cluded: “... vasoconstriction, decrease in blood flow rate and fre-
quency of plasma spacing, blocking of blood flow in varying num-
bers of nutritive capillaries, shunting of blood from arterioles to
venules. ...’” These microcirculatory changes were said to result in
a decrease of nutritive blood flow in tissue.

As mentioned in the discussion of CHD, Kjeldsen ( 31, 32) stud-
ied several smoking patients with occlusive peripheral vascular
disease whose COUb levels were significantly higher than those of
control smokers. The levels of COHb in many of these patients were
comparable to those associated with experimental atherosclerosis
in animals. Astrup, et al. (4) have suggested that prospective stud-
ies should be performed to investigate the relationship between
COHb levels and the incidence of arterial disease.

In the Prague study (19) intermittent claudication was signif-
icantly (P < .01) more common among cigarette smokers than non-
smokers. Twenty percent of the men in the age group of 60 to 64
who were heavy smokers (more than 25 cigarettes a day) had inter-
mittent claudication.

Raf (44) reported that all but 4 of the 98 patients admitted for
peripheral vascular surgery at the Karoline Hospital, Sweden, were
smokers.

Mathiesen, et al. (8) in Denmark followed the spontaneous
course of arterial insufficiency in 211 patients. Cessation of smoking

increased the number of patients displaying spontaneous improve-
ment.

ORAL CONTRACEPTIVES, THROMBOPHLEBITIS,
AND SMOKING

In two studies from Great Britain and one from the United
States, it was reported that the use of oral contraceptives was asso-
ciated with a significantly increased risk of developing venous
thromboembolism (46, 58, 59). The British investigators also noted
in their initial report that the affected patients were, on the average,
heavier smokers than controls (58). However, after an additional
year of study, a similar effect was not noted and they concluded
(59) : “... the earlier difference between the smoking habits of the
two groups can thus reasonably be attributed to chance (P = 0.08).”
The American investigator (45) found “...no evidence that smok-
ing, acting either independently or in conjunction with oral contra-
ceptives, is a factor in idiopathic thromboembolism.”

Cigarette smoking has not been clearly demonstrated to be a fac-
tor that contributes to the risk of idiopathic thromboembolism asso-
ciated with the use of oral contraceptives. Nevertheless, the
possibility that it may act to increase that risk has not yet been
completely ruled out.

26
HIGHLIGHTS OF CURRENT CARDIOVASCULAR
INFORMATION

In addition to the comprehensive summary from the 1971 report,
“The Health Consequences of Smoking” (56), cited earlier in this
chapter, the following statements are made to emphasize the most
recent developments in the field:

1, Recent epidemiological studies from several countries con-

(1

(2

(3

(4

)
)

—

—

—

(6)

(7

—

firm that cigarette smoking is one of the major risk factors
contributing to the development of CHD. Avoidance of ciga-

rette smoking is of importance in the primary prevention of
CHD,

Studies in man and animals have shown a greater myocardial
arteriole wall thickness in smokers than nonsmokers.

Experimenta: and epidemiological investigations implicate
the elevation of carboxyhemoglobin levels in smokers as a
contributor to the development of CHD and arteriosclerotic
peripheral vascular disease.

Cigarette smoking is considered to be the Major cause of
pulmonary heart disease (cor pulmonale) in the United
States in that it is the most important cause of chronic non-
neoplastic bronchopulmonary diseases. Avoidance of ciga-
rette smoking is of importance in the primary prevention of
pulmonary heart disease.

