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  (P<O.O2)
(163).    biupsy and
         IRVngL-.


(Actual number of dcnths shown in percnthcser)
  SM = Smokers.    NS = Nonsmokers

Author.
  YCBl.8
country,  Nutr$y;nd                             RLYUll3                                 Conimcnti
reference    populnlion

Auerbach   662 mnles au-                       Deproc 01 tmchcal and brachid arlct-iofw thickcniw
et al.     top&d at Esrt                               .( bv pcroccntq~e of amokcral
1968.     Orange VA                              0.044    as-0.D    1.0-11    1.6-1.9    r.o+
U.S.A.    Hospitnl.     Never smoked (122)  .,,.,I,.,........  46.1      31.3      13.3      1.3      
(IO.              <20 cignretto/dny (120)  , ~.  11.7      22.0      33.6      28.4      4.4
                 20-40 cigarettes/day (284)  . . . . ..~........  6.0      R.6      37.4      40.9      8.1
                >40 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