ciated with a particular type of pulmonary emphysema. While the
majority of lungs of emphysematous patients reveal bullous or
centrilobular deformities, particularly of the upper lobes, this
hereditary disorder reveals a panacinar change, most severe in the
lower lobes (101, 215, 226). Patients with emphysema who are
found to have the homozygous deficiency have been observed to
include a greater percentage of female patients than is usually ob-
served in the general emphysema population. Their disease begins
earlier, is more severe, is characterized by dyspnea rather than
cough, and frequently is unassociated with a history of preceding
bronchitis (101,215, 226). Radiographic studies of A,AT-deficient
patients have revealed decreased vascularization of the lower lobes
and increased vascularization of the upper lobes (101, 21.1). It is
estimated that between 1 and 2 percent of patients with COPD have
this homozygous deficiency (7'8, 216). In family studies, it has been
found that almost all the homozygous individuals are symptomatic
by the age of 40 and that those who are not usually show alterations
in pulmonary function studies. Guenter, et al. (!18) studied `7 per-
sons with homozygous deficiency. Of the five symptomatic individ-
uals, 4 smoked and all had abnormal timed vital capacity. Neither
of the two asymptomatic individuals smoked or had this change in
vital capacity. All 7, however, were noted to be hypoxemic at rest
and to have decreased pulmonary diffusing capacity.

It has been suggested (15:) that the lack of this proteinase in-
hibitor in the serum of homozygous patients predisposes them to
emphysema in the following manner: Leukocytes present in the
blood contain significant amounts of proteinase enzymes as part of
the overall defense mechanism against infection ; the breakdown of
these cells during acute infection releases proteinases into the pul-
monary tissues and these, without the presence of a normal inhib-
itor, may contribute to the breakdown of the structural proteins of
lung tissue.

Heterozygous individuals have been defined as those who show
levels of A,AT intermediate between those of normals and those
with homozygous deficiency. At the present time, there is much
debate about whether or not heterozygotes for A,AT are at a
greater risk of developing COPD than are A,AT normals. A major
difficulty is the lack of a precise definition of heterozygosity. At
present, the best method for the determination of the level of A,AT
appears to be that of crossed serum immunoelectrophoresis be-
cause levels of trypsin inhibitory capacity (TIC) have been shown
to rise acutely with infections.

Welch, et al. (126) feel that heterozygotes do not show an in-
creased susceptibility to COPD. The hetelozygotes which they
studied showed symptoms of bronchitis and did not present the

151


lower lobe perfusion defects frequently noted in homozygotes. They
also found no difference in the number of COPD patients among the
heterozygotic and the general population. Other investigators, no-
tably Lieberman, et al. (IS.;, 15S), Kueppers, et al. (244), and
Larson, et al. (118) found significantly increased percentages of
COPD patients among those with heterozygous deficiency as corn--
pared with the general population. Lieberman, et al. (155) ob-
served that the percentage of heterozygotes among a group of
healthy industrial workers was 4.7 percent while that among a
group of patients with emphysema was 18.1 percent. In a recent
review, Falk and Briscoe (7.9) considered that the available evi-
dence points to an increased prevalence of COPD among hetero-
zygotes.

Of more central interest to this discussion, however, is the pos-
sible relationship of smoking to the predisposition of disease among
the heterozygote population. Kueppers, et al. (144) studied three
populations: younger controls, older controls, and a group of
COPD patients. They observed that of the 25 heterozygotes with
COPD, only 2 were over 70 years of age, both were female and non-
smokers. The remaining 23 were cigarette smokers. Nevertheless,
studies which adequately sort out the factors of genetic susceptibil-
ity and cigarette smoke exposure have yet to be reported.

An important question is to what extent the relationship between
smoking and COPD is influenced by identifiable genetic factors. At
present, it is possible to identify what appears to be only a very
small group of susceptibles for whom genetic factors may be para-
mount in the pathogenesis of their ailment. Of greater public health
import is whether lesser degrees of genetically identifiable suscep-
tibility interact with cigarette smoking to account for a significant
proportion of the problem.