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27
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31
CHAPTER 3

 

Non-neoplastic Bronchopulmonary Diseases
Contents

Page

Introduction ....... 0.0... 000. cece cece cece eueuenues 37
Epidemiological Studies .............0. 0c ccc ceeeecceee 38
COPD Mortality ..... 0.0.0 0c cece ccc eeees 38
COPD Morbidity ........ 00.00 cece eee 39
Cessation of Smoking ........... 0.0 ccc ecceeeeeees 41
Occupational Hazards ........... 0.0... ccc eee eeeee 42
Genetic Factors ..... 00.0.0... cece cee cece cease 44
Pathological Studies ... 00... occ eee eee ec cececceceee 45
Experimental Studies ......0.0.. 0.0 cece cececccccueue 45
Human Studies ........0.. 0... cece cece ceeecee 45
Animal] Studies ........ 0. ccc cece cece ee 46
Overall Clearance .......00 000. ccccccecceccceeees 47
Phagocytosis ..........0 0.00... cece cece eeeee 47
The Surfactant System ....00...0... ccc cceeeceuee 48
Other Respiratory Disorders ..... ........-0.0-cceeuee 48
Highlights of Current Bronchopulmonary Information .... 48
References 20.0... 0... cece cece eee cccceeueveeeeneens 49

35
INTRODUCTION

Chronic bronchitis and emphysema are the chronic bronchopul-
monary diseases of greatest health importance in the United States
(71). The 1971 report, “The Health Consequences of Smoking”
(70), summarized the relationship between smoking and these dis-
eases as follows:

1.

Cigarette smoking is the most important cause of chronic
obstructive bronchopulmonary disease in the United States.
Cigarette smoking increases the risk of dying from pulmo-
nary emphysema and chronic bronchitis. Cigarette smokers
show an increased prevalence of respiratory symptoms, in-
cluding cough, sputum production, and breathlessness, when
compared with nonsmokers. Ventilatory function is de-
creased in smokers when compared with nonsmokers,

Cigarette smoking does not appear to be related to death
from bronchial asthma although it may increase the fre-
quency and severity of asthmatic attacks in patients al-
ready suffering from this disease.

The risk of developing or dying from COPD among pipe
and/or cigar smokers is probably higher than that among
nonsmokers while clearly less than that among cigarette
smokers.

Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smok-
ing is associated with improvement in ventilatory function
and with a decrease in pulmonary symptom prevalence,

Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with
nonsmokers of the same age.

For the bulk of the population of the United States, the im-
portance of cigarette smoking as a cause of COPD is much
greater than that of atmospheric pollution or occupational
exposure. However, exposure to excessive atmospheric pol-
lution or dusty occupational materials, and cigarette smoking
may act jointly to produce greater COPD morbidity and
mortality.

37
7. The results of experiments in both animals and humans have
demonstrated that the inhalation of cigarette smoke is asso-
ciated with acute and chronic changes in ventilatory func-
tion and pulmonary histology. Cigarette smoking has been
shown to alter the mechanism of pulmonary clearance and
adversely affect ciliary function.

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes
characteristic of COPD in the bronchial tree and pulmonary
parenchyma more frequently than do nonsmokers.

9. Respiratory infections are more prevalent and severe among
cigarette smokers, particularly heavy smokers, than among
nonsmokers.

10. Cigarette smokers appear to develop postoperative pulmo-
nary complications more frequently than nonsmokers.

Recent epidemiological, autopsy, and experimental studies con-
firm and extend the foregoing statements.

EPIDEMIOLOGICAL STUDIES

COPD MoRrRTALITY

Over a period of 4 to 8 years, Burrows and Earle (70) studied 200
patients with symptomatic COPD whose mean FEV, was 1.0,+ 0.4
liter. Ninety-seven percent of these patients had a history of ciga-
rette smoking ; the average consumption for the entire group of 200
individuals was 23 cigarettes a day over a period of 41 years. Upon
entry into the study, 59 percent were still regular smokers and 38
percent had discontinued smoking. Eighty-nine percent of the group
were males and the mean age was 59.1 years.

A 47 percent 5-year mortality was observed in these 200 patients,
and most deaths were “...directly attributable to the underlying
lung disease or one of its complications.” The relationship of con-
tinued smoking to the course of the disease was difficult to interpret.
Patients who stopped smoking prior to entry into the study had a
poorer survival than those who continued to use cigarettes, This was
related to a tendency for patients to give up smoking when their
illness was severe, and “... the apparent advantage of smokers was
eliminated when patients with similar FEV, levels were compared.”
The authors reported no reduction of mortality in the group of pa-
tients who stopped smoking, even when smokers and ex-smokers
with similar FEV, levels were compared.

