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, 21.1). It is estimated that between 1 and 2 percent of patients with COPD have this homozygous deficiency (7'8, 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. (!18) studied `7 per- sons with homozygous deficiency. Of the five symptomatic individ- uals, 4 smoked and all 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 (15:) 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. (126) feel that heterozygotes do not show an in- creased susceptibility to COPD. The hetelozygotes 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. (IS.;, 15S), Kueppers, et al. (244), and Larson, et al. (118) found significantly increased percentages of COPD patients among those with heterozygous deficiency as corn-- pared with the general population. Lieberman, et al. (155) ob- served that the percentage of heterozygotes among a group of healthy industrial workers was 4.7 percent while that among a group of patients with emphysema was 18.1 percent. In a recent review, Falk and Briscoe (7.9) 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 geographica! 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 (81,20.4). 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, I-71, ISG, 1.1.:). 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 Xd- 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 (1.78)) 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 \vere 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 wxs 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 A?`. 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 CadlTzium--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 fibers, 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 (Z&3), 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- bath, 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 TABLE 8.-Stltdies concerning the relation of human pulmonary histology and smoking' (Actual number of deaths shown in parentheses) SM = Smokers. NS = Nonsmokers Author. Year, country, Nwnne",pd Results reference population Chang, 62 males and 43 Distentia of goblet rrlls (hy percent of smoking group) 1957, females autopsied w of U.S.A., within 5 hours of NOW Ft?W `h of surfarc RWjIICC Korea death (no data NS(22) 13.6 22.7 31.8 22.7 (47). available on case SM(49) 12.2 10.2 10.2 1x.4 selection) comments Most of surface 9.1 26.5 The auth6rs also noted that smokers' lungs Whole mL7face showed shorter cilia and thicker epithelium 22.5 (20 percent nonsmokers and 36 percent smokers had respiratory disease.) Ide et al.. 93 males autopsied Mean thickness of tracheal and Meax cilinry height in tmchca No cigar or pipe 1959, within 6 hours of bronchial epithclium (a) in and bronchus on cigarette smokers were included. U.S.A. death. No cases cigarette smokers and nonsmokers .smolcw~ and nonsmokers (129). of pneumonia Trachea IIronchas TTlXhCa nronchlu or lung disease NS(23) 52.x 47.7 (23) 6.39 5.95 included. Light(31) 62.0 57.5 (29) 5.62 5.49 HeavY(l0) 66.2 61.9 (10) 4.89 4.66 Auerbach 654 males over Age-standardizrd pcrcentnge distribution of subject8 The authors also noted s et al., 60 years of r&w? acrordiwg to dcwrcr of 71LptuTv of the alvcolur septum8 dose-reponse relation- 1963. nutopnied at Dcyrcc oj TUptlCrC o-0.25 0.5-0.75 1.0-1.25 1.5-1.75 2.0-2.25 "7.5-3.00 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 .4 5.1 16.2 39.2 39:; tN one had ever smoked tc urrent cigar 24.6 45.4 26.2 3.8 cigar&n regularly. tc . urrent pipe 5.4 23.0 53.5 15.9 2.2 Current pipe, cigar 4x 1.6 46.5 33.6 7.5 .~ TABLE L-Studies conceming the dation of humun pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM z Smokers. NS = Nonsmokers - ___- -__. Author, yenr, Number and cou"trY. type of Results Comments reference pop"lntion _.~ __ ~ .-- _- _~~__ -.__- -~- -._- Anderson 39 malts and Swcrity of emphysema (mean deg+ee) The a"thors also noted that: et al., 32 fe1nales M&8 Ft.W&8 Every person showing se- 1964, (Caucasians) NS(4) .._....._.,.............._ 1.5 3 (not sip"ifiea"t) (20) 1.0 (12) 1.9 tp40 cigarettes/day . . . . . . . . . 2.3 Megahed 60 male patients Mucous okmad hypertrophy et al., with chronic Percent 1967. bronchitis under- NS . . . . . . 29 (2/7) Egypt going bronchial SY . . . . . . 77 (33/43) (P10 cigarettes/day (66) _, 1.3 1.4 31.5 45.3 I Nume~~~us eh caeriments. detailing rhangcs iu bronchial epithelium are dctnilcd t~bul~~rl~ in tha C:~ncr~~ ohnrltvr 2.0s 4.4 X.1 20.5 __- EXPERIMENTAL STUDIES ANIMAL STUDIES A number of investigators have studied the effect of the inha]a- tion of cigarette smoke on the macroscopic and microscopic strut- ture of the tracheobronchial tree and pulmonary parenchyma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table Al6 of the cancer chap- ter. Studies more directly concerned with the pathology of COpD are listed in table 9. They show that cigarette smoke exposure is associated with changes similar to those found in humans with COPD, i.e., bronchitis, parenchymal disruption, alveolar septal 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 8'75 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 TARLE 9.