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female smokers: They suggested that men respond differently to habitual! cigarette smoking at an earlier stage than d'o women. Few reports have shown a consistent dose-response relationshipp between cigarette smoking and functional abnormality. In a recent study, Burrows, et al. (23) demonstrated an inverse relationship between ventilatory function and pack-years, even in subjects who denied! cough and sputum. The long-term effects of cigarette smoking on lung function have been examined in several prospective studies. These have usually shown that the rate:of decline of FEV in smokers is greater than in the nonsmoker (67). This was again suggested in the 10-year followup of the Framingham cohort (8). In a large prospective study of Londoni working men, Fletcher, et al. (57) recognized a"suscept'ible" group of smokers whose rate of decline in FEV was steeper than that for nonsmokers. However, there was another group of smokers who lost FEV almost as slowly as did nonsmokers. The authors suggest that the.effect of smoking on FEV in "susceptible" individuals may be underestimated by focusing on the mean FEV of all smokers, as is usually done in prevalence surveys. As noted earlier, they found no relationship between the rate of decline in FEV and' productive cough when~ smoking habits were taken into account. This is in conflict with Gregg's data (62), in which only smokers with bronchial hypersecretion were likely to develop function- al decline. In summary, the majority of epidemiological surveys have found a higher prevalence of functionali abnormalities ini smokers as compared to nonsmokers. There are conflicting data as to the effect of smoking on pulmonary function in different racial groups and whether men and women with equivalent smoking habits have similar reductions in pulmonary function. It is clear that cigarette smoking produces a: more rapid decline in FEV and~ a higher prevalence of productive cough. However, it is unclear whether the presence of productive cough by itself predicts the risk for a more rapid decline in~ FEV independent of that increased risk associated with cigarette smoking. It has been suggested that there may be a "susceptible" group of smokers whose rate of decline in FEV is much greater than that in both~ "unsuscepti- ble" smokers and nonsmokers and that "unsusceptible" smokers and nonsmokers have similar rates of decline in FEV. Therefore, preva- lence surveys of functional abnormallties in all smokers may underesti- mate the impact of cigarette smoking in the "susceptible"' population. Cessation and Reversibility of Functional Changes Smoking, cessation results in a reduced prevalence of symptoms in~ all age: groups and in reduce& mortality rates. The effects of smoking cessation on pulmonary function have been~ considered at various stages of functional abnormality. 6-22 Buif cessat volum 12 mc found resurr. ties ir f indin aL (37 airwa! As pulmc welli -, impr( follov 159), venti comp obser declit howe fo11oS and i decli, smok nons° halvf to nc recoi decli follo (1'oa; smali smol as tY In, perf still acce Lun Aue hab; aut(

Buist, et al, (22) followed a group of 75 smokers attending a smoking cessation clinic and observed significant improvementt in closing volume; closing capacity, and the slope of the alveolar plateau at 6 and 12 months in subjects who stopped smoking. McCarthy, et al. (105) found similar improvement in 131 subjects who stopped smoking; resumption of smoking led to subsequent development of abnormali- ties in the slope of the alveolar plateau and closing capacity. These findings are especially pertinent in view of the suggestion~ by Cosio, et al. (37) that some of the pathologic changes present when tests of small airway functions are abnormal can be reversed. As a group, ex-smokers usually perform better on conventional pulmonary function testing than smokers, but they do not perform as welll as nonsmokers (67), Several studies have confirmed that there is improvement in performance on standard spirometric function tests following cessation of smoking in small numbers of patients (85, 115, 159), but there is stilli debate as to whether the normal decline in ventilatory function (i.e., FEV) is accelerated in ex-smokers as compared to