38
Reduction of cigarette smoking was associated with a history of
reduced expectoration, smaller measured sputum volume, and
“...a favorable course of the vital capacity (P <.01)....”

The 1971 report, “The Health Consequences of Smoking” (70),
included an analysis of the variety of ways in which smoking may
be related to disease. COPD was cited as an example in which smok-
ing probably initiates a disease process by producing progressive,
irreversible damage. The 200 patients reported by Burrows and
Earle (10, 11) may be representative of patients who have experi-
enced progressive and irreversible pulmonary damage after many
years of exposure to cigarette smoke. In such cases, “... cessation
of smoking leaves impaired function which does not improve appre-
ciably but does not continue to deteriorate from continued exposure
to cigarette smoke. However, such function may deteriorate through
aging or through exposure to other harmful agents” (70).

COPD MorRBIDITY

New reports of chronic bronchopulmonary disease prevalence
support the findings of earlier studies in which a greater prevalence
was found among smokers than nonsmokers.

A repeat study of a Berlin, New Hampshire, population sample,
which included more than 1,500 individuals, was carried out in 1967
by Ferris, et al. (27). In both this survey and the earlier 1961 sur-
vey, a greater prevalence of chronic nonspecific respiratory disease
was found in cigarette smokers than nonsmokers.

The 1967 Berlin study demonstrated that cigarette smokers who
inhaled deeply or moderately had generally higher prevalences of
chronic nonspecific respiratory disease than those who did not inhale
or inhaled only slightly.

After standardization for age, sex, and smoking habits, the pre-
valence of chronic nonspecific respiratory disease in the 1967 survey
sample was slightly lower than in 1961. This may be accounted for
by a decrease in air pollution.

In a random sample of 609 residents of Glenwood Springs, Colo-
tado, a high prevalence of chronic bronchitis was found to be
strongly related to smoking, particularly of cigarettes, and this rela-
tionship was independent of age, sex, or history of dust exposure at
‘ork (52). Chronic airway obstruction was found to be predomi-
nantly a disease of elderly male smokers and increased in frequency
‘ith increasing age after 49 years.

_ The Tecumseh study is a well-known continuing epidemiologic
investigation of the entire community of Tecumseh, Michigan. In
this Study the relationship of parental longevity to ventilatory
funetion and prevalence of chronic nonspecific respiratory disease

39
among sons was recently analyzed (17). Death before age 65 of
either parent was related to low values of 1-second forced expiratory
volume among the sons. Maternal death before age 65 was also asso.
ciated with increased prevalence of chronic bronchitis and emphy.
sema among sons. Some, but not all, of these relationships wer.
accounted for by differences in smoking habits of the sons. The
authors also concluded: “The evidence strongly suggests that con.
stitutional factors are involved” (17).

A higher prevalence of chronic bronchitis was found among
smokers than nonsmokers (P < .01) in a study of 710 Yugoslavian
workers (43). There was a direct relationship between the lifetime
number of cigarettes smoked and the presence of chronic bronchitis,

Several papers have been published recently comparing respira.
tory symptoms such as cough and sputum production among
smokers and nonsmokers in different populations. Two of the ney
studies were prospective investigations (15, 38). In all instances,
symptoms were more common among cigarette smokers than non.
smokers (1, 6, 8, 15, 88, 52, 68, 75)'. In the three studies which re
ported on pipe and cigar smokers, the frequency of respiratory
symptoms in this group was, in general, intermediate between those
of cigarette smokers and nonsmokers (6, 15, 52).

Results of studies of pulmonary function in representative sam.
ples of different populations (6, 17, 38, 63), surveys of employees,
(15, 48, 57), and normal volunteers (75) indicate that cigarette
smokers have lower average pulmonary function than nonsmokers,

Pulmonary diffusing capacity was found by Van Ganse, et al.
(72) to decrease in men and women with aging and with an increase
in current or lifetime cigarette consumption.

