Sackett, et al. (al) have demonstrated a clear dose-relationship be-
tmeen cigarette smoking and t.he severity of aortic atherosclerosis at
autopsy. Their study of 1,019 consecutive autopsies, on patients who
had been interviewed about their smoking habits prior to death,
showed a significant increase in the severity of aortic atherosclerosis
with increasing use of cigarettes, measured both by intensity and by
duration of smoking.
An autopsy study from Russia by Avtandilov, et al. (3) demon-
strated a significantly greater degree of atherosclerosis in the coronary
arteries of smokers than in those of nonsmokers.
Viel, et al. (aS) h, zve reported on the severity of coronary athero-
sclerosis at autopsy of 1,150 men and 290 women who died violent
deaths in Chile. Information on smoking habits vas available on 566
men. The authors report no relationship between atherosclerotic le-
sions and the use of tobacco. The degree of atherosclerosis was ex-
pressed as the percentage of the surface of the intima of the left
anterior descending coronary artery covered by fatty streaks and
fibrous plaques. An examination of the data presented in graphic
form indicates that the moderate and heavy smokers appear to show
consistently higher percentages of diseased areas than the nonsmokers.
But the statement of the authors implies that t,hese differences were
not statistically significant when subjected to an analysis of variance.
A study by Astrup was reviewed in the 1968 Report (27). This
study showed that in rabbits on a high cholesterol diet, chronic carbon
monoxide exposure has a marked atherogenic effect.
Kjeldsen, et al. (15) compared the vascular patholo,gy in rabbits
fed a high cholesterol diet and maintained iti an hypoxic atmosphere
(10 percent oxygen) with that in rabbits exposed only to the high
cholesterol diet. The authors demonstrated that hypoxia leads to an
increase in the degree of plaque formation in the coronary arteries and
in the amount of visible aortic atheromatosis, as well as to an increase
in the aortic content of cholesterol and triglycerides. In addition, the
hearts of the hypoxic animals showed marked perivascular xantho-
matosis, often infiltrating the surrounding myocardium. In sum-
marizing this experiment and their previous findings of increased
atheromatosis in hypercholesterolemic rabbits subjected to high
carboxyhemoglobin (COH:b) levels, the authors (6) state that tissue
hypoxia seems to be an important factor in initiating these lesions,
regardless of the manner in which the hypoxia is produced. Although
the COHb levels in the rabbits and the degree of hypoxia were much
higher than that experienced by human smokers, these results suggest
a mechanism by which smoking might contribute to atherosclerosis.
Hass, et al. (18)) extending studies reviewed in the 1968 Report
(27)) have demonstrated that the administration of injections of nico-

26


tine to hypercholesterolemic rabbits who are also given vitamin D
enhances the peripheral atheromatous calcific arterial disease which
is produced `by the combination of hypercholesterolemia and vitamin
D administration. The addition of nicotine to the regimen also resulted
in the frequent occurrence of thromboarteritis in the distal calcified
arteries of cardiac and skeletal muscle, and of the smooth muscle of
the gastrointestinal tract. The nicotine effect was reproduced by sub-
stituting appropriate dosages of adrenalin for nicotine and abolished
by adrenalectomy.

Lellouch, et al. (16) h ave reported that the administration of a
mono-amine oxidase (MAO) inhibitor to rabbits on a regimen of
daily nicotine injections significantly reduced the number of animals
who developed fibrotic lesions of the aorta in response to nicotine.
Further work is in progress to elucidate the mechanism of the MAO
effect.

Evidence presented in this and previous reports suggests that ciga-
rette smoking promotes atherosclerosis.

THROMBUS FORMATTON AND BLEND Fnow

Hess, et al. (IS) discovered aggregations of platelets, erythrocytes,
fibrin, detached epithelial cells, and some as yet unidentified cells on
the aortic and carotid walls of rabbits subjected to cigarette smoke.