-Experiments concerning the effect of the inhalation of cigarette smoke ?Lpon the tmchco-bronchial tree and pulmonary parenchyma of animals' (Actual number of animals shown in parentheses) Author, A. Type of Yes=. country, A::Y exposure B. Duration Results reference strain C. Material Leuchten~ 603 CF1 A. Inhalation. berger, female mice. B. Up to 8 ciga- Number et al., 1960, U.S.A. (1.w). r&es/day for "Pto2yeaI-s. C. Cigarette smoke. Number of mica showing specified chnngca Number Months c?zposu+e 0 l-3 4-R 9-23 l-23 Of of NO Mild cigarettes mice ehangr bronchitis 0 150 146 2 10&200 36 20 9 260-600 36 19 10 600-1600 34 19 7 25-1526 151 xx 33 Severe bronchitis with atyptin 2 (no atypism) 7 7 8 30 Holland et al.. 1963, (121). 60 rabbits. A. Inhalation. R. Up to 20 ciga- rettes/day for 2-5. C. "Normal ciga- rette smoke". N0tTld Controls Exposed Cytology of tmchcobrouchial murosa Focal hypcrplnaia (30)21/30 6/30 (30) 7/30 10130 Gcnerdired hyyerplaaia 3/30 I)/30 Hernander Adult Grey- A. Inhalation. et al.. hound B. Twice daily/ I!lf,f, doas. 5 per week. U.S.A. C. Cigarette (111). smoke. Number of sections I. Controls (8)112 II. All exposed (15) 205 III. Exposed l year CR)107 Mm )s number of mo,zths 10.50 4.60 14.74 Mmn pnrrnchymal Groups disruption/dog W?IlpilTHl P-U&O O.il.50 I-111 insignificnnt 0.!)58:1 II-I insignificant 0.6421 III-IV P <0.05 I.2350 IV-I P <0.02 TABLE 9.--Experiments concerning the effect of the inhalation of ciga,rctte smoke U~O?L tltc tmcheo-l~roncl~ial twc and pulmonary parcncll,z/ttia of animals' (cont.) (Actual number of nnimnls shown in parentheses) huerbach et al.. 1967, U.S.A. (f&16). Results ~- Beagle dogs. A. Active inhalation Controls (lo)-No evidence of pulmonnrv fibrosis or s&al rupture. via tracheostomy. Exposed (lo)-Early (sacrificed) : B. Up to 12 cigRrcttes 1. Alveolar space dilatarion. per day for up 2. I'ad-like attachments to alveolar septa. to 423 days. Medium czpo.wm: Septal wall thickening. C. Cigarette smoke. Latest crposarc: 1. Focal subpleuriil pulmonary fibrosis. 2. Ruptured alveolar septa. 3. Granrtlomata. FrWX& et al.. 1968. U.S.A. (88). Beagle dogs. A, Active inhalation Electron microscopic results: via tracheostomy. After 44 days - Increased number of goblet cells. B. Up to 12 ciaarettes Decreased number of cilia on surface lining cells. per dny for "P After 420 dsys- Increased number of epithelial cell layers. to 423 days. Loss of ciliated columnnr cells. C. Cigarette smoke. Frequent interruptions in basement membrane. lNumerous experiments detailing changes in bronchial epithelium aredetailed tabularly in the Cancer Chapter 80 - 20 12.9 5.7 '. 0 GROUP N: GROUP F: GROUP L: GROUP Ii: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% as many cigmttes) as Group H FIGURE l.-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 AlO. 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, 1.97) 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 hydi*oxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 161 98.6 80 - 60 - 24.3 GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (% ss msny cigarettes) ss Group H FIGURE 2.-Percent of lung sections with grade II or III emphysema. SOURCES Hammond, et al. (10.4). 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 (18,1g, 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- pliance. 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 (1.~1) 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 inhaIation 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 he 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 Overa. Clecirance 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. (115) 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. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (125) obtained similar results in rabbits. In a relat.ed study, Albert, et al. (2) studied the bronchial clear- ance times of 9 nonsmokers and 13 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. . . . Numerous experiments have shown that cigarette smoke or cer- tain constit.uents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium it/ ~`i?*o and it) ~it,,o 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 matte1 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, 61) 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 (131) 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. Phugocytosis 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. a?ATeus. 