In general, a dose-response relationship between cigarette con-
sumption and the development of respiratory symptoms and/or im.
paired pulmonary function was found in both men and women; as
cigarette consumption increased, these abnormalities were found
more frequently (6, 38, 52, 72, 75).

Woolf and Suero (75) studied the respiratory effects of cigarette
smoking in 298 normal women. The prevalence of cough, sputum
production, wheezing, and shortness of breath increased progres.
sively with increased cigarette smoking. The results of the follow.
ing tests of pulmonary function were significantly lower in smokers’
than in nonsmokers: forced vital capacity, forced expiratory vol.
ume in one second, maximal mid-expiratory flow, arterialized capil.
lary blood oxygen tension at rest, specific conductance, and pulmo.
nary diffusing capacity and fractional uptake of carbon monoxide
during exercise.

Seely, et al. (62) examined 365 high school students in the New
Haven area. They found that students with 1 to 5 years’ smoking ex-
perience had excessive cough, sputum production, and shortness of

40
breath. These young smokers also had lower flow rates at mid-vital
capacity and at lower lung volumes than nonsmoking students. The
authors have raised the question of whether smoking by high school
students may lead to developmental arrest of the lung. They feel
that follow-up pulmonary function studies in adolescents who stop
smoking will help clarify this question.

In a study of 556 high school students from Oklahoma City,
Addington, et al. (2) reported that respiratory symptoms were sig-
nificantly more frequent in smokers than nonsmokers, but no signif-
icant differences were noted in the FEV, and the mean vital
capacity.

Snider, et al. (65) investigated 1,403 patients with documented
pulmonary tuberculosis for the presence of obstructive pulmonary
disease. Airway obstruction was found in 62 percent of white men,
37 percent of nonwhite men, 36 percent of white women, and 17
percent of nonwhite women. Sixty-eight percent of the patients
were current smokers and 15 percent were ex-smokers. Heavy
smoking had less effect on the presence of airway obstruction than
advanced tuberculosis or older age. These data were interpreted as
showing the predominant importance of tuberculosis as a factor
leading to airway obstruction in tuberculous patients. However, the
authors also concluded: “The present data suggest the possibility
of an additive effect of smoking with tuberculosis in producing air-
way obstruction.”

CESSATION OF SMOKING

The salutary effect of stopping cigarette smoking on COPD mor-
tality and morbidity has been noted in previous reports of the
Surgeon General (69, 70).

A recent statement from the “Pulmonary Heart Disease Study
Group” of the Inter-Society Commission for Heart Disease Re-
Sources (41) also emphasized this point: “The overwhelming cause
and effect relationship between smoking, bronchitis-emphysema and
pulmonary heart disease is such that there is little doubt that a radi-
cal reduction or elimination of the cigarette habit would result in a
greatly lowered incidence of the chronic respiratory diseases and
cor pulmonale.”

In recent studies, a decrease in the prevalence of respiratory
Symptoms among ex-cigarette smokers has been demonstrated (10,
15, 75), Higgins, et al. (38) interpreted data from 1957 and 1966
Surveys of chronic respiratory disease in England as suggesting that
the benefits of giving up smoking on respiratory symptoms are less
in those who have smoked for many years than in those who have
Smoked for shorter periods.

Baker, et al. (5) undertook a therapeutic program for previously

41
unrecognized mild to moderate cases of COPD. One hundred thirty-
four men were included in this study. Eighty-five percent of these
men were cigarette smokers, 11 percent were ex-smokers, and 4 per-
cent were nonsmokers. At the 6-month follow-up, 61 subjects were
still in the treatment program. Patients were encouraged to stop
smoking, and at the 6-month follow-up 34 percent of the cigarette
smokers had stopped smoking, while 34 percent decreased their
cigarette consumption by at least half. At the follow-up evaluation,
approximately two-thirds of those who either gave up smoking or
decreased their cigarette consumption showed improvement in
symptoms. Thirty percent of those whose smoking habits did not
change showed improvement in symptoms. No significant differ-
ences were found in the pulmonary function studies at the follow-up
evaluation. Alteration of smoking habits was the single factor most
closely related to symptomatic improvement.

