ciated with a particular type of pulmonary emphysema. While the majority of lungs of emphysematous patients reveal] bullous or centrilobular deformities, particularly of the upper lobes, this hereditary disorder reveals a panacinar change, most severe in the lower lobes (101, 215, 226). Patients with emphysema who are found to have the homozygous deficiency have been observed to include a greater percentage of female patients than is usually ob- served in the general emphysema population. Their disease begins earlier, is more severe, is characterized by dyspnea rather than cough, and frequently is unassociated with a history of preceding bronchitis (101, 215, 226). Radiographic studies of A,AT-deficient patients have revealed decreased vascularization of the lower lobes and increased vascularization of the upper lobes (101, 21.3). It is estimated that between 1 and 2 percent of patients with COPD have this homozygous deficiency (78, 216). In family studies, it has been found that almost all the homozygous individuals are symptomatic by the age of 40 and that those who are not usually show alterations in pulmonary function studies. Guenter, et al. (98) studied 7 per- sons with homozygous deficiency. Of the five symptomatic individ- uals, 4 smoked and al] had abnormal timed vital capacity. Neither of the two asymptomatic individuals smoked or had this change in vital capacity. All 7, however, were noted to be hypoxemic at rest and to have decreased pulmonary diffusing capacity. It has been suggested (154) that the lack of this proteinase in- hibitor in the serum of homozygous patients predisposes them to emphysema in the following manner: Leukocytes present in the blood contain significant amounts of proteinase enzymes as part of the overall defense mechanism against infection; the breakdown of these cells during acute infection releases proteinases into the pul- monary tissues and these, without the presence of a normal inhib- itor, may contribute to the breakdown of the structural proteins of lung tissue. Heterozygous individuals have been defined as those who show levels of A, AT intermediate between those of normals and those with homozygous deficiency. At the present time, there is much debate about whether or not heterozygotes for A,AT are at a greater risk of developing COPD than are A,AT normals. A major difficulty is the lack of a precise definition of heterozygosity. At present, the best method for the determination of the level of A, AT appears to be that of crossed serum immunoelectrophoresis be- cause levels of trypsin inhibitory capacity (TIC) have been shown to rise acutely with infections. Welch, et al. (226) feel that heterozygotes do not show an in- creased susceptibility to COPD. The hete:ozygotes which they studied showed symptoms of bronchitis and did not present the 151 lower lobe perfusion defects frequently noted in homozygotes, They also found no difference in the number of COPD patients among the heterozygotic and the general population. Other investigators, no. tably Lieberman, et al. (153, 155), Kueppers, et al. (144), and Larson, et al. (148) found significantly increased percentages of COPD patients among those with heterozygous deficiency as com- pared with the general population. Lieberman, et al. (155) ob. served that the percentage of heterozygotes among a group of healthy industrial workers wag 4.7 percent while that among a group of patients with emphysema was 18.1 percent. In a recent review, Falk and Briscoe (79) considered that the available evi- dence points to an increased prevalence of COPD among hetero. zygotes. Of more central interest to this discussion, however, is the pos- sible relationship of smoking to the predisposition of disease among the heterozygote population, Kueppers, et al. (144) studied three populations: younger controls, older controls, and a group of COPD patients. They observed that of the 25 heterozygotes with COPD, only 2 were over 70 years of age, both were female and non- smokers, The remaining 23 were cigarette smokers, Nevertheless, studies which adequately sort out the factors of genetic susceptibil- ity and cigarette smoke exposure have yet to be reported. An important question is to what extent the relationship between smoking and COPD is influenced by identifiable genetic factors. At present, it is possible to identify what appears to be only a very small group of susceptibles for whom genetic factors may be para- mount in the pathogenesis of their ailment. Of greater public health import is whether lesser degrees of genetically identifiable suscep- tibility interact with cigarette smoking to account for a significant proportion of the problem. AIR POLLUTION Numerous epidemiological studies have been conducted in order to examine the effect of air pollution on human nonneoplastic res- piratory disease. Three major types of studies have been utilized: observation of the mortality and morbidity due to an acute episode of increased air pollution, observation of the day-to-day