AIR POLLUTION

Numerous epidemiological studies have been conducted in order
to examine the effect of air pollution on human nonneoplastic res-
piratory disease. Three major types of studies have been utilized:
observation of the mortality and morbidity due to an acute episode
of increased air pollution, observation of the day-to-day variation
in mortality and its relation to air pollution levels, and geographica!
comparisons. The majority of studies fall into the third category,
and these are detailed in table A6.

A number of studies did not show an association among air pol-
lution, respiratory symptoms, and pulmonary dysfunction (81,20.4).
More recent studies which evaluated the factors of smoking, social
class, and air pollution separately noted a greater prevalence of

152


COPD symptoms, pulmonary dysfunction, and COPD mortality
in areas of high pollution (12, I-71, ISG, 1.1.:). Lambert and Reid
(146) observed that in the absence of cigarette smoking the corre-
lation between COPD symptoms and air pollution was slight and
suggested that the two factors may interact to produce higher rates
of disease.

The evidence which has accumulated in the past 7 years gives
further support to the conclusion of the Surgeon General's Xd-
visory Committee on Smoking and Health as stated in its 1964 Re-
port that: "For the bulk of the population of the United States, the
relative importance of cigarette smoking as a cause of chronic
bronchopulmonary disease is much greater than atmospheric pol-
lution or occupational exposures."

OCCUPATIONAL HAZARDS

Exposure to various dusty occupational environments has been
shown in many studies to be associated with the development of
various forms of nonneoplastic lung disease. Lowe (1.78)) in a re-
view of the relationship of occupational exposure and chronic
bronchitis, noted that among workers exposed to dust significant
increases in COPD mortality \vere observed. These occupations
included coal mining, tinning, galvanizing, riveting, and caulking.
Commenting on a previously unreported study of more than 20,000
steel workers, he observed that the relationship between mean dust
exposure levels and COPD prevalence wxs much stronger among
smokers than among nonsmokers.

More recently, Bouhuys and Peters (37) reviewed those specific
industrial exposures related to lung disease. COPD was found to be
associated with exposure to coal dust, asbestos, bagasse dust, iso-
cyanates, various irritant gases, and textile dusts (cotton, flax, or
hemp).

Studies which have investigated the interrelationship between
smoking, industrial exposure, and COPD are listed in table A?`. Ad-
ditional compounds, not listed in the table, but which also appear to
be related to COPD, are chlorine (49) and washing powder dust
(97). Cigarette smoking and harmful dust exposures appear to act
in a combined manner in the production of COPD.

Although an increased prevalence of COPD is found with cer-
tain occupational exposures, in none is the relationship as strong
as that between COPD and cigarette smoking. To demonstrate an
increased occupational risk, careful analysis of smoking habits is
required. The relative importance of cigarette smoking appears to
be much greater than occupational exposure as an etiologic factor
in COPD.

153


CadlTzium--Chronic industrial exposure to cadmium in man has
been found to induce pulmonary emphysema without significant
accompanying chronic bronchitis (34, 35, 210).

Nandi, et al. (177) recently investigated the contribution of the
cadmium in cigarette smoke to the pathogenesis of emphysema.
Analyzing whole cigarettes, ash, and fibers, they found that an
average of 69 percent of the cadmium present in the cigarette (ap-
proximately 16 micrograms/20 cigarettes) is inhaled in the smoke,
In a related study (Z&3), these investigators showed that the level
of cadmium in water-soluble liver protein on autopsy was three
times greater in those patients with a history of chronic bronchitis,
emphysema than that found in those without such a history. Un-
fortunately, no smoking histories were available.

PATHOLOGICAL STUDIES

The relationship between smoking habits and pathological
changes in the bronchial tree and pulmonary parenchyma has been
investigated by several groups of workers. Metaplastic changes,
although found in nonsmokers, are much more common in smokers
(table 10, Cancer Chapter), and a dose-relationship of increasing
metaplasia with increased smoking has been evident in many of the
studies.

Pathological studies which deal primarily with pulmonary
parenchymal and non-metaplastic bronchial changes are presented
in table 8. Goblet cell distention, alveolar septal rupture, thickened
bronchial epithelium, and mucous gland hypertrophy have been
found to be more frequent in smokers than in nonsmokers. Auer-
bath, et al. (17) noted a dose-response relationship between the
amount of smoking and the degree of septal rupture.