OCCUPATIONAL HAZARDS

As observed by Bouhuys and Peters (7), the relative contribu-
tions of cigarette smoking and industrial exposure to the loss of
lung function may at times be difficult to determine.

Recent studies in wool, textile, grain elevator, shipyard, pulp mill,
steel, and underground mining industries have documented a higher
prevalence of chronic bronchitis among cigarette smokers than non-
smokers (9, 19, 19, 20, 39, 42, 47, 50). Similar studies in steel, pulp
mill, machine shop, and welding industries indicate a greater fre-
quency of respiratory symptoms and/or diminished pulmonary
function in smokers than in nonsmokers (22, 28, 30, 39).

Japanese investigators recently reported that former employees
of a poison gas factory had a high prevalence of chronic bronchitis
and expiratory slowing; a history of chronic bronchitis was ob-
tained from 67 percent of smoking men and 47 percent of nonsmok-
ing men who had manufactured mustard gas or lewisite (54).

In recent months several articles have been published on coal
workers’ pneumoconiosis. Because coal miners are not allowed to
smoke at work, they must smoke their cigarettes during a shorter
period of time than non-miners; nevertheless, the average coal
miner smokes as many cigarettes a day as does the non-miner (51).
Thus, his exposure tends to be more intense during the period in
which he is smoking. Also, the documented hazard of chronic expo-
sure to coal dust may be compounded by the deleterious effect of
smoking on ciliary function.

Ashford, et al. (4) studied approximately 30,000 working coal
miners in Great Britain. Their data suggest that smoking and pneu-
moconiosis act independently in the production of pulmonary symp-
toms.

42
A total of 801 working, anthracite coal miners from Pennsylvania
were investigated by Tokuhata, et al. (68). Twenty-four percent of
the smoking miners had pulmonary function impairment as com-
pared with 11 percent of miners who did not smoke. Because the
smokers developed their pulmonary function abnormalities after a
much shorter underground work exposure, the authors suggested
that smoking may significantly accelerate the development of
pneumoconiosis among coal miners.

Rasmussen and Nelson (61) studied 368 soft-coal miners from
the Southern Appalachian coal fields. All workers included in the
study had been involved in the coal industry for at least five years.
Miners with a smoking history of 30 pack-years or more showed a
significant (P <.01) reduction of FEV, when compared to non-
smoking miners. Impairment of oxygen transfer was greater in both
the 15 to 29.9 pack-year group and the 30 plus pack-year group than
among the lifelong nonsmokers (P < .01).

One hundred sixty-two dyspneic soft-coal miners, who gave his-
tories of lifelong abstinence from cigarette smoking, were examined
by Rasmussen (60). Of these patients, 85.6 percent had some X-ray
evidence of pneumoconiosis. The group as a whole was “. . . not rep-
resentative of all coal miners, nor of all symptomatic coal miners.”
Even though 56 percent of these miners had “normal” ventilatory
Capacities, i.e, an FEV, which was 75 percent or greater of the
predicted normal vital capacity, more than 90 percent had an
alveolar-arterial oxygen gradient during exercise which exceeded
19.9 mmHg. In more than 95 percent of the “normal” group, this
gradient was not associated with significant arterial oxygen desatu-
ration during exercise. The loss of pulmonary function in the entire
8roup of non-cigarette smokers was somewhat less than that found
in a group of miners composed of cigarette smokers and non-
smokers; nonetheless, these findings demonstrate that, in the ab-
sence of cigarette smoking, coal dust exposure may be associated
With abnormalities in oxygen transfer during exercise, despite the
Presence of a normal FEV,.