nonsmokers. In the Framingham study, Ashley, et al. (8) observed that men and women who continued to smoke had a greater decline in forced vital capacity (FVC) than those who stopped; however, they could not demonstrate consistent changes in the FEV, following smoking cessation. They attributed this to the impreciseness and insensitivity of the FEVrmeasurement. In women ex-smokers„the decline in FVC was similar to that of female nonsmokers; in male ex- smokers, the decline in FVC was slightly greater than that of male nonsmokers. Fletcher, et al. (57) observed that cessation of smoking halved the rate of loss of FEV and returned; the rate of decline in FEV to normal in "susceptible" smokers. However, the lost FEV was not recovered. Smoking cessatiom had' no effect on the normal rate of decline in "unsusceptible"' individuals. Similarly, in a two-year followup of 118 continuing, ex-smokers, aged 27 to 56, Manfreda, et al. (100) noted that subjects who continued to refrain from smoking had a smaller decline in FEV,.a/FVC ratio than did smokers; in the male ex- smokers„ the decline in ventilatory function fell at about the same ratee as that for nonsmokers. In summary, it is clear that smoking cessation leads to: improve& performance on standard pulmonary function tests. However there is still debate as t'o whether the normal decline in ventilatory' function is accelerated in ex-smokers as compared to nonsmokers. Lung Pathology Auerbach, et al. (10) studied the relationship between age, smoking habits,, and emphysematous changes in whole lung sections obtained' at autopsy frorn 1,443 males and 388 females. A total of 7,324 sections 1 I II 0 I 0 II 0 I 6-23

TABI ~ mm thick were graded on a: scale of 0 to 9 according to the severity of emphysema. No distinction was made between centrilobular and panlobular emphysema. The men were classified by age, type of smoking (pipe cigar or cigarette), and amount of cigarette smoking M  Ag ,,. Smoking habits were ascertained by interviews with relatives. Within each of the six smoking categories, the mean degree of emphysemaa increased with age. Adjusting the data for age revealed~ that the mean degree of emphysema was lowest among men who never smoked, was higher in pipe or cigar smokers, and highest among regular cigarettee smokers. A dose-response relationship was found for the number of -2 ` <f cigarettes smoked per day and! the severity of emphysema. These data are presented in Tables 5 and 6. In a subsequent histologic st'udy of tissue from 1,582 men and 368 womeny Auerbach, et al. (9) were able to show that rupture of alveolar septa (emphysema) and fibrosis and thickening of the small arteriess and! arterioles were far greater in smokers than in nonsmokers and increased with increasing amount smoked (Tables 7 and 8). When these researchers examined former cigarette smokers, they found that those who had stopped more than 10 years prior to death '= • % th h lb ic h th h d t d l h d l k d th ose w o g c anges an o a s oppe ess a ess mar e pa than 10 years before death. But even in~ those who had stopped for more than 10 years, there was a greater degree of pathological change in those who had been smoking more than one pack per day than in those who had been smoking less than one pack per day (Table 9). In a clinicopathologic study of 196 men and 46 women, Mitchell, et al. (107) found that the totali exposure to cigarettes was related to clinicali symptoms of chronic airway obstruction and to both alveolar and airway pathologic features. The severity of patholbgic change was related to the amount of smoking. ~~ 70 Several recent studies have shown evidence of small airway 01 abnormalities in young smokers. Cosio, et al. (37) found squamous metaplasia of the airway epithelium as well as chronic inflammatory infiltrate and a slight increase in the connective tissue in the walls of the small airways. Kleinerman and Rice (83) found significantly more emphysema, parenchymal pigment, and chronic bronchiolitis in the lungs of smokers as compared to age-matched nonsmokers (median age 27.5 years). , 191 •sU In summary, cigarette smokers demonstrate more frequent abnor- ~ ~ Sol malities in macroscopic and microscopic lung sections at autopsy than do nonsmokers. Furthermore, there is a dose-response relationship A 4' Smt between these chanaes and the intensity of smokina. Hist'olozic ~I in ' th l i i tt ll i id f ogy was more common gare rways pa o n c e ev sma a ence o of 1& I nisn -matched nonsmokens in an auto s stud k th in p y y age smo ers an sudden-death victims. "3( patl 6-24

