TABLE L-Comparison of mucus gland size in smokers and nonsmokers Findings in smoking category Assessment of mucus gland enlargement Author Light and NOW moderate Heavy smokers Smokers smokers smokers Reid index Reid (1960) 0.46 0.43 Thurlbeck et al. (19631 0.43 0.50 0.45 0.53 Thurlbeck and Angus 11964) 0.44 0.49 Bath and Yates 119681 0.45 0.49 Hayes (19691 0.32 0.33 Scott (1973) 0.41 0.46 Mucus gland proportion Ryder et al. (1971) (men) 14.5% 17.8% Ryder et al. (1971) women) 14.5% 17.1% Sobonya and Kleinerman (1972) 11.2% 10.7% Scott 119731 14.1% 14.4% C&o et al. (1980) Increased Pratt et al. 11980~ 9.3% 12.6% Frequency of cases Field et al. 119661 (men) with MGH ' expressedField et al. (1966) lwomenl as a percentage of Megahed et al. (1967) cases m the group Petty et al. (19671 Vargha 11969) 12% 37% 18% 26% 14% 61% 8.8% 37% 18% 44% 1 MGH = Mucus gland hypertrophy inflammation and edema of the wall (Reid 1954), increase in bronchial smooth muscle (Hossain and Heard 1970; Takizawa and Thurlbeck 19711, and diminished cartilage, which is related more to emphysema than to chronic bronchitis (Thurlbeck et al. 1974a). Peripheral (Small) Airways General Review As indicated, it was as recent as 1968 that the obstruction in patients with chronic airflow obstruction was conclusively shown to be due mainly to lesions in airways less than 2 or 3 mm in diameter. However, abnormalities in these airways had long been recognized. Indeed, Laennec (1962) pointed out in 1826 that air remained trapped in emphysematous lungs even when the major bronchi had been opened, and he reasoned that the source of the air-trapping was obstruction in the airways peripheral to the opened ones Since then, numerous descriptions have been made of the peripheral airways in severe chronic airflow obstruction (see Table 2). Smokers were not compared with nonsmokers in any of these series. The probable reason is that for a long time it was thought that bronchiolitis was an infective complication of chronic bronchitis. Only very recently, and from studies in patients with mild chronic airflow obstruction, 226 has the link between smoking and peripheral airway lesions become established. Hogg et al. (1968) not only found that the peripheral airways were the site of airflow obstruction in patients with severe disease, but also observed that peripheral airways contributed only about 15 percent of resistance to flow in normal lungs. It followed that considerable disease could be present in these peripheral airways without airway resistance being measurably increased. It was reasoned also that standard tests of expiratory function, such as the FEVl and the FEFww, might not be abnormal in the presence of significant disease. Thus a variety of "tests of small airway function" were devised; these evolved to the single breath nitrogen washout test and to flow volume studies, in some instances comparing the effect of breathing helium mixtures with the effect of breathing room air. It soon became apparent that these tests could be abnormal when the FEVl was greater than the 80 percent predicted and that tests of small airway function could return to normal after cessation of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al. 1981). The term "small airways disease" was and is often applied to these abnormalities. It then became of interest to determine what the lesions in the airways were. Long before this, Reid (1955) had studied nine lungs resected from patients with chronic bronchitis and two lungs from chronic bronchitics obtained at autopsy. She found excess intraluminal mucus and narrowing and obliteration of airways, as assessed subjectively. Because the surgical patients also had lung cancer, most likely they were chronic smokers. Matsuba and Thurlbeck (1973) compared the airways of chronic bronchitics to those of nonbronchitics in nonemphysematous lungs. All the bron- chitics were smokers and two nonbronchitics were smokers. Morpho- metrically, they found obvious narrowing of airways less than 2 mm in diameter, which also contained excess mucus. The important study by Cosio et al. (19781, using surgically resected lungs, showed for the first time that abnormal tests of small airway function were related to abnormal morphology. There were 34 smokers and 2 nonsmokers in their group. A variety of abnormali- ties were observed, including inflammation, squamous cell metapla- sia, ulceration, fibrosis, pigmentation, and increased muscle. They developed a score that summed the observed lesions (the total pathology score), and divided their patients into four groups on the basis of this score. They showed that as the total pathology score increased, tests of small airway function (single breath nitrogen test and flows on air and helium mixtures) deteriorated, as did standard tests of pulmonary function such as the FEVl and FEFzsx. The data concerning smoking are hard to interpret, but the smoking index (number of cigarettes smoked per day times number of years smoked) increased from groups I to III and was similar in groups III 227 TABLE 2.