REVIEW ARTICLE

P

athology and Pathophysiology of Chronic ObstructivePulmonary Disease

Atsushi Nagai

Abstract

A variety of pathological changes have been observed inthe central airways, peripheral airways and lung paren-chyma of patients with chronic obstructive pulmonary dis-ease (COPD). The characteristic changes in the central air-ways include inflammatory cellular infiltration into the air-way wall and mucous gland enlargement. In the periph-eral airways, various morphological changes are observed,including mucous plugging, epithelial abnormalities, in-flammatory cellular infiltrates, fibrosis and distortion ; thesechanges lead to airway narrowing. In the lung parenchyma,emphysema defined as alveolar destruction and airspaceenlargement is present. Although the major sites of airflowlimitation in patients with COPD are most likely the pe-ripheral airways, lesions in both the peripheral airways andthe lung parenchyma contribute to chronic air flow limita-tions.(Internal Medicine 41: 265-269, 2002)

Key words: chronic bronchitis, emphysema, bronchial asthma,

airflow limitation, bronchiolitis, inflammation

Introduction

Chronic obstructive pulmonary disease (COPD) is a lead-ing cause of morbidity and mortality throughout the world ( 1 ).Although the precise prevalence of COPD is unknown, thenumber of patients suffering from this disease is increasing. Inaddition, the development of COPD is related to a past historyof cigarette smoking (2-6). The definition of COPD is basedon functional abnormalities. Most previous definitions havecharacterized the disease as a respiratory condition in whichthe patient's airflow is limited as a result of chronic bronchitisand/or emphysema (7, 8). However, the Global Initiative forChronic Obstructive Lung Disease (GOLD) very recently pub-lished a NHLBI/WHO workshop report in which COPD wasdefined as a disease state that is characterized by a limited air-flow and that is not fully reversible (1). Airflow limitations are

usually both progressive and associated with an abnormal in-flammatory response of the lungs to noxious particles or gases.This workshop report states that chronic bronchitis and em-physema are no longer included in the definition of COPD be-cause the former disease is of minor importance in calculatingthe impact of airflow limitations on the morbidity and mortal-ity rates for COPD and the latter disease is a pathological term.This definition reflects the current knowledge of the pathologyand pathophysiology of COPD.

Pathology

C

entral airways

Patients with COPD exhibit enlarged bronchial mucousglands and an increased number of goblet cells (9-1 1) (Figs. 1,2). These morphological changes may lead to mucus hyperse-cretion, although an increase in the number of goblet cells hasnot been consistently observed (12-14). The accepted defini-tion of chronic bronchitis is chronic or recurrent excess secre-tion of mucous into the bronchial tree. Since the main sourceof bronchial mucous was thought to be the submucosal glands,the enlargement of these glands was considered to be a histo-logical hallmark of chronic bronchitis. The degree of mucousgland enlargement is measured as the ratio of the thickness ofthe bronchial mucous glands to the thickness of the bronchialwall; this ratio is referred to as the Reid index (13). An earlierstudy reported a significant difference in the Reid index valuefor patients with chronic bronchitis (0.41-0.79) and nonbron-chitic patients (0.14-0.36). The index was thus thought to bea useful diagnostic tool. However, subsequent works haveshown considerable overlap between the Reid index frequency

distributions for patients with chronic bronchitis and

n

onbronchitic patients ( 15).

Recent developments in bronchoscopy have enabled in-flamed central airways to be more closely observed. Conse-quently, predominant inflammatory cellular infiltrations in thesubepithelial region of the bronchial wall have been identifiedas activated CD8+ T-lymphocytes and macrophages (16). Anumber of neutrophils have been found in the bronchial lu-men, and some neutrophil infiltrates have been identified nearbronchial epithelium and submucosal glands (17). When exac-

From the First Department of Medicine, Tokyo Women's Medical University, TokyoReprint requests should be addressed to Dr. Atsushi Nagai, the First Department of Medicine, Tokyo Women's Medical University, 8- 1 Kawadacho, Shinju-ku,

Tokyo 162-8666

Internal Medicine Vol. 41, No. 4 (April 2002) 265

Nagai

Figure 1. The mucous glands of a patient with COPD form amuch higher proportion of the bronchial wall (HE stain, xl50).

erbated, the number of eosinophils infiltrating the subepithe-lial region increases (1 8).

P

eripheral airways

The peripheral airways are considered to be the major sitesof increased airway resistance in patients with COPD (19).Various structural changes can be observed in these regions,including goblet cell metaplasia, squamous metaplasia, inflam-matory cellular infiltrations, an increased amount of smoothmuscle, fibrosis and pigmentation (19-24). Mucous pluggingis also frequently observed in the airway lumen. These patho-logical changes may lead to an increase in airway wall thick-ness and the subsequent narrowing of the airway lumen (Fig.

3)(25).

Knowledge of how inflammation leads to structural changesis important for an understanding of the relationship betweenpathological changes and the severity of air flow limitation.Inflammation appears to be the earliest stage of lesion forma-tionand, by itself, can cause mild chronic airflow limitations(26). Fibrosis and goblet cell metaplasia are thought to follow

i

nflammation (27) and cause irreversible airflow limitations.

Recent studies focusing on the nature of the inflammatory

Figure 2. Scanning electron micrograph showing secretion ofmucous (arrow) from increased goblet cells (x6,000).

