the nonsmoking controls. So relationship of this increased preya- lence could be demonstrated to ;LIr)hfl,-antitr?-psin defcienc>- (.we below). In addition, nonsmoking reIati\.es and -;nroking controls were observed to sho\v approsimntely the same pre\.:llence of :tb- normalities. However. due to the large proportion of females in the nonsmoking relative group and to the clustering of tuo-thirds of the affected relatives in 10 families, firm conclusions cannot nt present be dralvn from this study concerning the relative contribu- tions of smoking and of heredity to the pathogenesis of COPD. In order to determine the relative significance of smoking and heredity in the pathogenesis of COPD, Cederlof, et al. (;;s, ;c) have used the twin-study methods on registries in both Sweden and the USA. The specific details of this method are described in the sec- tion on Coronary Heart Disease. As may be noted from a summary of their work at the end of table A 2, the authors compared the symptom prevalence among monozygotic and dizygotic twins who were both discordant and concordant for smoking habits. The\ observed that the h~~permorbidit~ for COPD symptoms related to smoking persisted even after controlling for zygosity and concluded that a causal relationship of smoking and COPD symptoms iv-as sup- ported. HoLvever, genetic factors were still found to have an appre- ciable influence. Lundmann (1.59) has applied this method to the study of pulmonary function. He studied 37 monozygotic and 62 dizygotic tlvin pairs, measuring forced expiratory voiumes and nitrogen washout gradients, and matched the various pairs for smoking discordancy. He observed that both of these parameters were adverseI>. affected in txvins ivho smoked and that these changes were correlated \vith cigarette consumption. The results are out- lined at the end of table X3. AZr,I~a-,-a,~ti~~.~~sin (X,XT) -Of more recent note and discus- sion has been the discovery of an association between a hereditary predisposition to COPD and the relative or absolute absence of alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78) was the first investigator to observe a relationship between the presence of markedly decreased serum trypsin inhibitory capacity and panlobular emph!-sema. Since Eriksson's paper, much added research has been published concerning many facets of this intrigu- ing area. It appears that X,-XT deficiency is inherited as an autosomal recessive trait (~8, 2IG) although Kueppers (IL') considers the transmission to be by an autosomal codominant allele. It hlis been estimated that up to 5 percent of the general population may be heterozygous for this gene (1.51) although full cross-sectional studies of the population remain to be done. Homozygous or severe deficiency of this enzyme has been asso- 176 ciated with a particular type of pulmonary emphysema. \Vhile the majority of lungs of cmphysematous patients reveal ~UIIOLIS or centrilobular deformities, particularly of the upper lobes, this hereditary disorder reveals a panncinar 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 emphy-sema 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 , "~5, ~6) _ 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 (78 , 216). In family studies, it has been found that almost all the homozygous individuals are symptomatic by the age of -10 and that those ivho are not usually show alterations in pulmonary function studies. Guenter, et al. (38) studied 7 per- sons with homozygous deficiency. Of the five symptomatic individ- uals, .I 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 (I.?;) that the lack of this proteinase in- hibitor in the serum of homozygous patients predisposes them t.o 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, \vithout 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 X,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 dificultv 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 he- cause levels of trypsin inhibitory capacity (TIC) have been shown to rise acutely with infections. Welch, et al. (26) feel that heterozygotes do not show an in- creased susceptibility to COPD. The heterozygotes tvhich they studied showed symptoms of bronchitis and did not present the 177 lolver lobe perfusion defects frequentI>- noted in homozygotes. The>- also fo~~nd no difference in the number of COPD patients among the heterozygotic and the gtner:\l population. Other inve~iiigators, no- tably Lieberman, et al. (I.,;, I.;.;), Rueppers, et al. ( IAL), and L;irson, et al. (I.;$) found significantly increased percentaF;es of COPD patients among those lvith heterozpgous deficiency as com- pared with the general population. Lieberman, et al. (~55) ob- served that the percentage of heterozygdtes among a group of healthy industrial xvorkers was 1.7 percent while that among a group of patients with emphysema was 18.1 percent. In a recent re\,iew, Falk and Briscoe (79) considered that the available evi- dence points to an increased prevalence of COPD among hetero- zygotes. Of more central interest to this discussion, however, is the pos- sible relationship of smoking to the predisposition of disease among the heterozygote population. Kueppers, et al. (IL-$) studied three populations: younger controls, older controls, and a group of COPD patients. They observed that of the 25 heterozygotes with COPD, only 2 \vere 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 \vh.at 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 m 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 A& A number of studies did not show an association among air pol- lution, respiratory symptoms, and pulmonary dysfunction (81,205). More recent studies which evaluated the factors of smoking, social class, and air pollution separately noted a greater prevalence of 178 COPD symptoms, pulmonary ds,sfunction, and COPD mortality in areas of high pollution (21, 122, l;li, 2,;s). Lambert and Reid (146) observed that in the absence of cigarette smoking the corre- lation bet\\-een 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 Wealth 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." Exposure to various dusty occupational environments has been shown in many studies to be associated with the development of various forms of nonneopiastic lung disease. Lowe (158)) 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 Jvorkers, he observed that the relationship betrveen mean dust exposure levels and COPD prevalence was much stronger among smokers than among nonsmokers. Alore 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?. Act; ditional compounds, not listed in the table, but which also appear to be related to COPD, are chlorine ($9) and washing powder dust (!?7), 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 etioIogic factor in COPD. 179 Cad,,zilc,)r-CC:hl.onic industrial esposure to cadmium in man has been found to induce pulmonary emphysema without significant accompanying chronic bronchitis (32, 35, 210) Nandi, et al. (177) recently investigated the contribution of the cadmium in cigarette smoke to the pathogenesis of emphysema. Analyzing \I-hole cigarettes, ash. and filters, the>- found that an average of 69 percent of the cadmium present in the cigarette (ap- proximately 16 microgram5 20 cigarettes) is inhaled in the smoke. In a related study (2.53). 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. PXTHOI~OGIC~I~ STUDIES The relationship betn-een smoking habits and pathological changes in the bronchial tree and pulmonary parenchpma has been investigated by se\-era1 groups of lvorkers. Xetaplastic 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 parenchgmal 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. (;, 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 centrilohular emphysema, 98 percent \vere smokers. Xore 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. 180 hlcgnhed 50 male patients Mucous eland hupcrlrophu et II.. with chronic Pcrcm& 1967. bronchitis under- NS . . . . . . . . . . . ..~........ PO Egypt (2/7) goinK bronchial ShI . ,. ,, .I., ., I 77 (33/431 (P40 cigarcltn/day (66) . . 1.3 1.4 31.6 45.3 20.6 ' Numerourr experiments dttailing changes in bronchial epithelium ore dctoilcd tnbulnrly in the Cnnccr chapter. ESPERI.\IESTXL STCDIES Xsrsrx~ STUDIES A number of investigators have studied the effect of the inhala- tion of cigarette smoke on the macroscopic and microscopic str-uc- ture of the tracheobronchial tree and Pulmonary parench>.ma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table Xl6 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 vvith COPD, i.e., bronchitis, parenchymai disruption, alveolar septal rupture, alveolar space dilatation, and the loss of cilia and ciliated celIs 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 \vho inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyma lvith 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 120 days or more of esposure, the num'ber 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. 3Iitotic 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 87.5 days, or approxi- mately 29 months. The animals which died during the experiment and the animals sacrificed after day 875 \vere examined for Pul- monar3' psrenchymal 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. 184 IOO- --__- 91.7 a0 - 20 - 17.9 I.- 57 0 00 GROUP N: GROUP f: GROUP L: GROlJP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% 25 many clpretter) as Gro"D H 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 hyperplnsia 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. 187 GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (`A as many cigaretb) a* Group H FIGURE Z.-Percent of lur:g 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 t,o those observed after cigarette smoke inhalation. The hronchoconstriction 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. 