variation in mortality and its relation to air pollution levels, and geographical! comparisons. The majority of studies fall into the third category, and these are detailed in table A6. A number of studies did not show an association among air pol- lution, respiratory symptoms, and pulmonary dysfunction (81, 204). More recent studies which evaluated the factors of smoking, social class, and air pollution separately noted a greater prevalence of 152 COPD symptoms, pulmonary dysfunction, and COPD mortality in areas of high pollution (12, 122, 146, 233). Lambert and Reid (146) observed that in the absence of cigarette smoking the corre- lation between COPD symptoms and air pollution was slight and suggested that the two factors may interact to produce higher rates of disease. The evidence which has accumulated in the past 7 years gives further support to the conclusion of the Surgeon General’s Ad- visory Committee on Smoking and Health as stated in its 1964 Re- port that: “For the bulk of the population of the United States, the relative importance of cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than atmospheric pol- lution or occupational exposures.” OCCUPATIONAL HAZARDS Exposure to various dusty occupational environments has been shown in many studies to be associated with the development of various forms of nonneoplastic lung disease. Lowe (/58), in a re- view of the relationship of occupational exposure and chronic bronchitis, noted that among workers exposed to dust significant increases in COPD mortality were observed. These occupations included coal mining, tinning, galvanizing, riveting, and caulking. Commenting on a previously unreported study of more than 20,000 steel workers, he observed that the relationship between mean dust exposure levels and COPD prevalence was much stronger among smokers than among nonsmokers, More recently, Bouhuys and Peters (37) reviewed those specific industrial exposures related to lung disease. COPD was found to be associated with exposure to coal dust, asbestos, bagasse dust, iso- cyanates, various irritant gases, and textile dusts (cotton, flax, or hemp). Studies which have investigated the interrelationship between smoking, industrial exposure, and COPD are listed in table A7. Ad- ditional compounds, not listed in the table, but which also appear to be related to COPD, are chlorine (49) and washing powder dust (97). Cigarette smoking and harmful dust exposures appear to act in a combined manner in the production of COPD. Although an increased prevalence of COPD is found with cer- tain occupational exposures, in none is the relationship as strong as that between COPD and cigarette smoking. To demonstrate an increased occupational risk, careful analysis of smoking habits is required. The relative importance of cigarette smoking appears to be much greater than occupational exposure as an etiologic factor in COPD. 153 Cadmium—Chronic industrial exposure to cadmium in man has been found to induce pulmonary emphysema without significant accompanying chronic bronchitis (34, 35, 210). Nandi, et al. (177) recently investigated the contribution of the cadmium in cigarette smoke to the pathogenesis of emphysema. Analyzing whole cigarettes, ash, and filters, they found that an average of 69 percent of the cadmium present in the cigarette (ap- proximately 16 micrograms/20 cigarettes) is inhaled in the smoke, In a related study (153), these investigators showed that the level] of cadmium in water-soluble liver protein on autopsy was three times greater in those patients with a history of chronic bronchitis / emphysema than that found in those without such a history. Un- fortunately, no smoking histories were available. PATHOLOGICAL STUDIES The relationship between smoking habits and pathological] changes in the bronchial] tree and pulmonary parenchyma has been investigated by several groups of workers. Metaplastic changes, although found in nonsmokers, are much more common in smokers (table 10, Cancer Chapter), and a dose-relationship of increasing metaplasia with increased smoking has been evident in many of the studies. Pathological studies which deal primarily with pulmonary parenchymal and non-metaplastic bronchial changes are presented in table 8. Goblet cell distention, alveolar septal rupture, thickened bronchial epithelium, and mucous gland hypertrophy have been found to be more frequent in smokers than in nonsmokers. Auer- bach, et al. (17) noted a dose-response relationship between the amount of smoking and the degree of septal rupture, Anderson, et al. (4, 5) studied the difference in the type of emphysema shown by smokers and nonsmokers. In their study, listed in table 8, they noted that the group of patients with panlobu- lar emphysema was comprised of equal numbers of smokers and nonsmokers while of patients with centrilobular emphysema, 98 percent were smokers. More recently, the same authors studied lung macrosections from 80 nonsmokers. While most were normal, 24 demonstrated parenchymal dilatation and disruption consistent with panlobular emphysema. Thurlbeck, et al. (217) have also ob- served that centrilobular emphysema rarely occurs in nonsmokers. 