TABLE 5.-Degree of emphysema in current smokers• and in nonsmokers according to age groups Age group Degree of emphysema Subjects who never smoked regularly Current. pipe or cigar smokers Current cigarette smokers# <'/2t l/i-1>f 1-2t 2+ t 0-0.75 53 18 12 3 2 - 1-1.75 2 11 4 9 24 5 2-2.75 - 1 2 17i 130 56 <60' 3-3.75 - L 5 12 50 38 4-4.75 - - - 4 8 7 5-&.75 - - - - 4 5 1 7-9.00 - - - - 3 1 Total9 55 31 23 45 221 112 Mean 0.10 0.83 1.29 2.37 2.56 2.86 SD 0.04 013 0.26 0.16 0.07 0.10 0-0.75 35 17 4 - - - 1-1.75 1 8 1 - 4 1 2-2.75 2 3 4 5 37 23 64-69 3-3.75 2 2 2 9 42 24 4-4.75 - - 1 8' 11 9 5-6.75 - - - 1 8' 1 7-9:00 - - - 1 5 4 Totals 40 30 12' 19 107 62' Mean 0.39 0.95 1.90 3.59 3.39 3.37 SD .0.13 0.16 0.34 0.35 0.15 0.2(1 0-0.75 68' 21 2 - - - 1-1.75 4 28 10: 8 2 2 2-2.75 5 22 13 23 40- 9 70 or 3-3<75 4 8 5 10 38 18 older 4-4.75 - 2 1 7 11, 7 5-6.75 - 1 - 2 9 3 7-9.00 - - - 1 12 5 Totals 81 82' 31 51 112' 44 Mean 0.50 1i66 Z15 2.98 3.68 3.91 SD 0.39 0.11 0.17 0.20: 0.17 0.27 • Subjecta who smoked regularly up to time oftiterminal iillness. tPackages/day. 60CRCE: Auerbach, 0. (10) ; L Smoking and the Pathogenesis of Lung Damage In recent years, numerous investigators have examined the mecha- nisms by which' smoking might induce lung damage. Three major pathogenetic possibilities by which' smoking may damage the Iungs' 6-25 m ur a 9 I

TABLE 6.-Age-standardized percentage distribution of malee subjects in each of four smoking categories according to degree of emphysema Degree of emphysema Subjects who never smoked regularly M Current! pipe or cigar smokers M Current cigarette smokers (%) <1' 11+ • 0-0.75 (none) 90.0 46.5 13.1 0.3 1-1.75 (minimal) 3.8 33.0 16.4 5.2 2-2.75 (slight); 3.3 13.01 33.7 42.6 3-3.75 (moderate) 2:9 6.3 25.11 32.7 4=9.00(advanced to far advanced) 0 1.2 11.7 192. Totals 100.0 100.0 100:0 100.0'. •Packages6day, SOURC& Auerbach, 0. (10) TABLE 7.-Means of the numerical values given lung sections at autopsy of male current smokers and nonsmokers, standardized for age Subjects who Current pipe never smoked or cigar Current cigarette smokers, regularly smokers <.5 Pk. .5-1' Pk. 1-2 Pk. >2 • Pk. Number of subjects 175 141 66 115 440 216 Emphysema 0.09 0.90 1.43 1.92 2:17 227 Fibrosis Thickening, of 0.40 1.88 2.78 3.73 4.06 4.28: arterioles Thickening of 0.10, 1.11 L35 1.66 1.82 1.89. arteries 0.02 0.23 0.42' 0.68' 0.83 0.90 NOTE: Numerical valueswere determined I by rating each lung section on seslAS ~ of, 04 for emphysemaa and' thickening of arterioles, 0-7 for fibrosis, and Oa3!for thickening of!arteries: . SOURCE: Auerbach, 0. (9) have been scrutinized. They are: (1) altering, protease-antiprotease balance in the lungs, (2) compromising immune mechanisms, and (3) interfering with pulmonarycDearance mechanisms. Proteolytic Lung Damage Emphysema is characterized by irreversible destruction of alveolar septal tissue. If severe, this dlsruption may result in loss of elastic

TABLE' 8:-Means of the numerical values given lung sections at autopsy of female current smokers and nonsmokers; standardized for age <11 Pk: >11 Pk. Number of subjects 252 33'. Emphysema 0.05 ll37 Fibrosis 0.371 2.89 Thickening of arterioles 0.06 126 Thickening of arteries 0.01 0.40 NOTE: Numerical values were determinedby ratio<g: each lung sectionn on sealesof 0-4 for emphysema and thickening ofthe arterioles, 0.7 for £ih'rosis, and i0-3 fon thickeningof the arteries. SOURCE: Auerbach,,0: (9) TABLE 9.-Means of the numerical values given lung sections at autopsy of male former cigarette smokers;, standardized for age Formerdy Stnoked Stopped > 10 yr. Stopped < 10 yr. Number of subjects 35 66 51 Emphysema 0.24 0.70 1.08 Fibrosis 1i14 1.74 2.44 Thickening of arterioles 0.57 0.93 1.25 Thickening of arteries 0.04 0.16, 0.36 <1 Pk. Pk. <1 Pk. Pk.. 1i70 3.46 1.57 0.64 131 1169 3.30 1.59 0.61 NOTE: Numerical values for each finding were determined b'yy rating each lung section onecales.of 0-4 for emphysema and thickening of the arterioles, 0-7for.fibrosis, and 0. 