-Occurrence of lesions of peripheral airways in patients with severe chronic airflow obstruction Authors Disease invest:gated Abnormalities found Laennec (1962) Spain and Kaufman ( 1953) Reid (1954) Emphysema Chronic bronchitis Leopold and Gough (1957) Centrilobular emphysema McLean (1958) Emphysema Anderson and Foraker (1962) Pratt et al. (1965) Anderson and Foraker (1967) Hogg et al. (1968) Mitchell et al. (1968) Bqnon et al (1969. 1970) Karpick et al. 119701 Linhartova et al. (19711 Matauba and Thurlbeck (1972) Linhartova et al. 11973, 1974, 19771 Scott and Steiner (1975) Scott c 19761 Mitchell et al. (1976) Emphysema Emphysema Centrilobular emphysema Emphysema Emphysema with severe chronic airflow obstruction Chronic airflow obstruction and severe emphysema Cm pulmonale and centrilobular emphysema Respiratory failure Emphysema Severe emphysema and chronic airflow limitation Emphysema Car pulmonale Chronic airflow obstruction Chronic airflow obstruction obstruction Obstruction to flow in peripheral airways Mural inflammation and fibrosis of bronchioles Bronchiolitia, broncbiolar oblit- eration, and mxus plugging Inflammation, fibrosis with narrowing of 60% of bronchioles supplying centrilobular space Inflammation of proximal rea- piratory bronchioles, mucus plugging, and loss of bronchioles Collapse of bronchioles due to loss of alveolar attachments Loss or distortion of the radial support of bronchioles Loss of bronchioles in patients under age 70 Inflammation and fibrosis of bronchi and bronchioles and nNKus plugging Inflammation, atrophy, goblet cell metaplasia, squamous metaplasia, and mucus plugs in bronchioles Inflammatory narrowing and fibrosis, loss of bronchioles. and mucus plugging Goblet cell metaplasia Plugging of bronchioles with inflammatory cells and mucus Loss of lumen of airways less than 2 mm in diameter due primarily to narrowing and InUCus plugs Distortion, tortucsity, and irregular narrowing of bronchioles Lack of tilling bronchioles of less than 1 mm Loss of airway lumen Chronic inflammation (r=0.48), narrowing (OB), fibrosis (0.27). goblet cell metaplasia (0.241, and fewer small airways (-0.18) 228 and IV. The lesions that were different in group II from lesions in group I were squamous cell metaplasia, inflammation, and fibrosis. Fibrosis and squamous cell metaplasia increased steadily from groups I to III. Increased muscle and goblet cell metaplasia occurred only in group IV. One extrapolation of these data is that inflamma- tion in the peripheral airways is the initial event produced in response to cigarette smoke. This inflammation leads to, or is associated with, squamous metaplasia and mural fibrosis. Goblet cell metaplasia and increase in muscle subsequently occur and are associated with decrements of function. Berend et al. (1979) did a similar study on 21 smokers and 1 nonsmoker, and added the important information that airway narrowing occurred and was associated with abnormalities of the single breath nitrogen washout test and the FEFs75. The data were reanalyzed subsequently (E&end et al. 1981b) and showed that inflammation was the lesion associated with the most abnormalities in tests of expiratory function. Airway inflammation was significant- ly related to abnormalities of the FEV1, FEFzF~x, slope of phase III of the single breath nitrogen test, and closing volume expressed as a percentage of vital capacity. The authors also noted that as the total pathology score got worse, the airways diminished in caliber in surgically derived lungs, but not in autopsy lungs. They noted that airway caliber was larger in autopsy lungs than surgical lungs, and suggested that this represented functional narrowing due to in- creased muscle tone, which was caused by release of mediators affecting the muscle directly or reflexly. Studies of lungs at autopsy have shown correlations between airway lesions and abnormal tests of function. Petty et al. (1980, 1982) have shown that correlations exist between inflammation, and increased muscle and elevations in the closing capacity; that occlusion of airways by cells and mucus, inflammation, and in- creased airway muscle are related to abnormalities of the slope of phase III of the nitrogen washout; that airway narrowing is closely related to the FEVi, FEFs75, and slightly less well related to closing capacity. Similarly, Berend et al. (1981a) showed an association between post-mortem closing capacity and both peripheral airways inflammation and a total pathology score. Decrease in maximum flow at a transpulmonary pressure of 5 cm HzO was related to inflammation and the total pathology score, but not as well related to airway narrowing (Berend and Thurlbeck 1982). Morphologic abnormalities similar to those found in autopsy lungs have been found in surgically excised lungs derive* almost entirely from smokers, and these in turn have been related to abnormal tests of small airway function. Smoking and Lesions of Peripheral (Small) Airways An increase in goblet cells was the first abnormality of peripheral airways noted in smokers. The observation was made in bituminous coal