An autopsy study of 144 Appalachian coal miners was carried out
by Naeye, et al. (58). Several parameters of cardiac and pulmonary
structure were examined with regard to the effect of smoking. The
Volume of pulmonary macules and nodules containing coal dust and
the concentration of silica crystals and collagen in these macules
and nodules were unrelated to smoking. Right ventricular hyper-
tr ophy, defined according to an index developed by Naeye, was pres-
ent in all groups of miners but was more severe in the bituminous
Workers who smoked cigarettes. The emphysema index, which is a
Measurement of the percent of lung tissue comprised of abnormal
ar space, was determined only in bituminous coal miners. It was

43
significantly greater in cigarette smokers than in nonsmokers,
Goblet cell hyperplasia, which appeared to be present in the entire
group, was somewhat greater in the bituminous coal miners who
smoked than in the nonsmokers, but the differences were not statis.
tically significant.

Several investigators have concluded that cigarette smoking by
itself is more important in the production of respiratory disease,
other than pneumoconiosis, among coal miners than is exposure to
coal dust (24, 34, 58, 68). Rasmussen questions this view (60),
There is no consensus in recent publications on what role cigarette
smoke may play in the development of coal workers’ pneumoconio-
sis (24, 51, 58, 58, 68).

Weiss (72) examined 100 asbestos textile workers and found a
greater prevalence of pulmonary fibrosis among cigarette smokers
than nonsmokers. The prevalence increased with increasing amount
and duration of cigarette smoking and with increasing duration of
exposure to asbestos.

GENETIC FACTORS

An infrequent genetic error, homozygous alpha,-antitrypsin de-
ficiency, has been commonly associated with the premature develop-
ment of severe, panacinar emphysema. It is postulated that alpha,-
antitrypsin is essential to protect the lung against the destructive
action of naturally occurring proteinases (36).

Related questions of current interest deal with the prevalence and
significance of the heterozygous deficiency state (intermediate
serum antitrypsin deficiency) and the interaction of smoking with
the severe and intermediate deficiency states. Mittman, et al. (49)
recently reviewed the limited data available on the smoking habits of
patients with alpha,-antitrypsin deficiency ; the cigarette smoke ex-
posure of patients with the intermediate deficiency appears to be
greater than that of patients with the severe deficiency.

Cigarette smoking has been reported to be a possible precipitating
factor in the development of COPD in the homozygous deficiency
state (40). Some studies (26, 44, 49, 67) have demonstrated an
association between the heterozygous deficiency state and the devel-
opment of COPD, while other studies have not (35,62). Mittman,
et al. (49) have suggested that the intermediate deficiency may
predispose to lung disease by accentuating an individual’s suscepti-
bility to the harmful effects of external irritants. Whether or not
cigarette smoking acts together with the homozygous or hetero-
zygous deficiency states to increase the risk of developing either
panacinar emphysema or the more common forms of COPD has not
been adequately studied.

44
PATHOLOGICAL STUDIES

In previous investigations, a correlation has been found between
cigarette smoking and the histologic changes characteristic of
bronchitis and emphysema (70).

An autopsy study of 60 patients with COPD was performed by
Cullen, et al. (16). Although they did not find a correlation between
the smoking history, total emphysema score, type of emphysema, or
bronchial histologic features, the authors noted that only three pa-
tients were non-cigarette smokers. These three patients were pipe
or cigar smokers. Eight patients who had stopped smoking three
years before death had the same bronchial histologic abnormalities
as those who continued smoking until death. This suggests that the
bronchial abnormalities had become irreversible at the time of
smoking cessation.

Dunnill and Ryder (21) carried out a quantitative study of the
relationship between chronic bronchitis, emphysema, and smoking.
The lungs of 353 patients were examined at autopsy, and a smoking
history was available in 179 cases. A small but significant (P <.005)
difference was found between smokers and nonsmokers in the per-
centage volume of bronchial mucous glands. Emphysema, mainly
the centrilobular type, was found significantly (P < .001) more fre-
quently in men and women smokers than nonsmokers, and it oc-
curred at a much younger age in the smokers.

EXPERIMENTAL STUDIES
HUMAN STUDIES

Anderson (3) observed in a few patients with and without COPD
that cigarette smoking can produce V/Q (ventilation/perfusion)
changes resulting in a significant average drop in PaO, (partial
Pressure of oxygen in arterial blood).