3 for thickening of the arteries. SOURCE: Auerbach, 0.: (9) recoil, enhanced~ collapsibility of the airways, and airflow obstruction. The elastic properties of the' lung are attributed~ to the appropriate distribution of elastin in its connective tissue framework. Recent data suggest that the lung damage observed in emphysema may be due to injury of this elastic framework by proteolytic enzymes released (and not inhibited) in the lung. Formulation of this hypothesis was'cak,alyze& by the discovery that emphysema is extremely common in individuals who are severely deficient in alpha-l-antitrypsin (48), a glycoprotein that inhibits several proteases. Subsequently, it was postulated that conditions interfering with the normal balance between protease and antiprotease activity could give rise to an excess of free protease (i.e.,, elastase) in the lung and initiate lung' destruction~(1Q9). Subjects who Current cigarette never smoked smokers regularly 6-27 0 0 0 6 0 no

The proteases are a group of enzymes which probably serve a wide range of functions in the normal host. Proteases with particular elastolytic capability (elastases) are synthesized and released by alveolar macrophages which are found in increased numbers in bronchopulmonary lavage fluid of smokers. They are also present in significant concentrations in polymorphonuclear leukocytes (PMNs). The antiproteases, of which alpha-l-antitrypsin is the most abun- dant, are found primarily in blood although alveolar macrophages and bronchial secretions are additional sources of antiproteases. An excess of protease within the lung may arise from any circumstances in whi& there is increased release of protease which is not matched by availability of antiprotease activity at the site of such release. Various types of experimental support for the proteolytically mediated hypothesis of lung damage have been presented in recent years (15, 75, 77)132). Crude leukocyte extracts can digest lung tissue (76, 92); and homogenates of leukocytes can prodtzce emphysema (101, 103) when instilled into the lungs of animals: The degree of damage depends on the proteolytic activity of the instillate (82). Recently, Senior, et al. (129) instilled purified human loukocyte elastase into the tracheas of hamsters. At two months the lungs of the animals showed mild, patchy emphysema. In a related study, Schuyler, et al. (126) administered elastase to hamsters intravenously and demonstrated significant loss of elastic recoil at low lung volumes when their lung histology was normal. The authors suggested that submicroscopic lesions may antedate obvious morphologic evidence of emphysema. The mechanisms by which cigarette smoking may alter the protease- antiprotease balance have been the subject of several recent investiga- tions. Janoff and Carp (74a) demonstrated that unfractionated cigarette smoke condensate suppressed antiprotease activity in vitro. Elastin-agarose gels were impregnated with cigarette smoke conden- sate. Elastases were then allbwed to diffuse through the gels toward a counter-diffusing sample of antiproteases. The effectiveness of the antiproteases in blbcking the enzyme was determined by the extent of elastin destruction in the plates. Elastins, proteases, and antiproteases from different sources, in6iding, purified human leukocyte elastase and human alpha-l-antitrypsin, were tested. In all situations, the cigarette smoke condensate suppressed the inhibitory activity of the antiprotease. In a followup study, Carp and Janoff (26) demonstrated that fresh cigarette smoke also suppressed elastase-inhibitory activity of human serum. In addition, treatment of serum with model oxidantss caused a similar suppression of elastase inhibition. These in vitro observations suggested to the researchers that emphysema in cigarette smokers might be due in part to the suppression of antiprotease activity by oxidizing agents present in cigarette smoke: 6-28 11 Ir dem elas vitr' bete acti smo smo rele imn stuc den airv i& v T' has nor and stu( lav: and sus C smc in obs an dis• pla cor evi Ka grc prc stu rel en. 66, pu: (1) thc inc mZ ac1 mc ~;