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 t.o 165 TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function Author, Y-u-, country. reference Bickerman and Barach, 1954, U.S.A. (31). Number and type of A. Method = B. Material 1 C. Duration of RemIta population I. 66 male and 25 female patients with chronic nontuberculous respiratory disenws ( swrage age 50). II. 20 male and 7 female normal suh- jects (average age20). smoking A. Pulmonary function. B. 3 cigarettes. C. 30 minutes. Vital capacity ( VC) I. lo/91 decrease. II. No significant change. Ma&nd breathing capacity B/91 patients showed IO/91 deerease. VC incresse due to No significant change. clearance of secre- tions. All mild or moderate smokers. Eich, et al.. 1957. U.S.A. (76). I. 31 patients with obstructive PUb~OIWY emphysema. II. 14 normal subjects. III. 6 patients with respiratory complaints. All habitual smokers. A. Esophageal balloon technique to mecL9ure pulmonary compliance and resistance. B. 1 cigarette. C. Undefined. Mean airway resistance I. Statiaticslly significant increase. II. No change. III. No change. Mean aimmu compIiance No change. No change. No change. TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulnaonam function (cont.) Author, Ye*=, cou"trY, reference Attinger et al., 1958, U.S.A. (19). Number and type of population I. 20 normal subjects (10 Sm. 10NS). II. 34 patients with various diseases; 9 rheumatic heart diseases, 8 pul- mOn*rY mlPhY- sema, 7 asthma, 5 pulmo"aly fibrosis, 5 undefined. A. Method 1 B. Material 1 C. Duration of smoking A. Esophagal balloon I. No change. Ftesulta CO"l"E"ts No change. technique to meas"re pulmonsry compliance and resistance. B. l-4 cigarettes. II. Expiratory resistance rose No change. C. 10 minute interval signiticantly only among between patients with cigarettes. emphysema. Motley and 125 males and A. Pulmonary 41 smokers Pulmomrg~ compliance Various groups of KUZ"l*", 16 females function. (8 "ornlals, normals and cardio- 1968. (24-70 years of I%. 2 cigarettes. 33 patients Significant decrease after pulmonary patients U.S.A. age-"ormals C Undefined. with cardio- smoking. showed little or no (f74). and patients). pUl"lO"*lY change in arterial disease). p02 during exercise and at rest follow- ing cigarette smoke inhalation. .-. Nadel and I. 22 patients with A. Body plethy- Airwev cmdvctance/thoracic gas vdumC Nicotine hitsrtrate CO"VO& cardiopulmonary smography. I. 18/22 significant decrease (inhibited by pretreatment aerosol evoked no 1961, disease--all B. 15puffs. with isoproterenol aerosol). change. U.S.A. smokers. C. 5 minutes. II. 31/36 significant decrease (inhibited by pretreatment with (176). II. 36 normals (21 isopmtercnol aerosol). smokers, 16 nonsmokers). Author, war, countlY, reference Number and type of population A. Method 1 B. Material ' C D;a&a$";gof - -.. Results Comments Sim""ss"", 1962, Sweden. (207). Zll"ld et al., 1963. England, (240). I. 9 male and 7 female normals (most smokers). II. 15 male nnd 1 female pulmonary disease patients (most smokers). ~ I. 6 male and G female nonsmokers. II. 6 male and 6 female smokers (18-32 years of age.) A. Pulmonary function. B. l-2 cigarettes. C 5-6 minutes PCP cigarette. MmnFEVl o (immediately ejtcr) I. Significant decrease. II. Significant decrease. McanFEVl o (45 minutes letcr) No significant decrease. Significant decrcnse. No siunifirnnt changes ohserved in FEV/FVC. A. Body plethy- smography. B. 1 cigarette. C. Undefined. Airway resistance I. Significant increase. II. Significant increase. 1965. Ireland (48). __- McDermott and Collins, 1965, Wales (160). I. 12 normal v"lu"teers (all smokem). 11. G patients with chronic "on- specific lung disease. I. 32 normals. II. 2X with chronic bronchitis (All ciga- rette smokers 35-GO years of age.) A. Pulmonary function Arterial blood studies. B. 1 cigarette. C. Undetined. I. All showed a decrease in diffusing capacity. II. 4/6-significant decrease in arterial O2 tension. No change in vital capacity or FEV. A. Body plethy- smography. B. Cigarette. C. Undefined. Mean airway resiatancc Light smokers showed I. Significant increase. greater changes than II. Significant increase. heavy smokers. Miller and 10 normal SProule, cigarette 1966, smokers U.S.A. (40 years (1GG). ofage). A. Esophaeeal ballwn technique. B. 1 cigarette. C. One inhalation Pc3-Y ao-FO seconds. FEvo.5 No significant change Dynamic compliance Significant decrease. Inspiretory and erp,iratory rceistmca Significant increase Sterling. 