workers. In nonsmokers, about 0.66 percent of peripheral airway cells were found to be goblet cells; in smokers, this rose to about 1.0 percent (Naeye et al 1971). The critical observation, both factually and conceptually, was that of Niewoehner et al. (1974). In an autopsy study of men under the age of 40 who died suddenly elsewhere than in the hospital, they compared lesions of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls) in smokers and nonsmokers. Emphysematous lungs were excluded, and the smoking history was obtained by personal interview with close relatives, using a standard questionnaire. The researchers found that intraluminal mucus, mural edema, peribronchiolar pigment, peribronchiolar fibrosis, denuded epithelium, mural inflammatory cells, and respiratory bronchiolitis were more severe in the smokers. The last three were significantly different statistically. They empha- sized the importance of respiratory bronchiolitis, which consisted of aggregates of brown macrophages in and around the first and second order respiratory bronchioles and was associated with edema, fibrosis, and epithelial hyperplasia in adjacent bronchioles and alveolar walls. Bronchiolitis was found in all of the smokers, but in only 5 of the 20 nonsmokers, and it was the lesion that showed the greatest difference between smokers and nonsmokers. Since respira- tory bronchiolitis was found in precisely the same regions where centrilobular emphysema is found in subjects 20 years older, the researchers suggested that this lesion might evolve into emphysema. This observation fits well the proteolytic-antiproteolytic hypothesis of the pathogenesis of emphysema. Ebert and Terracio (1975) compared the peripheral airways in resected lungs of 22 smokers and 3 nonsmokers and found that the number of Clara cells (the tall nonciliated airway cells thought to be secretory, although the nature of their secretion is not completely certain) was diminished, as assessed subjectively, and the number of goblet cells was increased, as assessed quantitatively. Two laboratories have concentrated on the association between smoking and lesions of vessels as well as of airways. One has used autopsy-derived lungs (Casio et al. 1980; Hale et al 1980); the other, surgically excised lungs (Wright et al. 1983a, b, in press). The first material has the advantage that the entire lung can be examined, but has the disadvantage that agonal changes may affect the airway; the second has the advantage that agonal changes are absent and structure-functional studies can be done, but has the serious disadvantage that usually only a part of the lung is examined. Because of the wide variation in severity of emphysema from lobe to 230 lobe, emphysema in the whole lung cannot be assessed from a single lobe. Also, airway inflammation may not be evenly distributed through the airways (Berend 1981; Hale et al. 1980). Cosio et al. (1980) studied 14 nonsmokers with an average age of 71.6 years and 25 long-term smokers with an average age of 58.4 years. The total pathology score was significantly higher in the smokers; in them, but not in the nonsmokers, the total pathology score was significantly related to age. Respiratory bronchiolitis was more common in the smokers, and of the components of the total pathology score, goblet cell metaplasia (p \\ 1,. `c'.. `\ Q.. `\ <`X.. \. \x FIGURE S.-Average emphysema score in male and female nonsmokers in Montreal, Cardiff, and MaIma, by decade NOTE All The average for the three cities. SOURCE l'burlbeck et al t 1974bl 242 FIGURE b.-Average emphysema score in male and female heavy cigarette smokers (>pack per day) and ex-smokers, by decade N(3TE: All: The average for the three aties SOURCE Tburlteck et al 11974bl 243 women are more modest, with an average emphysema score of 8 to 12 from the sixth to the ninth decade. Pratt et al. (1980) studied the effect of smoking on cotton textile workers and on workers not exposed to cotton. They found that the incidence of centrilobular emphysema was 6.7 percent in non- smoking non-cotton-textile workers, 6.9 percent in nonsmoking cotton-textile workers, 26.5 percent in smoking non-cotton-textile workers, and 26.2 percent in smoking cotton-textile workers. The variation in the incidence of centrilobular emphysema involving more than 25 percent of the lung was even more dramatic-1.1,0.4, 11.0, and 12.6 percent for the respective categories. Thus, despite the limitations in interpretation of the types of emphysema and in recognition of the presence of emphysema, the association between smoking and emphysema-particularly severe emphysema-is overwhelming. In the various series referred to, of the 227 patients with severe emphysema, only 3 were nonsmokers. Summary and Conclusions 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of small airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. This lesion may be an important cause of abnormalities in tests of small airways function, and may be involved in the pathogenesis of centrilobular emphyse- ma. 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