In another study from the same laboratory,, Blue and Janoff (16) demonstrated that cigarette smoke condensates elicited the release of elastase from human PMNs. When human PMNs were incubated in artt'ro with cigarette smoke condensate, three enzymes were released: beta-glucuronidase, acid phosphatase, and elastase. The elastase was active in digesting elastin, even in the continuing presence of cigarette smoke condensate. When mixtures of human PMNs and cigarette smoke condensate were instilled into rat lung in vitro, elastase was released and could be: traced to connective tissue targets using immunohistochemical and enzyme-histochemical techniques: This study appears to be particularly relevant in view of previous studies demonstrating that cigarette smoke recruits leukocytes into the lung airways (81,124'), immobilizes them (46), and, inhibits their chemotaxiss in vitro (17). The role of the pulmonary macrophage in proteolytic lung damage has been evaluati& by severali investigators. Alveolar macrophages are normally important in, cleansing the lower airways by phagocytising and digesting foreign particulate matter. Bronchopulmonary lavage studies have documented increased total numbers of macrophages in lavage fluid~ of smokers as compared to nonsmokers (65, 1,56). Keast and Holt (79) exposed mice to smoke via a special~ apparatus and found sustained elevations in bronchopulmonary macrophage populations. Changes in the ultrastructure of macrophages have been reported in smokers. Pratt, et al. (116) observed pigmented cytoplasmic inclusions in macrophages from cigarette smokers. Brody and Craighead (18) observed that the pigmentation appeared~ to be due, at least in part, to an increased number of lysosomes and phagolysosomes: In addition, distinctive "smoker's" inclusions were observed within these cyto- plasmic organelles which appeared plate-like and' cryst'allographically consistent with kaolinite. The authors presented some preliminary evidence that these particles are derived from, inhaled tobacco smoke. Kaolinite is a common clay mineral found in the soil in many t,obacco growing regions and is sometimes used as a tobacco additive in the production of cigarettes for the purpose of reducing tar content. A few studies have shown that when macrophages engulf kaolinite they release beta-gulcuronidase and lactic acid dehydrogenase, lysosomal enzymes believed to play a role in cell!death and fibrogenesis in vivo (3, 66, 157). In a recent study, Matulionis and Traurig (10.4) exposed pulmonary macrophages of mice in situ to cigarette smoke tLnd found: (1): an increase in number, variety, and size of lysosome-like bodies, in the macrophage; (2) the appearance of multinucleation; and (3) an increased size of the macrophages. After cessation, of smoke exposure, macrophage morphology and population size returned toward normal. A considerable increase in elastase-like esterase and protease activity was demonstrated by Harris,, et al. (64) in human alveolar macrophages in smokers as compared' to nonsmokers. In a subsequent- 6-29 M M a I I I 8 I

study, Rodriguez, et al. (119) demonstrated that human alveolar macrophages from smokers released elastase into serum-free culture mediums unlike those from nonsmokers. Elastase was not detectable in cell homogenates from either smokers.or nonsmokers, implying that this enzyme is not stored. The authors suggested that cigarette smokers have the potentiall for a 20-fold increase in elastase released in the lungs when the increased number of macrophages in lungs of smokers also is considered. Potentially important effects of cigarette smoke`also have been demonstrated on alveolar macrophage pinocytosis (164)1 cell adhesion (61), cell migration (154); and protein synthesis (94', 95, 163): The data relating the effect of cigarette smoke to alveolar macrophage phagoocytosis and bacteriocidal activity are conflicting (61, 130, 135, 137) but generally have shown cigarette smoke to have a suppressant effect. At least some of the toxic effects of the gas phase of cigarette smoke on macrophage activity may be due to the oxidant, acrolein (74): In summary, a number of recent investigations have suggeste& that a destruction of the: elastic framework of the lungs seen in COLD may result from a protease-antiprotease imbalance. Although definitive evidence is lacking, it appears that alveolar macrophages and PMNs are the most important sources for the proteases: Cigarette smoke appears to increase the rate of synthesis and release of