Anderson, et al. (4, 5) studied the difference in the type of
emphysema shown by smokers and nonsmokers. In their study,
listed in table 8, they noted that the group of patients with panlobu-
lar emphysema was comprised of equal numbers of smokers and
nonsmokers while of patients with centrilobular emphysema, 98
percent were smokers. More recently, the same authors studied
lung macrosections from 80 nonsmokers. While most were normal,
24 demonstrated parenchymal dilatation and disruption consistent
with panlobular emphysema. Thurlbeck, et al. (217) have also ob-
served that centrilobular emphysema rarely occurs in nonsmokers.

154


TABLE 8.-Stltdies concerning the relation of human pulmonary histology and smoking'
                 (Actual number of deaths shown in parentheses)
                    SM = Smokers.    NS = Nonsmokers

Author.
  Year,
country,  Nwnne",pd                              Results
reference     population

Chang,    62 males and 43     Distentia of goblet rrlls (hy percent of smoking group)
1957,     females autopsied                                  w of
U.S.A.,    within 5 hours of        NOW       Ft?W     `h of surfarc    RWjIICC
Korea     death (no data  NS(22) 13.6        22.7        31.8        22.7
(47).     available on case SM(49) 12.2        10.2        10.2        1x.4
        selection)

comments

Most of
surface
  9.1
26.5

        The auth6rs also noted
         that smokers' lungs
Whole mL7face  showed shorter cilia
         and thicker epithelium
  22.5      (20 percent nonsmokers
         and 36 percent smokers
         had respiratory disease.)

Ide et al..   93 males autopsied                Mean thickness of tracheal and      Meax cilinry height in tmchca   No cigar or pipe
1959,     within 6 hours of               bronchial epithclium (a) in         and bronchus on cigarette      smokers were included.
U.S.A.    death. No cases                cigarette smokers and nonsmokers       .smolcw~ and nonsmokers
(129).    of pneumonia                    Trachea     IIronchas              TTlXhCa     nronchlu
        or lung disease  NS(23)    52.x        47.7        (23)      6.39        5.95
        included.      Light(31)    62.0        57.5        (29)      5.62        5.49
                  HeavY(l0)     66.2        61.9        (10)      4.89        4.66

Auerbach   654 males over                         Age-standardizrd pcrcentnge distribution of subject8     The authors also noted s
et al.,     60 years of r&w?                        acrordiwg to dcwrcr of 71LptuTv of the alvcolur septum8      dose-reponse relation-
1963.     nutopnied at    Dcyrcc oj TUptlCrC          o-0.25   0.5-0.75   1.0-1.25   1.5-1.75   2.0-2.25   "7.5-3.00  ship between smoking
U.S.A.    East Orange    Never smoked    19.4     50.5     24.9      3.6      1.6           and degree of rupture.
(17).     VA Hospital.   Current cigarette            .4      5.1     16.2      39.2   39:; tN one had ever smoked
                   tc urrent cigar         24.6     45.4     26.2      3.8           cigar&n regularly.
                  tc .
                    urrent pipe     5.4     23.0     53.5     15.9      2.2       
                  Current pipe, cigar    4x      1.6     46.5     33.6      7.5       
                                          .~


TABLE L-Studies conceming the dation of humun pulmonary histology and smoking (cont.)

                          (Actual number of deaths shown in parentheses)
                                    SM z Smokers.     NS = Nonsmokers
-                     ___-                                                          -__.
Author,
  yenr,     Number and
cou"trY.      type of                                Results                                  Comments
reference     pop"lntion
_.~ __ ~ .-- _- _~~__ -.__-         -~-                                        -._-
Anderson   39 malts and                     Swcrity of emphysema (mean deg+ee)                 The a"thors also noted that:
et al.,     32 fe1nales                            M&8                     Ft.W&8         Every person showing se-
1964,     (Caucasians)    NS(4) .._....._.,.............._ 1.5 3 (not sip"ifiea"t)        (20) 1.0
                                   (12) 1.9 tp<oOo5)
                       3           vere disease was R smoker.
U.S.A.    ll"dCQWi"g     SM (35)  __ .  2.3                               Among those with panlobu-
(5).     routine autopsy                                                           ISI. emphysema, there WZLT
        (40-97 years                                                            an equal distribution of
        of age.)                                                                   smokers and nonsmokers
                                                                        while nmong those with
                                                                           centrilohular emphysema
                                                                           98 percent were smokers
                                                                        and only 2 percent were
                                                                           nonsmokers.