11 normal adults 1967. (E smnkers, England 3 nonsmokers) (219). Chiang and 7 male normal W*nEC. nonsmokers 1970. (L-43 years Formosa of age). (51). A. Body plethy- smography. B. 15 inhalations. C. 5 minutes. Airway rcsiatancc Significant increase (Return to normal in 30 minutes). A. Pulmonary function Nitrogetr roaskcwt L1my clcnrancc Aleeolar dilution All luna volumes, Nitrogen washout. B. 2 cigarettes. C. Undefined. tima Significant increase. A. Body plethy- smography. B. 1 cigarette. C. Undefined. Guvatt 110 subjects; et al.. 50X smoked 1970. between meas- England ures 202 (lml). did not fimoke. - ' All the experiments listed concern studies of sulmonary function be- fore and after smoking the epecified number of cigarettes (unless other- wise specified). illll,.L! Significnnt increase. factor excrpt for residual Significant \-olumr showed no decrense. significant change. No significant change in any of the flow rates. Brunckoconstrictio?~ On the avernge. non- Significant increase with smoking. smokers and es-smokers sh<,wed tnonchodilation and nm<,kers showed I,~~rnch~~constriction. Thr authors postulate that the result among nonsmokers is due to the> rclcnsc of ndrenal hoymonrs in these sub- pxts. ~-_- __ TABLE 12.--Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance Author, Yea=. countru, reference Subjects Method RBUkS Comments Laurenzi Swiss-Webster Mice exposed to Significant increase in S. aureu8 retention in mice expceed to: et al.. male mice. aerosol of s. au7euuB (a) hypoxia-retention ratio 2.5 (10 percent Oa). 1963, and sacrificed at (b) cigarette smoke-retention ratio 4.5. U.S.A. intervals following (149). exposure to various stimuli. LaBelle et al.. 1966, U.S.A. (145). Albino female rabbits. Silver iodide or colloidal gold intratrachesllu. 17-30 hours of exposure to cigarette smoke caused no change in pulmonary clearance as compared with controls breathing room air. Bair and Sprague-Dawley Radioactive 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/? 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 (2.9). cessation. Albert et al., 1969. U.S.A. (9). -- 36 subjects undergoing 117 experiments. so perct?nt 90 percent t Approximate values. clearance clearance None of 9 nonsmokers Radioactive tagged Number of Average time time had 60 percent times FeOZ particles eubjects age (minutes) (minutes ) over 200 minutes or measured with Nonsmokers . 9 28 88 367 90 percent times over Scintillation All smokers . . . . . . 14 33 172 t496 600 minutes while counter. 20-29 cigarettes/day . . . . 7 29 191 ts19 6/14 smokers exceeded 30-40 cigarettes/day I 36 163 t414 both these limits. Uranium miners . . 3 62 310 580 Cigar and pipe smokers 4 46 81 316 Emphysema patiats . 2 66 330 676 TABLE 12.-Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.) Author, year. country, reference Subjects Method Results Commenta Albert et al., 1969, U.S.A. (8). Holma, 1969, U.S.A. (125). Donkeys exposed to cigarette smoke by nasal cstheter. Rsdiosetive tagged Average Trachael transit Those donkeys exposed Fe02 particles number time to the greatest measured with cigarettes in Perrent clearance Halftime clearance amount of smoke Scintillation .%hour period Control Cigarsttc Control Cigarette Control Cigarette showed residual counter. 1X-24 58 69 1.2 1.9 0.6 1.2 impairment of 36 58 64 1.0 3.4 0.4 6.8 clearance for et least 2 months after acute exposure. Rabbits (anesthetized). C+* monodisperse Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 nuffs/X minutes) caused polystyrene a "significant" increase in lung retention 10 minutes following cessation of aerosol. exposure. originate in tobacco smoke. The authors suggested that the tobacco 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 al. (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. Normal pulmonary func- 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 A14. Exposure of rat and dog lung extracts to cigarette smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165, 2.24). 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 bronchopulmonar~ disease. Table Al.5 presents a summary of these studies. Lowe (1.57) observed an excess of smokers among `i0.5 tuberculosis patients, but Brown and Campbell (43) in a similar study found that the difference was not present lvhen 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 (lOS,181, 183) have reported increased 172 -ates of respiratory illnesses among smokers. Finklea, et al. (83) studied a male college population (prospectively) during the 1968-69 influenza epidemic. They found that smokers of all amounts experienced more clinical illness than did nonsmokers and that this relation 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 cases 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 Klebsiellu 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. (7'5). 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 bran. 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 in 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 (178) 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- 175