188 Similar experiments in dogs shelved that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment ivith atropine. Xs a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Nest recently, Xviado and his colleagues (00, 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 we11 as to partial tracheal ligation. In 10 rats exposed to cigarette smoke tlvice 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 c\ompared with animals who underwent only tracheal ligation. STUDIES IN I-TUhIhNS 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 (&8) also observed decreases in pulmonary dif- fusing capacity and arterial 0, 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 1ViIliams (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. 189 Finally, Robertson, et a1. (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 the 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 CONCEKNING PULMONARY CLWRANCE Owercdl Gkarance The ability of the lqng 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 tabIe 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. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (185) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial ciear- ante 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 suIfur dioxide or cigarette smoke. 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. 190 CiliarY acti\`it?: has been shown to be affected bp particulate matter as me]] a.~ by the gas phase components of cigarette smoke. The re]- ative importance of these tno large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 6J) consider the particulate phase to be of greater importance while Battista and Kensler (~8, 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 (1.31) studied the effect of the direct exposure of cigarette sinoke 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 tosic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. Phayocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and hlasin (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 a]veo]ar macro- phages to clear cultures of S. au?-eels. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. botiis 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 rc- versible and was due mainly to gas phase components. LMyrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO,. Roque and Pickren (19.5) 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 activit? was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought to 191 rcfcrrn-ci pop;lallon smoking Blckerman I. 66 mslc and A. Pulmonary and 26 Icmale function. Reaultd Commentd Vi&d ctlmcib (VC) I. lo/91 dccrcaae. Maximal brcafhing capacity 9/91 patient8 showed lo/e1 dccreaae. VC LIICTPLWC due to BBnzh, paLlent B. 3 cigarettes. II. No aignlficant change. No aign(flcnnt change. ClebrlnCC of apcrc- 1954. with chronic C. 30 minutes. liona. All mild cr U.S.A. nontubcrculous mdcratr enwkcra. (11). rCSpira\OV di3eam (avernge ego 601. II. 20 male snd 7 female normsl aub- jecta (average age20). Elcb. I. 31 patients with A. Esophrgwl bslloon Mc4.n uiru,ay rcriatawc Mean airwov compliancs ct al.. obxtrucllvc twhnisuc to 1. Stntiatlcolly ai~nincant No chsngc. 1917, Pllllnlmnry m~1p~s11rc Dulmonnry InCrNL?IP. U.S.A. eml'hyncma. com~~llnt~rc nnd II. No chnnuc. No change. (76). ll. 14 normul rusiatnncc. III. No chsngr. No change. subjwtd. 8. 1 cigarrttc. III. 6 patients with C. Undcfind. respiratory cumplainls. All habitual smokcn. -- Chupmon, I. 12 normal A. Pulmonarv function 1. All showed P dccrcnse In diRtwing ca~acily. lDGS, volunteer. Artcriul blood II. 4/b--aiynlficont dccrrnac in artcrinl O1 tcl~sl00. Ireland (nil smokera). atudiea. No change in vilnl cnpacily or FEV. (48,. 11. 6 pnticnla with B. I ciulrctre. chronic non- C. Undelirrcd. apccilic lung dieeaae. McDermott I. 32 normnle. A. Body Dlcthy. Afcon oirwav rcairtatwc Light amokcra ahowcd nnd II. 28 with chronic smosrnl,hy. I. Siu~iflcnnt incrcnac. prrnter chnrlu~n 1hnn COlliM. bronchitis B. Cigercttc. II. Sigoificnnt lncresse. hc.vy amokrrd. 1966. (All ciyn- C. Undefined. WDler rctte smokera (160). 3560 years of ace.) Author. A. hlcthod ' year. Number and ,3. Mnlcrinl J country. type or C. Durnliun of Result-4 COlll~Clila rcIcrmu! Dopulation emuking Miller and 10 normal A. Eaovhsuenl bnllwn DUWl77tic Inapimtory at-d Suroule, cignrcttt tcchniaue. FEVo 6 compliance cxyiratorv rcaiatanec 1966. smokcn l3. 1 cigarette. No signiicant Significant Significant U.S.A. (40 yeara C. One inhnlntion chnnge dccrcnae. increuse (166). al age). evcrY 30-60 seconds. Sterling, 11 "ormal adulta A. Body plethy- Airway rceidtance 1067, (8 smokers, smouaphy. Significant increase (Return England 3 nonsmokers). B. 16 inhalationa. to nom-al in 30 minutes). (113). C. 6 minutes. Cbiang and 7 male normal WanK. nonsmokers 1970, (c-48 yeat FWlTl03a of rae). (61). A. Pulmonary function Nitrogetr wnahout Nitrogen washout. time B. 2 cigarettes. Significant c. Undefined. iricrease. Guyatt 710 nubjecb: A. Ilodr plethy- et al., 608 smoked amograDhu. 