The discovery of a plasma factor which increases the in vitro syn-
thesis of fibrinogen by human liver biopsies has been reported by
Pilgeram, et al. (20) in older patients who have recovered from myo-
cardial infarction. This factor has been tentatively identified as free
fatty acid (FFA). The authors state that the association between
FFA and fibrinogen synthesis may provide the link between hyper-
lipemia and clotting. Cigarette smoking causes an increase in FFA
through its stimulation of catecholamine release.

Several recent studies have begun to elucidate the role which
changes in blood viscosity and certain features of the microcirculation
might play in the development of atherosclerosis and coronary heart
disease.

Dintenfass (7) has suggested that myocardial infarction and coro-
nary thrombosis may be the result of a number of factors, separate
or interrelated, all leading to a high viscosity of the blood. These
factors may affect the migration and adhesion of platelets, the volume
of plasma, and the rigidity of the red blood cell. Phenomena leading
to high blood viscosity may occur in focal areas leading to occlusion of
small vessels, resultant ischemia, and an infraction of either subclinical
or catastrophic proportions, depending on the location and number
of vessels involved. Dintenfass also believes that an increase in blood


viscosity precedes the clinical manifestations of the high blood vis-
cosity syndrome and that the increased blood viscosity seen in post
myocardial infarct patients is a reflection of the etiology rather than
the effect of the disease.

Local hypoxia leading to an increase in the rigidity of the blood cell
might be produced by cigarette smoking through the increase in
COHb. Platelet adhesiveness is increased by smoking, probably sec-
ondary to the release of catecholamines (97).

In a study of 50 lvhite males with myocardial infarcts and 40 con-
trols, Stables, et al. (9%`) found that the patients with myocardial
infarct had a mean hematocrit level significantly higher than that of
the controls. Studies of blood volume indicated that a reduction in
plasma volume rather than an increase in red cell ,mass among the
myocardial infarct patients accounted for the elevated hematocrit.

CARBON MONOXIDE

Several reviews of the pathophysiology of exposure to carbon mon-
oxide (CO) have appeared recently. These are pertinent to the discus-
sion of the relationship of smoking to health, since cigarette smoke
contains amounts of CO sufficient to cause a COHb level of 5 to 10
percent in the smoker, depending on the amount smoked and degree
of inhalation (9,20).

Bartlett (4) has pointed out that because the absorption of CO from
the ambient environment is dependent upon the concentration of CO
in the environment as contrasted to that in the blood, smokers with a
COD% level of 5 percent will not absorb CO from inspired air unless
the concentration of CO in the air exceeds 30 parts per million. How-
ever, he also states that because the excretion of CO between cigarettes
will be lower in CO polluted air, the smoker will have a higher long-
term average COHb level in a polluted environment. Patients with
heart disease may be particularly susceptible to the hypoxic burden
caused by the presence of COHb.

Goldsmith, et al. (10) have stated that for the U.S. urban popula-
tion, cigarette smoking is probably the most important cause of
increased COHb above the endogenous level produced by heme catabo-
lism, followed by automobile exhaust, occupational sources, and home
heating and cooking devices, in that order.

Although Dinman (6) minimizes the importance of the effect of CO
levels of 5 to 10 percent on the myocardium, he states that a short-
coming in his approach is that focal areas of myocardial ischemia are
not reflected in the determination of oxygen saturation made from
samples of blood taken from the coronary sinus. Such areas of ischemia
might be important in initiating fatal arrhythmias. Levels of COHb

28


which decrease further the oxygen supply to the ischemic myocardium
might be readily provided by cigarette smoking.

Eliot, et al. (8) have reported effects of cigarette smoking on the
oxygen affinity of hemaglobin independent of the presence of CO.
Their results suggest that cigarette smoking may have both acute and
chronic effects on oxygen affinity which differ in direction. The authors
caution, however, that the in viva oxygen affinity of hemoglobin may be
different from that implied by the static equrlibrium data. Further
research is in progress.