154 sst TABLE 8.—Studies concerning the relation of human pulmonary histology and smoking’ (Actual number of deaths shown in parentheses) SM = Smokers. NS = Nonsmokers Author, year, Number and country, type of Results Comments reference population Chang, 62 males and 43 Distention of goblet cells (by percent of smoking group) The authors also noted 1957, females autopsied 1%, of Most of that smokers’ lungs ULS.A,, within 5 hours of None Few 14 of surface surface surface Whole surface showed shorter cilia Korea death (nodata NS(22) 13.6 22.7 31.8 22.7 9.1 oe and thicker epithelium (47). available on case SM (49) 12.2 10.2 10.2 18.4 26.5 22.5 (20 percent nonsmokers selection). and 36 percent smokers had respiratory disease.) Ide et al., 93 males autopsied Mean thickness of tracheal and Mean ciliary height in trachea No cigar or pipe 1959, within 6 hours of bronchial epithelium (u) in and bronchus on cigarette smokers were included. U.S.A. death. No cases cigarette smokers and nonamokers smokers and nonsmokers (129). of pneumonia Trachea Bronchus Trachea Bronchus or lung disease NS(28)....... 52.8 47.7 (23) 6.39 5.95 included. Light (31) 62.0 57.5 (29) 5.62 5.49 Heavy (10) 66.2 61.9 (10) 4.89 4.66 Auerbach 654 males over Age-atandardized percentage distribution of subjects The authors also noted a et al., 60 years of age according to degree of rupture of the alvcolar septume dose-response relation- 1963, autopsied at Degree of rupture 0-0.25 0.5-0.78 1.0-1.25 1.5-1.75 2.0-2.25 2.5-8.00 ship between smoking U.S.A. East Orange Never smoked 19.4 50.5 24.9 3.6 1.6 and degree of rupture. (17), VA Hospital. Current cigarette A 5.1 16.2 39.2 39.1 tNone had ever smoked fCurrent cigar os 24.6 45,4 26.2 3.8 cigarettes regularly. {Current pipe nd 23.0 53.5 15.9 2.2 4.R 7.6 A6.5 33.6 7.5 Current pipe, cigar OSL Author, TABLE 8.—Studies concerning the relation of human pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM = Smokers. NS = Nonsmokers year, Number and country, type of Results Comments reference population Anderson 39 males and Severity of emphysema (mean degree) The authors also noted that: etal, 32 females Males Females Every person showing se- 1964, (Caucasians) NS (4) 1.5 oe (20) 1.0 vere disease was a smoker, U.S.A. undergoing SM (35) 2s alin (12) ro} (P<0.05) “among those with panlobu- (5). routine autopsy lar emphysema, there was (40-97 years an equal distribution of of age.) smokers and nonsmokers while among those with centrilobular emphysema 98 percent were smokers and only 2 percent were nonsmokers, Anderson 107 males and Percentage distribution of Mean severity of emphysema et al., 58 females tobacco usera in 165 necropsies Mean Statistical 1966, autopsied for by degree of emphysema severity Category Severity Significance U.S.A. whom smoking None ..... . 36 (12/383) SM(1M4) oe eee 28) (6). data was Mild ......, 69 (58/84) NS(51) ....... 0.9 ¢ P< 9-001) available, Moderate 91 (80/33) Male(107) 2.2 Severe... sees. 93 (14/15) Female(58) 1.2¢(P<0.001) Never smoked ........... . O09 <20 cigarettes/day ............ 1.9 20-40 cigarettes/day .......... 2.4 >40 cigarettes/day ............ 2.8 Megahed 50 male patients Mucous gland hypertrophy et al., with chronic Percent 1967, bronchitis under- NS oo. ec ee cence ee 29 (2/7) Egypt going bronchial SM oe, 17 (3/43) (P<0.02) (163), biopsy and lavage. 2G TABLE 8.—Studies concerning the relation of human pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM — Smokers. NS = Nonsmokers Author, year, Number and country, type of Results Comments reference population Auerbach 562 males au- Degrce of tracheal and bronchial arteriolar thickening etal, topsied at East (by percentage of smokers) 1968, Orange VA 0.0-0.4 0.5--0.9 10-14 1.5-1.9 2.04 U.S.A. Hospital. Never smoked (122) 21... . cece ee ee eee 46.1 39.3 13.3 1.3 aan (14). <20 cigarettes/day (120) 11.7 22.0 33.5 28.4 4.4 20-49 cigarettes/day (254) .. 50 8.6 37.4 40.9 8.1 >40 cigarettes/day (66) ..... 1.38 1.4 31.5 45.3 20.5 ' Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer chapter. EXPERIMENTAL STUDIES ANIMAL STUDIES A number of investigators have studied the effect of the inhalg. tion of cigarette smoke on the macroscopic and microscopic struc. COPD, i.e., bronchitis, parenchymal] disruption, alveolar septa] rupture, alveolar space dilatation, and the loss of cilia and ciliated cells in the bronchial] mucosa, The investigations of Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs who inhale cigarette smoke through tracheostomas de. velop progressively more severe lesions of the bronchi and paren. chyma with increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed: In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 420 days or more of exposure, the number of cell layers in the bronchial] epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. Mitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs were exposed to varying doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were “smoked” for 875 days, or approxi- mately 29 months, The animals which died during the experiment and the animals sacrificed after day 875 were examined for pul- monary parenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. 