1910. betwe?" mens- B. 1 cigarette. Englnnd urm 202 `2, Undefined. (100). did not smoke. w `All the exucriments listed concern studies of pulmonnry function b+ z iore and after smoking the epecifled number of cigarettee (unless otber- wise soeeifLd). Author. YCLI. cuunlry, rclcrcnee Subjccta Method LaUrCnXl Swiss-Webster Xlicc exposed to Significnnt incrcjbsc in S. ourcu8 rctcntion in mice cxp+8c%l to: CL nl., male mice. nermul of s. DurcuI (n) hyrruxin-retention ratio 2.5 (IO prrccnt 02). 196% and ancrificcd at (b) cignrcttc smuhc-rctintion riilio 4.5. U.S.A. Intcrvnla following (149). CXwrure 10 vilrious stimuli. LSDCIIC Albino female Silver idideor 17-30 hours uf cx~~wrc to cirrnrvttc amukc caused no change In pulmunnr/ et al.. mbbib. colloidnl gold elenrnnce ns cumjlnrcyl with controlr breathing room air. 1966. intrntrachellly. U.S.A. (1151. Bair and SpraaudJhwlw Radioactive aer&. Acute cxposurc to cignrctte smoke hnd no proo, oflect on clenrance. Chronic Dillcy. frmale rata, erl>orurc tu ciplrrctte rmukc cut) to l&20 cigarettes/7 hour day/6 dnu wwk L967. mule beogle dep. Radioactive aerwol. for "1, to 420 doye) hod no ubscrvnblc rllcctr. The authors noted, however, U.S.A. thnt normnl clrnrance rntcx were too low to rcflcct anything but complete (05). cerse.tion. so pcrcmt 90 pcrcrnt t ADproximntc villuc3. clcaronce CICOIUIICe None of `I nonamokcrs Albert 3G subjecta Radlonctive tagged Number oj "lvcraoc time time hnd GO pc~ccnl time-a et al.. undergoing 117 FeOZ particles subjcctr aoe (minulcr) (mixuterI over 200 minu(cY or 1969. uperimcnts. mensured with Nonsmekerr . 0 28 88 367 90 p~,rcmL limes over U.S.A. Scintillation All smokers ,. ,. . , , . 14 33 172 1406 600 ntinuta while (2). counter. `X+20 cigarettcs/dny ..,,,... 7 23 191 t519 6/14 am,>kws cxcwlcd 30-40 cisorettes/day ,.._,.,.. 7 36 163 1474 both thcsc limits. Uranium miners ,. 3 62 310 b80 Cigar nnd ~ipc smokrra ,..... 4 46 07 3'76 Emphywmu patients . . 2 66 330 G7G TAEZLE le.--E'zperinamts concerning the effect of cigarette smoke on human and animal pulmona~ clearance (cont.) Author. Y-r, CO""tl-7, rcfcrence Subjects MOtbOd nesuita COnlml?ntn Albert Donkey8 exwsed Radioactive tagged AVWQ7C Tmchoel franail Thmc donkeys CxDoacd et al., to CiKF,Rtte FcOz particles number lime to the KrCnl`-Bt 1969. smoke by nasnl measured wilb cigarcllca in Percent clcara?lcc Ilaltlime clmrance emount of smukc U.S.A. catheter. Scintillation z-hour period COnlrOl CiQ~rclle Cotllrol Cioarclle Conlrd Cigartile showed rczidunl (3). CO"nter. 1n-24 5.3 GO 1.2 1.9 0.G I.? Impnirmrnt of 3c 5R 64 1.0 3.4 04 6.8 clrsrnnrc fur nt h.nt 2 month3 afkr ucuk CXpW"rC. Helms. Rabbits ' CP' monodisperse Ihmsurc tu Irrsh ciaurct~c smoke (1.6 cc. nulTr, 40 puiTsl8 minxten) caured 1069, (nncsthctlrcd). PolYstYrcne n "sianificnnt" increnrc in lung retention 10 minutes followinK cessation of U.S.A. aer0301. eX,lOS"rC. (IIS). 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 mncrophages 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 phosphoiipids and mucopolysaccharides which are present in the alveolar lining. Normal pulmonary func- tion is influenced and partly determined by the integrity of this system (103). 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 Iung extracts to cigarette smoke has been found to induce a notable decrease in the maximal 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. OTNER 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 (4s) 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 (1U8,181,183) have reported increased 198 rates of respiratory illnesses among smokers. Finklea, et al. (8~) studied a male college population (prospectively) during the 1!XS-F9 influenza epidemic. They found that smokers of ail amounts experienced more clinical illness than did nonsmokers and that this r&tion was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (290)) 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. MaIe 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 tihallenged with h'lcbsiclla pneumoniae or Di$ococcw pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke eshibited 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 mortaiity, 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 sWirr& 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 Klcbsiellu 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 shoxved 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- ceptibiljty to respiratory disease noted in smokers is presently undefined. 199 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera- tive PUhonarY 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 hron- 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 (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 CtabIe A17) -. 200