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   M., LEHTOSUO, E. J., ALIWBTA, P. Dietary prevention of coronary heart
   disease: Long-term experiment. I. Observations on male subjects. Ameri-
   can Journal of Clinical Sutrition 21(4) : 255-276, April 1968.
S55. VEBESB, L. Bluthilduntersuchungen bei nikotinvergifteten Ratten. Deutsche
   Zeitschrift fiir Gerichtliche Medizin 56(2) : 62-65,1965.
556. VIXTR~, I. B., MANTILLA, G. D., BERNET, C. V., OLLETA, 5% M., SALA, R. C.,
   BODRfGUEZ, R. O., BELTRAN, J. S. Algunos aspectos de las didipemias en
   la cardiopatia coronaria. Medicine Clinica 51(l) : 26-39, July 1%X
S57. VOOEL, J. H. K., JACXIBOWITZ, D., CHIDBEY, C. A. Distribution of nor-
   eqinephrine in the failing bovine heart. Correlation of chemical analysis
   and fluorescence microscopy. Circulation Research 24(l) : 71-84, January
    1969.
S5S. ZIJBB~~AN, B. M. Atopic symptoms caused by tobacco hypersensitivity. South-
   ern Medical Journal 61(11) : 1175-1179, November 1968.


CHAPTER 2

Smoking and Chronic Obstructive
   Bronchopulmonary Disease

Contents

SUmmary----------------------------------------------
ChronicBronchitis----------- ______________________ -_---
Prevalence of Chronic Obstructive Bronchopulmonary Disease-
PulmonaryEmphysema___-------------------------------
Experimental Studies in Man ____________________ -__-_--__
Studiesin Animals-------------------------------- ______
OtherStudies_------------------------------------------
Cited References---------------- _______________ -_-----__
Chronic Obstructive Bronchopulmonary Disease Supplemental

Bibliography-----------------------------------------

Page
37
37
38
38
39
40

42

43

46

35


SMOKING AND CHRONIC OBSTRUCTIVE
  BRONCHOPULMONARY DISEASE

SUMMARY

Additional evidence which supports .the previous judgment of a
cause and effect relationship between cigarette smoking and chronic
obstructive bronchopulmonary diseases, especially chronic obstructive
bronchitis, continues ,to accumulate from both the United States and
abroad. New work has been published in the past year which prov,ides
additional information on the possible mechanisms by which cigarette
smoking can lead to the production of pulmonary emphysema. These
mechanisms include collapse of small airways, changes in pulmonary
surfactant, impairment of pulmonary clearance, disruption of the
normal architecture of the brofichial epithelium, and obstruction of
oapill,aries of the bronchi and alveoli. At present, there is no unified
hypothesis for the pathogenesis of pulmonary emphysema; however,
the pathogenetic mechanisms may involve more than one component
of lung tissue. Epidemiological and laboratory evidence supports the
view that cigarette smoking can contribute to the development of
pulmonary emphysema in man.

CHRONIC BRONCHITIS

Cigarette smoking is the most important cause of chronic bronchitis.
In the past year, studies from various countries have appeared in the
literature reconfirming this association. In studies of populations of
working men in Italy (15), the Netherlands (6)) England (16,35) and
the United States (9), smokers were found to have a significant in-
crease in either incidence or prevalence of chronic bronchitis as com-
pared to the nonsmokers. Studies of populations from rural and urban
Sweden (31) and rural Australia (25) produced similar findings. A
South African study (4.5) d emonstrated decreased forced expiratiry
volumes (FEV,) and peak expiratory flow rates (PEFR) with in-
creased tobacco consumption, even in those who did not have chronic
bronchitis.