elastase in vitro from human alveolar macrophages and increases their numbers. Antiproteases are inhibited' from counteracting protease activity in~ the presence of cigarette smoke in vitro. Possible deleterious effects of cigarette smoke also have been demonstrated on a variety of functions of the human alveolar macrophage: Interference with Immune Mechanisms The lungs have a highly developed lymphatic system and the capacity to effect local immune responses. Inhalation of tobacco smoke produces significant changes in cellular and humoral immunity in both animal and man. H'owever, the role of such changes in the pathogenesis of lung disease remains speculative. Waldman, et al. (151) reported that cigarette smokers of more than 1/2 pack per day had! an increased risk of influenza-like illnesses although the length of illness was no different than for nonsmokers. Finklea, et al. (52) noted that smokers had more frequent subclinical influenza: than nonsmokers; subsequently he observed that thee serological response (hemagl'utination antibody titers) to either vaccination or natural infection with A-2 antigens was similar to that in nonsmokers but not as long lasting (51). Cigarette smoke appears to adversely affect the nonspecific (phagocytosis) defense mechanisms provided by the: alveolar macro- phage. Evidence for an effect on the specific (immune) defense roles 6-30 pla, sev4 T ove (15, anc rea ma fac MI the me nol ers me ani I

® ® played by both macrophages and lymphocytes has been offered by several investigators. The alveolar macrophage system, plays an important role in the overall immune response as an antigenic "processor." Warr and Martin (154) studied alveolar macrophages lavaged from four healthy smokers and four healthy nonsmokers. Only two members of each group were reactive to skin~ tests with Candida albicans. The migration of macrophages from nonsmokers was inhibited by migration inhibitory factor (MIF) whereas macrophages from smokers did, not respond, to MIF. The cells from smokers were noted to migrate three times faster than those from nonsmokers. When Candida antigen was added to the medium„ cells from the nonreactive subjects (both smokers and nonsmokers) were not inhibited. The cells from the reactive nonsmok- ers were inhibited, but not those from reactive smokers. Thus, macrophages from smokers did not respond normally either to MIF or antigenic challenge. The B and T' lymphocytes participate in humoral and' cell-mediate& immune mechanisms, respectively. Warr, et al. (155) noted that a greater number of T cells and B cells were recovered by human bronehopulmonary lavage from smokers than from nonsmokers. Daniele, et al. (39)~ examinedt'heT and B cell populationsins peripheral' blood of smokers versus nonsmokers and found no difference in either the absolute number of cells or the lymphocyte response to phytohema. glhztinin (PHA) or concanavalin A. In a lavage study of five smokers the lymphocyte subpopulation did; not differ from~ that in nonsmoking subjects,(h=8), but cells from smokers showed a diminished response to PHA and concanavalin A. They concTud'ed that cigarette smoking may impair cellular immune defenses. In contrast, Silverman, et al. (131) found that young smokers had an increased number of T lymphocytes in peripheral blood and an enhanced response to PHA. No differences were found in the response of older smokers or those with a history of heavier cigarette consumption as compared to controls. A number of other studies havee examined the relationship of smoking to T-celli function; these are reviewed in the Chapter on Allergy and Immunity. Roszman and Rogers (121) noted that both the nicotine and the water-soluble fraction of whole cigarette smoke suppressed the immunoglobulin response of lymphoid cell cultures to antigen chal- lenge. When concentrations of over 200 micrograms per milliliter of nicotine of the water-soluble fraction were added, they were able to suppress completely the immunoglobulin response; this suppression~ also occurred in cells exposed 2 hours prior to the antigenic challenge. In, a subsequent experiment, they found suppression of mitogen- induced blastogenesis by cigarette smoke (120). Warr, et al: (156) examined immunoglobulin levels in bronchopulmonary lavage fluid in mm I 0 ® I 6-31