158 6cL TABLE 9.—Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-bronchial tree and pulmonary parenchyma of animals’ {Actual number of animals shown in parentheses) Author, A. Type of year, Animal exposure country, and B. Duration Results reference strain C. Material Leuchten- 603 CF, A, Inhalation, Number of mice showing specified changes berger, female mice. B. Up to 8 ciga- Number Number et al, rettes/day for Months of of No Mild Severe bronchitis 1960, up to 2 years. exposure cigarettes mice change bronchitis with atypism U.S.A, C. Cigarette smoke. 0 0 150 146 2 2 (no atypism) (152). 1-3 100-200 36 20 9 7 4-8 250-500 36 19 10 7 9-23 600-1600 34 19 7 8 1-23 25-1526 151 RR 33 30 Holland 60 rabbits. A. Inhalation. Cytology of tracheobronchial mucosa etal., B. Up to 20 ciga- Generalized Generalized 1968, rettes/day for Normal Focal hyperplaasis hyperplasia emphysema (123). 2-5. Controls 2... ese e eee eee eee ee ees (30) 21/30 6/30 3/30 1/30 C. ‘Normal ciga- Exposed (30) 7/30 10/30 9/30 11/30 rette smoke’’, Hernandez Adult Grey- A. Inhalation. Mean Mean et al., hound B. Twice daily/ Number of number of parenchymal Groups 1966 dogs. 5 per week, sections months disruption/dog compared P-value U.S.A. C. Cigarette I. Controls ............. (€8)112 we 0.7150 I-IIl insignificant (f11). smoke, Il. Allexposed ........... (15) 205 10.50 0.9583 II-I insignificant HII. Exposed 1l year ...... (8) 107 14.74 1.2350 iv-I p <0,02 OL TABLE 9,—Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-bronchial parenchyma of animals* (cont.) (Actual number of animals shown in parentheses) tree and pulmonary Author, A. Type of year, Animal exposure country, and B. Duration Results reference strain C. Material Auerbach Beagle dogs. A. Active inhalation Controls ....(10)—No evidence of pulmonary fibrosis or septal rupture. etal., via tracheostomy. Exposed ....(10)—Early (sacrificed) : 1967, B. Up to 12 cigarettes 1. Alveolar space dilatation. U.S.A. per day for up 2. Pad-like attachments to alveolar septa. (15, 16). to 423 days. Medium exposure: Septal wall thickening. C. Cigarette smoke. Latest exposure: 1. Focal subpleural pulmonary fibrosis. 2. Ruptured alveolar septa. 3. Granulomata. Frasca Beagle dogs. A, Active inhalation Electron microscopic results: etal., via tracheostomy. After 44 days — Increased number of goblet cells. 1968, B. Up to 12 cigarettes Decreased number of cilia on surface lining cells. U.S.A. per day for up After 420 days— Increased number of epithelial cell layers. (88). to 423 days. Loss of ciliated columnar cells. C. Cigarette smoke. Frequent interruptions in basement membrane. 1 Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer Chapter. 100 91.7 an i. z Q 5 w 60-— 7) Go z Ss _ a ms ° ke 407— z rT] o x ta 5 a 20 12.9 a 5.7 0.0 # : GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (4% as many cigarettes) as Group H Ficure 1.—Percent of lung sections with grade IV or V fibrosis. Sources: Hammond, et al. (104). Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table A10. It is clear that chronic exposure to low levels of NO, is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 197) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplasia and macrophage infiltration. Similarly, a dose-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 100 98.8 60F 40 PERCENT OF LUNG SECTIONS 24.3 GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (A as many cigarettes) as Group H FIGURE 2.—Percent of lung sections with grade II or III emphysema. Sources Hammond, et al. (104). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18, 19, 20, 21, 22, 179, 180, 199, 200, 201, 202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar to those observed after cigarette smoke inhalation. The bronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory units. 162 Similar experiments in dogs showed that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment with atropine. As a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Most recently, Aviado and his colleagues (20, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as well as to partial tracheal ligation. In 10 rats exposed to cigarette smoke twice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted, Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when compared with animals who underwent only tracheal ligation. STUDIES IN HUMANS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- plianee. Chapman (48) also observed decreases in pulmonary dif- fusing capacity and arterial O. tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (131) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 5 normal young males. Prior smoking of a cigarette in the subject’s normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and Williams (9) studied the acute effect of cigarette smoke inhalation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly liable to these changes. 