Figure 3. Light micrograph of lung parenchyma region in a pa-tient with severe COPD. The narrowed lumens in the airwaysand vessels are observed in the emphysematous lesions (HE stain,

x8).

cells have identified the infiltration of CD8+ T-lymphocytesinto the walls of the peripheral and central airways (16, 28).These findings suggest that a similar inflammatory processoccurs in both types of airways in COPD patients. The periph-eral airways are infiltrated by a number of macrophages that

a

re recruited via transforming growth factor-p l (29).On the basis of morphologic studies, the loss of alveolar

attachments (radial traction) around bronchioles has been pro-posed as the mechanism responsible for chronic airflow ob-struction (30, 3 1). Airway narrowing and bronchiolar deformi-ties have been associated with a loss of alveolar attachment(3 1-33), and a significant relationship between the loss of nor-mal attachments and the severity of emphysema has been iden-

266 Internal Medicine Vol. 41, No. 4 (April 2002)

Pathology and Pathophysiology of COPD

tified (33).

L ung parenchyma

In patients with emphysema, the lung parenchyma is char-acterized by an enlargement of the air spaces accompanied byalveolar destruction. Conventionally, three types of emphysemahave been described: centriacinar emphysema, panacinar em-physema and distal acinar emphysema. As distal acinar em-physema is not associated with air flow limitations, onlycentriacinar and panacinar emphysema will be described here.Centriacinar emphysema is characterized by alveolar destruc-tion in the respiratory bronchioles in the central area of theacinus. These lesions are predominantly found in the upperlobes of smokers. Panacinar emphysema involves the dilata-tion of the entire acinus, with the lower lobe dilated to a largerdegree than the upper lobe, deficiency of al -antitrypsin andan early onset are associated with panacinar emphysema. Bothtypes of emphysema are characterized by alveolar destructionwith loss of the capillary bed. The mechanism responsible for the development of emphy-sematous lesions is thought to be an imbalance in protease andantiprotease enzymes in the lung. Oxidative stress has also beenproposed as a potential mechanism (34), although this hypoth-esis has yet to be proven. Inflammation is assumed to causethe characteristic alveolar destruction seen in emphysematouslesions. Both neutrophils and macrophages play an importantrole in increasing protease activity in the lung. However, therewas no difference between the upper and lower lobes in thenumbers and types of inflammatory cells, whereas the severityof the emphysematous lesions is more extreme in the upperlobe (35, 36). Recently, the predominance of T-lymphocytes inemphysematous lungs has been reported. One study describeda significant association between alveolar wall destruction andthe number of CD8+ T-lymphocytes (37). However, our data

using specimens obtained from lung volume reduction surgeryhave shown a relationship between the number of CD4+ T-lymphocytes and alveolar wall destruction (unpublished ob-servation) (Fig. 4). Further study is necessary to determine the

p

recise role of T-lymphocytes in alveolar destruction.In summary, lesions develop when central airways are irri-

tated and respond with mucus hypersecretion and mucous glandenlargement. The peripheral airways respond by becoming in-flamed, leading to fibrosis and airway narrowing. In the paren-chyma, the inflammation results in alveolar wall destructionand emphysema.

Pathophysiology

Most patients with chronic airflow limitations have centralairway lesions, peripheral airway lesions, and emphysema invarying combinations of severity. Many reports have describedthe presence of peripheral airway lesions in patients with se-verechronicairflow limitations. However, the great majority

of these reports describe the patients as having either emphy-sema or chronic bronchitis; assessing the functional signifi-cance of individual morphological abnormalities is thus diffi-cult. To clarify the relative importance of central airway le-sions, peripheral airway lesions, and emphysema in expiratoryairflowabnormalities, quantitative functional-structural correla-

t

ive studies have been performed.

The clinico-pathological correlative studies showed thatperipheral airway lesions resulting in airway narrowing play asignificant role in causing airflow limitation. Emphysematouslesions were also found to limit expiratory airflow. The largeststudy, involving a wide range of airflow limitations, indicatedthat in patients with moderate to severe emphysema, the lossof elastic recoil induced by the emphysematous lungs has astronger effect on airflow limitation than that of the peripheral

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Internal Medicine Vol. 41, No. 4 (April 2002) 267

Nagai

Figure 5. Scanning electron micrograph shows that the loss ofalveolar attachments around peripheral airways contributes tothe narrowing of the lumen in the peripheral airways (x38).

lesions (24). When the emphysema is mild, however, the pe-ripheral lesions are most likely the primary cause of the air-

f

low limitation.

The loss of alveolar attachments around peripheral airwayscan contribute to the narrowing of the lumen in the peripheralairways, leading to airflow limitation (Fig. 5) (38). This effectmay occur as a result of emphysema, since the loss of alveolarattachments reflects the severity of emphysema which in turnis related to airflow limitation. A recent study using computedtomography of the chest to assess emphysema clearly showedthat the prevalence of grossly visible emphysema increases asFEV1 declines (Fig. 6), although the authors concluded that

a

irflow limitations and emphysema were not related (39).In summary, functional-morphologic correlative studies in-

volving quantitative assessments of the airways and lung pa-renchyma have indicated that emphysema may be the most sig-nificant factor in cases of moderate and severe chronic airflowlimitation; peripheral airway lesions also cause airflow limita-tion, but these lesions are likely to play a secondary role in thecase of serious COPD. In addition, central airway lesions areprobably not very important in airflow limitation. Concomi-tant lesions in the peripheral airways and lung parenchyma arethus responsible for chronic airflow limitations in the periph-eral airway regions.

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50^ 40CJc<D 30ua 20<Dw>ｻJl 10tf 0n

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