excessive airway hyperresponsiveness.Intriguingly, in cultured ASM, VDR represses RCAN1 expres-sion, a calcineurin inhibitor that regulates cardiac hypertrophy(11, 12), and additional studies are needed to determinewhether the effects of vitamin D in other contractile cell typesare applicable to ASM biology in asthma.

This study also raises the possibility that the VDR engages inmolecular crosstalk with glucocorticoid signaling in ASM. Al-though a causal effect of vitamin D deficiency in promotingASM hypertrophy could lead to a secondary steroid-resistantphenotype, it is also possible that vitamin D signaling modu-lates the activity of the glucocorticoid receptor in airwaysmooth muscle at the molecular level. Indeed, in peripheralblood mononuclear cells, the activation of MKP-1 by glucocor-ticoids is enhanced by vitamin D (13). In converse, the gluco-corticoid receptor is known to cooperatively induce targets ofvitamin D signaling in bone and kidney cells, and also inducesthe expression of the VDR itself (14). Moreover, VDR and theglucocorticoid receptor utilize overlapping transcriptionalco-regulators such as GRIP1 and steroid-activating factor 1,providing another mechanism for combinatorial crosstalk.The molecular intersection of VDR and glucocorticoid recep-tor signaling in ASM remains to be fully determined. It will beof particular interest to determine whether these signalingpathways converge to repress ASM hypertrophy indepen-dently from antiinflammatory effects, as is suggested by thefindings in this study.

Together, these data suggest that the effects of reduced vita-minD onASMmay occur independently of airway inflammation

1324 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011

and may provide a explanation for the reductions in lung func-tion observed with reduced serum 25(OH)D, both in asthma andin populations without asthma (15). Until the various hypothe-ses raised by this work are refined and tested further, we are leftconcluding that vitamin D status is an easily measurable andcorrectable clinical state that might have direct bearing on im-portant clinical parameters such as lung function, bronchodila-tor responsiveness, and airway hyperresponsiveness, in part viaeffects on ASM. The inclusion of appropriate surrogate clinicaloutcomes and translational mechanistic aims into ongoing andfuture clinical vitamin D supplementation trials in asthma is anopportunity to determine if this is the case.

Author Disclosures are available with the text of this article at www.atsjournals.org.

Anthony N. Gerber M.D., Ph.D.E. Rand Sutherland M.D., M.P.H.Department of MedicineNational Jewish HealthDenver, ColoradoandDepartment of MedicineUniversity of Colorado School of MedicineDenver, Colorado

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Copyrightª 2011 by the American Thoracic Society

DOI: 10.1164/rccm.201109-1737ED

Ambient Particulate Air Pollution, EnvironmentalTobacco Smoking, and Childhood Asthma: Interactionsand Biological Mechanisms

The World Health Organization (WHO) estimates that 24% ofthe global burden of disease is caused by environmental factorsthat can be averted (1). Understanding the role of the environ-ment in asthma is a natural ambition in the overall search tounderstand environmental burdens: In an individual expressingthe asthmatic phenotype, worsening of asthma control is logi-cally related to environmental agents, and the airways are di-rectly exposed to environmental challenges. As much as 44% ofthe asthma disease burden has been attributed to mitigableenvironmental risk factors, as opposed to genetic/familial fac-tors or risk factors such as outdoor exposure to pollens (deemednot modifiable) (1).

Childhood asthma is exacerbated by environmental agents,many of which are modifiable, including allergens from dustmites, cockroaches, and other animal and fungal sources; indoorexposure to dampness; indoor smoke from solid fuels; second-hand smoke (SHS); and ambient air pollution (1–4). On a typical

day children may be exposed to a number of different environ-mental agents at home, in daycare centers and schools, andoutdoors. Most research conducted thus far has focused onthe investigation of isolated risk factors. Little is known aboutthe effects on children of concurrent exposures to multiple riskfactors, and whether they interact with each other to potentiateadverse effects on asthma or whether one factor might producean effect that reduces the effect of another.

In this issue of the Journal, Rabinovitch and colleagues(pp. 1350–1357) report novel results from a repeated-measuresstudy of children aged 6 to 15 years that begins to address thisgap (5). Rather than focusing on individual asthma triggers inisolation, these investigators used an in-depth panel study ofa relatively small group of children with asthma to evaluatethe interactive effects of SHS and particulate matter air pol-lution, two common established environmental risk factors,on disease severity. In particular, they focused on how SHS

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