163 Finally, Robertson, et al. (194) studied the effect of unfiltered © and filtered cigarette smoke and cigar smoke upon bronchial] re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing che retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers, STUDIES CONCERNING PULMONARY CLEARANCE Overall Clearance The ability of the lung to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in table A13. LaBelle, et al. (145) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (2) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (125) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial clear- ance times of 9 nonsmokers and 14 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to sulfur dioxide or cigarette smoke. ~ Ciliary Function Numerous experiments have shown that cigarette smoke or cer- tain constituents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium in vivo and in vitro in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 164 Ciliary activity has been shown to be affected by particulate matter as well as by the gas phase components of cigarette smoke. The rel- ative importance of these two large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 64) consider the particulate phase to be of greater importance while Battista and Kensler (28, 29) con- clude that gas phase components are more important in the induc- tion of ciliastasis. Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (734) studied the effect of the direct exposure of cigarette smoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be toxic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. , Phagocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and Masin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells, and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit alveolar macro- phages to clear cultures of S. aureus. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. bovis to cigar- ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly re- versible and was due mainly to gas phase components, Myrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO. Roque and Pickren (195) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers, They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activity was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought to 165 99L TABLE 11.—Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function A. Method ? B. Material 1 C. Duration of smoking Results Comments A. Pulmonary function. B. 3 cigarettes. C. 30 minutes, Vital capacity (VC) T. 10/91 decrease. I. No significant change. Maximal breathing capacity 9/91 patients showed 10/91 decrease. VC increase due to No significant change. clearance of secre- tions, All mild or moderate smokers. Author, year, Number and country, type of reference population Bickerman I. 66 male and and 25 female Barach, patients 1954, with chronic U.S.A. nontuberculous (81). respiratory diseases (average age 50). II. 20 male and 7 female normal sub- jects (average age 20). Eich, I. 31 patients with et al., obstructive 1957, pulinonary U.S.A, emphysema. (76). Il. 14 normal subjects, IIL. 5 patients with respiratory complaints. All habitual smokers. A. Esophageal balloon technique to measure pulmonary compliance and resistance. B. 1 cigarette. C. Undefined. Mean airway resistance I. Statistically significant increase. II. No change. Ill. No change, Mean airway compliance No change. No change. No change, 291 TABLE 11.—Experiments concerning the acute effect of cigarctte smoke inhalation on human pulmonary function (cont.) Author, A. Method 2 year, Number and B. Material * country, type of C, Duration of Results Comments reference population smoking Attinger [. 20 normal A. Esophagal balloon I. No change. No change. etal. subjects technique to measure 1958, (10 Sm, pulmonary compliance U.S.A. 10 NS). and resistance. (18). II. 34 patients with B. 1-4 cigarettes. Ii, Expiratory resistance rose No change. various diseases; C. 10 minute interval significantly only among 9 rheumatic heart between patients with diseases, 8 pul- cigarettes. emphysema. monary emphy- sema, 7 asthma, 5 pulmonary fibrosis, 5 undefined. Motley and 125 males and A. Pulmonary 41 smokers Pulmonary compliance Various groups of Kuzman, 16 females function. (8 normals, normals and cardio- 1958, (24-70 years of B. 2 cigarettes. 33 patients Significant decrease after pulmonary patients U.S.A. age—normals C. Undefined. with cardio- smoking. showed little or no (174). and patients). pulmonary change in arterial disease). pd, during exercise and at rest follow- ing cigarette smoke inhalation. Nade}l and I. 22 patients with A. Body plethy- Airway conductance/thoracie gas volume Nicotine bitartrate Comroe, cardiopulmonary smography. I. 18/22 significant decrease (inhibited by pretreatment aerosol evoked no 1961, disease—all B. 15 puffs. with isoproterenol aerosol), change. U.S.A. smokers. C. 5 minutes. Il. 31/36 significant decrease (inhibited by pretreatment with (176). II, 36 normals (21 isoprotereno] aerosol). smokers, 15 nonsmokers). 