37


PREVALANCE OF CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE

The prevalence of chronic obstructive bronchopulmonary disease is
probably underestimated. In a study of death certificates, Moriyama,
et al. (39) have reported that chronic obstructive bronchopulmonary
disease is often omitted as a contributing cause of death. Mitchell,
et al. (38) also found that the disease often goes unreported. Barach,
et al. (5) maintain that much of the reported increase in the preva-
lence of chronic obstructive bronchopulmonary disease can be ac-
counted for by better diagnosis. However, Barach, et al. base their
statement on the supposition that the rising death rates from chronic
obstructive bronchopulmonary disease are incompatible with the fact
that many people are giving up smoking. However, it should be
pointed out that chronic obstructive bronchopulmonary disease asso-
ciated with cigarette smoking may be the result of many years of ex-
posure to cigarette smoke and the mortality rates from bronchitis and
emphysema would not reflect large-scale smoking cessation for some
time to come. Burrows (10) has pointed out t.hat the effects of cessa-
tion of smoking on the course of already existing chronic obstructive
bronchopulmonary disease may be difficult to assess, since it may be
that those who are disabled by severe disease tend to stop smoking
more often than those who have milder forms of the disease. The bene-
ficial effects of cessation of smoking could thus be masked.

PULMONARY EMPHYSEMA

Many agents appear to contribute to the development of emphysema,
but epidemiological and experimental evidence indicates that cigarette
smoking is the most important agent in the development of pulmonary
emphysema in man. Mention of the theories of pathogenesis of pul-
monary emphysema, long the subject of debate among medical scien-
tist.9 (1, 34, 46 47? 48, may help to serve as background for the
presentation of recent research on the role of cigarette smoking in the
development of emphysema.

Two major theories of the pathogenesis of chronic obstructive pul-
monary emphysema have been proposed. One theory states that the
primary lesion of emphysema is vascular and involves obstruction
either by thrombosis or by endarteritis of the pulmonary or bronchial
arterial branches. The resultant loss of nutrient supply is thought
to result in ischemic neeroeis of the alveolar wall and septa. The other
major theory states that chronic obstructive pulmonary emphysema
results from the direct effect of t,oxic inhalants on the pulmona.ry tissue,
in the areas of the terminal bronchioles and alveoli. According to this
theory, changes seen in the pulmonary and bronchial vessels are

30


secondary to the destruction of nonvascular tissue. It may well be that
t.he pathogenesis of pulmonary emphysema can involve several mecha-
nisms and that both of these theories may be applicable but not mutu-
ally exclusive (&) .

EXPERIMENTAL STUDIES IN MAN

Anderson, et al. (2) have reported preliminary results which indi-
cate that cigarette smoking causes acute changes in the ventilation/
perfusion relationships of the lung and that patients with chronic
obstructive bronchopulmonary disease appear to be particularly liable
to these changes. In some patients the changes are predominantly in
perfusion, a finding which lends support to the vascular theory of
pulmonary emphysema. In other patients, the changes are predomi-
nantly in ventilation, a finding which lends support to the theory of
the direct effect of inhalants in the pathogenesis of pulmonary
emphysema.

Anthonisen, et al. (3) investigated pulmonary function in 10 male
smokers with clinically mild chronic bronchitis, all of whom had
smoked cigarettes for at least 20 years. Besides the usual pulmonary
function tests, these investigators employed a technique for the assess-
ment of regional pulmonary function using radioactive xenon. Despite
the fact that overall pulmonary function was nearly normal in several
patients, all had decreased ventilation and depressed ventilation/per-
fusion ratios in some lung regions, with the basal areas being those
most commonly affected. The author suggested that significant dis-
ease in the peripheral airways may exist in patients whose chronic
bronchitis is clinically mild and who show no present impairment of
ventilatory capacity. The radioactive xenon test may reveal severe
compromise of the overall gas exchange when usual studies of ventila-
tory capacity do not reveal impairment. These changes in the distal
airways may become more significant clinically as the patient ages,
since aging has been shown to be associated with a diminution in the
compliance of the lung (29). Peters, et al. (40) have reported that the
lower flow rates found among college students who smoke, especially
at lower lung volumes, may reflect disease in the small airways. The
diminution in flow in these subjects wras ,approximately proportionate
to the total lifetime number of cigarettes smoked.