Clarke, et al. (14) studied the bronchoconstrictor effect of plain
and filtered cigarettes in 16 men. Filtration of either the particulate
or vapor phase of the smoke had a similar effect in reducing the
bronchoconstrictor response to cigarette smoke inhalation.

Using a reference cigarette developed by the University of
Kentucky, Diamond, et al. (18) measured pulmonary expiratory
resistance immediately after smoking. Heavy smokers, whose con-
trol resistance values were significantly higher than those of mod-
trate or nonsmokers, had a decrease in resistance, while nonsmok-
ers had an increase. Although selected ventilatory function tests did
hot change significantly after smoking, the author noted that the
Methods used in this study are probably not sensitive enough to
Measure constriction in peripheral airways, where smoking is
thought to exert an adverse effect.

45
ANIMAL STUDIES

Frasca, et al. (82) made electron microscopic observations in
areas of fibrosis and emphysema of the lungs of dogs, which had
been subjected to experimental cigarette smoking as reported by
Hammond, et al. (37). Details of the smoking procedure were re-
viewed in the 1971 report, “The Health Consequences of Smoking”
(70). The major findings in the study of Frasca, et al. were: a com-
plete loss or marked reduction in the number of alveolar septal capil-
laries, a marked thickening of the alveolar septa due to increased
amounts of collagen, thickening of the pleural stroma due to large
amounts of collagen, and the presence of increased numbers of
macrophages in both the pleura and parenchyma. Many of these
macrophages were filled with pleomorphic cytoplasmic inclusions,
Crystalline-like structures were found in membrane-bound inclu-
sions and ferritin-like particles occurred both in large membrane-
bound aggregates and lying free in the cytoplasm.

Flint, et al. (29) reported a significant increase in the number of
polymorphonuclear leukocytes recoverable from the lungs of guinea
pigs following exposure of these animals to cigarette smoke. Be-
cause no changes in serum alpha,-antitrypsin levels were found in
this setting, the authors hypothesized that an imbalance may occur
between proteolytic enzymes released by polymorphonuclear
leukocytes and the inhibitors of these enzymes.

“The stress effects of forced mouth-breathing and inhalation of
cigarette smoke on lung mitochondrial phosphorylation were studied
in the guinea pig by Kyle and Riesen (45). Mouth-breathing alone
was associated with impaired efficiency of phosphorylation at two
mitochondrial loci, while mouth-breathing guinea pigs exposed to
cigarette smoke lost efficiency at only one of these sites.

Aviado and coworkers have studied the effects of hormones on
the pulmonary response to cigarette smoke inhalation and intra-
venous nicotine injection. Subcutaneous progesterone administra-
tion, prior to nicotine or smoke exposure, reduced the bronchocon-
strictor response in rats (64). A similar experiment involving
pretreatment of dogs with glucocorticoids resulted in variable bron-
choconstrictor responses after exposure to cigarette smoke (12).

Nitrogen dioxide (NO,), a gas found in cigarette smoke and some
industrially polluted air, can destroy cellular membranes and sub-
cellular structures (25). Continuous administration of low concen-
trations of NO, in rats has produced an emphysema-like disease
(66). Falk has suggested that NO, may “.. . carry a major responsi-
bility for the high incidence of emphysema in cigarette smokers”
(25).

Stephens, et al. (66) examined ultrastructural changes in pulmo-
nary connective tissue of rats exposed to 2 to 20 p.p.m. of NO, for

46
varying periods of time. In the absence of significant cell destruc-
tion, striking alterations in both collagen fibrils and basement mem-
branes were found.

OVERALL CLEARANCE

Pavia, et al. (55, 56) examined the effect of cigarette smoking on
the mucociliary mechanism of the human lung. A temporary slow-
ing of mucociliary clearance was found in a group of 22 elderly
smokers (56). Eight of these subjects had mild restrictive impair-
ment and two had airway obstruction. When percentage clearance
by elderly cigarette smokers and nonsmokers was compared, sig-
nificant differences were not demonstrable (55). In the latter study,
patients with functional evidence of lung disease were not included.