89k TABLE 11.—Eaperiments concerning the acute effect of cigaretie smoke inhalation on human pulmonary function (cont.) Author, A. Method 1 year, Number and B. Material? country, type of C, Duration of Results Comments reference population smoking Simonssgon, I. 9 male and 7 A. Pulmonary Mean PEV,, Mean FEV, 4 No significant changes 1962, female normals function. (immediately after) (45 minutes later) observed in FEV/FVC. Sweden, (most smokers). B,. 1-2 cigarettes. I. Significant decrease. No significant decrease. (207), IT. 15 male and 1 C. 5-6 minutes II. Significant decrease. Significant decrease. female pulmonary per cigarette. disease patients (most smokers). Zamel I. 6 male and 6 A. Body plethy- Airway resistance et al., female nonsmokers. smography. I. Significant increase. 1963, II. 6 male and 6 B. 1 cigarette. II. Significant increase, England, female smokers C. Undefined. (240). (18-32 years of age.) Chapman, I, 12 normal A. Pulmonary funetion I. All showed a decrease in diffusing capacity. 1965, volunteers Arterial blood II. 4/6—significant decrease in arterial 04 tension. Treland (all smokers). studies. No change in vital capacity or FEV. (48). II. 6 patients with B. 1 cigarette. chronic non- C. Undefined. specific lung disease. McDermott I, 32 normals. A. Body plethy- Mean airway resistance Light smokers showed and II. 28 with chronic smography, I, Significant increase, greater changes than Collins, bronchitis B. Cigarette. IL. Significant inerease. heavy smokers. 1965, (All ciga- C. Undefined. Wales rette smokers (160), 35-60 years of age.) 691 TABLE 11.—Ewperiments concerning the acute effect of cigarctte smoke inhalation on human pulmonary funetion (cont.) Author, A. Method! year, Number and B. Material + country, type of C, Duration of Results Comments reference population smoking Miller and 10 normal A. Esophageal balloon Dynamic Inapiratory and Sproule, cigarette technique. FEV 4.5 compliance expiratory resistance 1966, smokers B. 1 cigarette. No significant Significant Significant ULS.A. (40 years C. One inhalation change decrease. increase (166). of age). every 30-60 seconds. Sterling, 11 normal] adults A. Body plethy- Airway resistance 1967, (8 smokers, smography. Significant increase (Return England 3 nonsmokers). B. 15 inhalations. to normal in 30 minutes) . (213). Cc. 5 minutes. Chiang and 7 male normal A. Pulmonary function Nitrogen washout Lung clearance Alveolar dilution All lung volumes, Wang, nonsmokers Nitrogen washout. time index factor except for residual 1970, (18-43 years B. 2 cigarettes. Significant Significant Significant volume showed no Formosa of age). C. Undefined. increase. increase. decrease. significant change. (51). No significant change in any of the flow rates. Guyatt 710 subjects; A. Body plethy- Bronchoconstriction On the average, non- et al., 508 smoked smography. Significant increase with smoking. smokers and ex-smokers 1970, between meas- B. 1 cigarette. showed bronchodilation England ures 202 C. Undefined. and smokers showed (100). did not smoke. bronchoconstriction. 1 All the experiments listed concern studies of pulmonary function be- fore and after smoking the epecified number of cigarettes (unless other- wise specified). The authors postulate that the result among nonsmokers is due to the release of adrenal hormones in these sub- jects. ozt TABLE 12.—Eaperiments concerning the effect of cigarette smoke on human and animal pulmonary clearance Author, year, country, Subjects Method Results Comments reference Laurenzi Swiss-Webster Mice exposed to Significant increase in S. aureus retention in mice exposed to: etal, male mice. aerosol of S. aureus (a) hypoxia—retention ratio 2.5 (10 percent 0,4). 1963, and sacrificed at (b) cigarette smoke—retention ratio 4.5. U.S.A. intervals following (149). exposure to various stimuli. LaBelle Albino female Silver iodide or 17-30 hours of exposure to cigarette smoke caused no change in pulmonary etal, rabbits. colloidal gold clearance as compared with controls breathing room air. 1966, intratracheally, U.S.A. (145). Bair and Sprague-Dawley Radivactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic Dilley, female rats, exposure to cigarette smoke (up to 18-20 cigarettes/7 hour day/5 day week 1967, male beagle dogs. Radioactive aerosol. for up to 420 days) had no observable effects. The authors noted, however, U.S.A, that normal clearance rates were too low to reflect anything but complete (28). cessation. 50 percent 90 percent ¢ Approximate values. clearance clearance None of 9 nonsmokers Albert 36 subjects Radioactive tagged Number of — Average time time had 50 percent times etal., undergoing 117 Fe0, particles subjects age (minutes) (minutes) over 200 minutes or 1969, experiments. measured with Nonsmokers ................ 