Fullmer, et al. (.%?? 23, %$) have found a high prevalence of Curseh-
mann's type spirals in the sputum of cigarette smokers. The easily
recognized spirals consist of inspissat.ed mucus and are casts of the
lumens of small bronchioles. These spirals were found in the sputum
of 23 of 24 cigarette-smoking women and in 97 of 100 cigarette-
smoking men. The total number of spirals on four slides prepared for

                                       39
360-9280-694


microscopic examination varied from 0 to 500. Six of 10 ex-smokers
had spirals in their sputum, but the number of spirals was reduced to
ti total of 10 or less on four slides. A nonsmoking control group ex-
posed to cigarette smoke at work showed a low prevalence of spirals,
while a control group of nonsmokers not exposed to cigarette smoke
at work showed no spirals in their sputum. Fullmer has suggested that
Curschmann's spirals may play a role in the development of em-
physema by producing obstruction at the bronchiolar level. The spirals
may also allow prolonged contact between admixed inhalants includ-
ing cigarette smoke and the bronchiolar walls. A study of the presence
of spirals in the sputum of a group of nonsmoking asthmatic bron-
chitics would be useful in an attempt to determine whether the presence
of spirals is a direct result of exposure to cigarette smoke, or is a charac-
teristic of the sputum of bronchitics, whatever the cause of their
bronchitis.

STUDIES IN ANIMALG

Frasca, et al. (17,18) have reported on electron microscopic observa-
tions of the bronchial epithelium of dogs exposed to cigarette smoke
by active inhalation through a tracheostoma. The epithelium of a dog
exposed to 44 days of smoking `by methods previously described by
Cahan, et al. (II) showed a proliferation of goblet cells and a partial
loss of cilia in the surface lining cells. After 420 days of exposure to
cigarette smoke, the number of cell layers in the 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 develop-
ment of chronic obstructive ,bronchopulmonary disease.

Tyler (~$9) and McLaughlin, et al. (37) have studied the physiology
and morphology of pulmonary emphysema in the horse. The lung of
the horse has been reported to be similar i,n subgross anatomy to that
of man (36). They have studied both the spontaneous disease, one of
the several causes of the syndrome known as "heaves," and a similar
but not identical pulmonary disease induced by the injection of chlor-
promazine or of styrene beads into the bronchial arterial circulation.
Their findings of obstructive lesions in the bronchial circulation and
of accompanying emphysematous changes in t'he pulmonary paren-
chyma provide indirect support of a vascular theory of emphysema.
Ricketts, et al. (42) were unable to produce emphysematous lesions
in sheep by occlusion of the bronchial artery ; however, species dif-
ferences in the distribution of this vessel may ~be an important factor

40


in both experimental and spontaneous disease. The bronchial artery
in tlhe horse is reported to supply the alveolar septa, whereas in the
sheep it is reported to reach only as far as the terminal bronchioles
(36) -

A pulmonary disease similar histologically to pulmonary emphy-
sema in man appears spontaneously in certain populations of rabbits
(IS?). Boatman, et al. (8) have studied this disease by means of the
electron microscope. Three of their findings which tend to support the
theory that the disease is primarily vascular in origin are as follows:
loss of capillary endothelium, partial or complete filling of the capil-
lary lumens with collagen, and frequent recanalization of the damaged
capillaries.

Freeman, et al. (19, SW, 21) have investigated the effect of chronic
exposure of rats to varying concentrations of nitrogen dioxide (NO*),
a gas which is found in cigarette smoke and in industrially polluted air.
These investigators showed that the exposure of rats over their lifetime
of 2 to 3 years to concentrations of 2 ( 21) parts per ,million of NO,
resulted in reduction in cilia of the bronchial epithelium, a reduction
in normal exfoliation, and the appearance of unidentified crystalloid
inclusions. Exposure for only 16 weeks to a higher concentration of 4
( +l) parts per million led to hypertrophy of the `epithelium of the
terminal bronchioles. Rats exposed to concentrations varying from 10
(+l) to 25 (+2) parts per million of NO? developed large, heavy,
nonedematous lungs accompanied by dorsal kyphosis. The increase in
weight of the lung was shown to be caused by widespread hypertrophy
of the respiratory epitihelium, especially in the bronchioles closely asso-
ciated with alveolar ducts and in the terminal bronchioles. Hyper-
trophy of the bronchial epithelium and accumulation of amorphous
proteimaceus material, fibrin strands, and macrophages resulted in nar-
rowing of the lumens of the terminal bronchioles at their junctions
with the alveolar ducts. Focal hypertrophy of alveolar epithelium
appeared to be associated with compression of alveolar capillaries. The
airspaces of the lung were increased in volume.