Deposition and clearance of inhaled 2,» particles of iron oxide la-
beled with ***Au were studied in 19 young, normal subjects by
Lourengo, et al. (46). While tracheobronchial clearance began im-
mediately after inhalation in nonsmokers, it was delayed for periods
of 1 to 4 hours after inhalation in smokers.

Frances, et al. (31) studied the effect of cigarette smoke on par-
ticle transport on donkey nasociliary mucosa. This mucosa was
found to be much more resistant to the effects of cigarette smoke
than that in the donkey tracheobronchial tree. More recently, Albert,
et al. (2) published a report that in one of three donkeys tolerance
to cigarette smoke had developed in the tracheobronchial mucosa.

Weissbecker, et al. (74) examined in vivo mucus flow rates in
cats exposed to cigarette smoke gas phase of varied composition.
Several compounds, e.g., isoprene and nitrogen dioxide, when added
in combination to the gas phase, were effective in reducing the
mucus flow, compared to the effect of the gas phase alone. Other
compounds, e.g., CO, diminished the mucostatic effect of the gas
Phase. Compounds producing mucostasis were ineffective when
added to cigarette smoke. These experiments indicate that effects
observed from pure compounds cannot be used to predict the effect
of cigarette smoke on mucus transport.

PHAGOCYTOSIS

The recent literature concerning the effect of tobacco smoke on
macrophage function is reviewed in the chapter on allergy of this
report.

Pratt, et al. (59) have extended their studies on the ultrastruc-
ture of human alveolar macrophages. Macrophages obtained from
Smokers tend to contain more heterogeneous inclusions than those
from nonsmokers. Angular and needle-like structures were observed

47
only in the inclusions of smokers. The authors concluded that these
structures “...may represent undigested smoke products... .”

In an investigation of early emphysema found in patients who
were autopsied, McLaughlin and Tueller (48) found brownish, pig-
mented alveolar macrophages in the intact parenchyma adjacent to
areas of emphysema. Such macrophages were not found in normal
lungs, but were found in sputum specimens of “... apparently
healthy cigarette smokers.” In heavy smokers many of the macro-
phages also contained iron particles.

THE SURFACTANT SYSTEM

Giammona, et al. (3) measured the surface tension of lung ex-
tracts and bronchial washings of dogs following exposure to ciga-
rette smoke. Elevated minimal surface tension values were found
in bronchial washings obtained from three dogs. The values re-
mained elevated for 48 hours after the cigarette smoke exposure;
the values obtained one week after the cigarette smoke exposure
were normal. The surface tension measurements of lung extracts
obtained from four autopsied dogs were normal.

OTHER RESPIRATORY DISORDERS

Finklea, et al. (28) studied acute, noninfluenzal respiratory dis-
ease in military cadets and found significantly higher incidence rates
for acute upper and lower respiratory illness among cigarette
smokers than nonsmokers. Intermediate rates were found for
lighter cigarette smokers, cigar, pipe, and ex-smokers.

HIGHLIGHTS OF CURRENT BRONCHOPULMONARY
INFORMATION

In addition to the comprehensive summary from the 1971 report,
“The Health Consequences of Smoking’ (70), cited earlier in this
chapter, the following statements are made to emphasize the most
recent developments in the field:

1. Recent epidemiological and clinical studies from several
countries confirm that men and women cigarette smokers have
an increased prevalence of respiratory symptoms and have
diminished pulmonary function compared to nonsmokers.

2. Investigations of high school students have demonstrated that
abnormal pulmonary function and pulmonary symptoms are
more common in smokers than nonsmokers.

48
8. Recent occupational studies confirm that cigarette smoking is
an important cause of COPD, acting both independently and
in combination with occupational exposure.

4, Recent experimental studies confirm that cigarette smoking
exerts an adverse effect on pulmonary clearance and macro-
phage function.

5. Pulmonary macrophages obtained from cigarette smokers ex-
hibit characteristic morphologic differences when compared
to those obtained from nonsmokers.

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ALBERT, R. E., ALESSANDRO, D., LIPPMANN, M., BERGER, J. Long-term
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