9 28 88 357 90 percent times over U.S.A. Scintillation Allsmokers ...............,. 14 33 172 496 600 minutes while (2). counter. 20-29 cigarettes/day ......... 7 29 191 T6519 6/14 smokers exceeded 30-40 cigarettes/day 7 386 153 474 both these limits. Uranium miners ............. 3 52 310 580 Cigar and pipe smokers ..... 4 46 87 375 Emphysema patients ......... 2 66 330 575 LZL TABLE 12.—Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.) Author, year, country, Subjects Method Results Comments reference Albert Donkeys exposed Radioactive tagged Average Trachael transit Those donkeys exposed et al., to cigarette Fe0, particles number time to the greatest 1969, smoke by nasal measured with cigarettes in Percent clearance Halftime clearance amount of smoke U.S.A. catheter. Scintillation 2-hour period Control Cigarette Control Cigarette Control Cigarette showed residual (3). counter. 18-24 58 69 1.2 1.9 0.6 1.2 impairment of 36 58 64 1.0 3.4 0.4 5.8 clearance for at least 2 months after acute exposure. Holma, Rabbits Cr*t monodisperse Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 puffs/8 minutes) caused 1969, (anesthetized). polystyrene a “significant” increase in lung retention 10 minutes following cessation of U.S.A. aerosol. exposure. (125). originate in tobaceo smoke. The authors suggested that the tobaeeo smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et aj, (187) observed that the macrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af. fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phospholipids and mucopolysaccharides which are present in the alveolar lining. Norma] pulmonary fune- tion is influenced and partly determined by the integrity of this system (203). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated, Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table Al4. Exposure of rat and dog lung extracts to cigarette smoke has been found to induce a notable decrease in the maxima] surface tension demonstrated by the extracts (94, 165, 224). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) in a recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTHER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonary disease. Table A15 presents a summary of these studies. Lowe (157) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbell (43) in a similar study found that the difference was not present when the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (108, 181, 183) have reported increased 172 sates of respiratory illnesses among smokers. Finklea, et al. (838) studied a male college population (prospectively) during the 1968-69 influenza epidemic. They found that smokers of all amounts xxperienced more clinical illness than did nonsmokers and that this -elation was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (220), involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. Male cigarette smokers reported 22 percent more eases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211). Mice were challenged with Klebsiella pneumoniae or Diplococcus pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke exhibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortality, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (75). These investigators exposed squirrel monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klebsiella pneumoniae as demon- strated by increased mortality and reduced lung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p.m. was fatal to all monkeys within three days. Infected controls showed symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibility to respiratory disease noted in smokers is presently undefined. 173 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera. tive pulmonary complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop bron. chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table A16). Wiklander and Norlin (229) examined the incidence of post. operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary compli. cations would be at their maximum. These authors found no sig- nificant differences between the frequency of complications jn smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported, Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total] sample, 66.7 percent developed pulmonary complications during the first postoperative week, All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers, When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for up to four days preoperatively had no apparent effect on the incidence of complications, Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter’s use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (172) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers, Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, per- sisting into the second postoperative day (table A17). 174 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUMMARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- 75