Other investigators have also reported an increase in alveolar size
in rodents exposed to NO,. Blair, et al. (7) exposed mice to 0.5 parts
per million of NO* for 6, 18, or 24 hours each day. The animals were
exposed to NO, for periods varying from 3 to 12 months; the degree
of change in the pulmonary histology appeared to increase with in-
creased total length of exposure. Besides producing enlarged alveoli,
exposure to NOz also produced early bronchiolar inflammation with a
concomitant reduction in the size of the distal airways.

41


OTHER sTuDIE6

In a recent extensive review of the nature and role of pulmonary
surfactant, Scarpelli (j&3) states that the lowering of surface tension
produced by the ,action of cigarette smoke on surfactant may pre-
dispose to the development of emphysema.

Cigarette smoke contains powerful ciliostatic agents (50, 61, 5~!?)
which can interfere with pulmonary clearance. Components of both
the particulate and the gaseous phases adversely affect ciliary activity.
Dalhamn, et al. (14) h ave pointed out that in assessing the effect of
one or another of the components of cigarette smoke on ciliary activity
in various animal systems particular attention must be paid to the
level of exposure, since at different dosages the particulate and gaseous
phases have different relative effects on ciliary activity. Other recent
work by Dalhamn, et al. (13) has further clarified the extent to which
certain components of cigarette smoke are retained in the human lung
and includes the observation that retention of `gaseous components
depends in part on adsorption of the gases on particulate matter.

Ballenger, et al. (4) have indicated that the in vitro ciliostatic
effects of oxidized nicotine are enhanced by prior infection of the
tissue explants with Influenza B Virus.

Holma (30) has reported that cigarette smoke has acute depressant
effects on pulmonary clearance in living rabbits.

Recently, observations have been published on the metabolism and
function of the pulmonary alveolar macrophage which, together
with mucus transport, performs the function of ridding the lung of
both inanimate particles and bacteria. Green (97) points out the im-
portance of the alveolar macrophage in pulmonary clearance of
infectious agents. He has also observed a deleterious dose-response
effect of cigarette smoke on the phagocytic activity of the macro-
phage and suggests that this effect may be related to the development
of chronic bronchopulmonary disease.

In another paper, Green (96) found that the cytotoxic activity of
cigarette smoke on pulmonary macrophages may be inhibited by
glutathione and cysteine. Izard (3%`) observed that the gaseous phase
of cigarette smoke or one of ,its components, ,acrolein, inhibited the
multiplication of cultures of DunalieZZa bioculata and also observed
that the addition of cysteine to the medium protected against these
effects of acrolein.

Heise, et al. (28) have reported that rabbit pulmonary alveolar
macrophages secrete lysozyme into a culture medium. Lysozyme may
be active in the clearance of bacteria from Ithe lung.
Roque, et al. (429 found a decrease in the activity of oxiodoreduc-
tases and hydrolases in the alveolar macrophages of smokers. They

42


also found that the reduction in these enzymes was directly propor-
tional to the amount of stored fluorescent material present in the
macrophages. This material is thought to originate ,in tobacco smoke.
Roque, et al. suggested that the itobacco smoke may have induced
abnormalities in the mitochondria of the macrophage.

Kilburn (33) theorizes that the pathogenesis of chronic obstructive
bronchopulmonary disease is related to the failure of macrophages
to be cleared from the alveoli and bronchioles because of impaction
of mucus. He suggests that dissolution of the cells exposes the alveoli
and bronchioles to damaging enzymes and to the phagocytosed par-
ticles contained in the macrophage.

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