                      -
Anderson   107 males and         Percentage didtribwtim of       Mean severity of cmphyeema
et al..     5R females         tobacco ~8~8 in 105 necropsiw                       MeWI   Statistical
1966.     autopsied for      bg degree of cnwhvsma severity       CategoN        Sevetitu Sign&mace
U.S.A.    whom smoking     None  . . . 36 (12/33)    SM(114)  . . . . . . . . . . . . .  2.3
(6).      data was        Mild . . . . . . . , 69 (68/84)    NS(51) ._.. .., . . .._..__.....  0.9 (p<o'ool)

        available.        Moderate  . . . 91 (30/33)    Male(107)  . . . . . . .  2.2
                     Severe . . . 93 (14/15)   Fernale  . . . . .
                                              Never smoked   I
                                       1.2 (P<O.OOl)
                                                        . . .  0.9
                                           <20 cigarettes/day  . . . . . . .  1.9
                                           20-40 cigarettes/day  . . . . . .  2.4
                                           >40 cigarettes/day  . . . . . . . . .  2.3

Megahed   60 male patients                         Mucous okmad hypertrophy
et al.,     with chronic                                     Percent
1967.     bronchitis under-               NS  . . . . . .  29   (2/7)
Egypt     going bronchial                SY  . . . . . .  77   (33/43)  (P<O.O2)

(163).    biopsy and
         lavsge.


TABLE 8.-Studies concerning the relation of human pulmonary histology and smoking (cont.)
                  (Actual number of deaths shown in parenth=cs)
                        SM - Smokers.    NS z Nonsmokers

Author,
  war.     Number and
country,      type of
reference    population

Auerhach   5c2 malts au-

Results                                  comments

Dcgrcc of trachral and brwnchial artcrinlar thickming

et al.,     topsict1 nt Enst                                   (bv percentngc of smokrss)
lW8,     Or:,ncc vn                               0.0&0./r    0.5.-0.9    1.0-1.4    1.5-1.9
U.S.A.    Hospital.      Never smoked (122)   _.  46.1      38.3      13.3      1.3
(14).              <20 eigarcttcs/day (120)              Il.7      22.0      33.5      28.4
                                  
                20-40 cigarettes/day (254)    5.0      8.G      37.4      40.!,
                >10 cigarettes/day (66)  _,  1.3       1.4      31.5      45.3

I Nume~~~us eh caeriments. detailing rhangcs iu bronchial epithelium are dctnilcd t~bul~~rl~ in tha C:~ncr~~ ohnrltvr

2.0s

4.4
X.1
20.5        __-


EXPERIMENTAL STUDIES

ANIMAL STUDIES

A number of investigators have studied the effect of the inha]a-
tion of cigarette smoke on the macroscopic and microscopic strut-
ture of the tracheobronchial tree and pulmonary parenchyma of
animals. Studies dealing with metaplasia and cellular atypism of
the trachea and bronchi are listed in table Al6 of the cancer chap-
ter. Studies more directly concerned with the pathology of COpD
are listed in table 9. They show that cigarette smoke exposure is
associated with changes similar to those found in humans with
COPD, i.e., bronchitis, parenchymal disruption, alveolar septal
rupture, alveolar space dilatation, and the loss of cilia and ciliated
cells in the bronchial mucosa.

The investigations of Auerbach and his coworkers (15, 16, 88)
have demonstrated by the use of both light and electron microscopy
that dogs who inhale cigarette smoke through tracheostomas de-
velop progressively more severe lesions of the bronchi and paren-
chyma with increased exposure to cigarette smoke. In electron
microscopic studies of specimens taken from the lungs of dogs thus
exposed to cigarette smoke, the following changes were observed:
In 5 dogs sacrificed after only 44 days of smoking exposure, there
was a proliferation of goblet cells as well as a partial loss of cilia
in the lining cells, and in 5 dogs sacrificed after 420 days or more of
exposure, the number of cell layers in the bronchial epithelium was
found to be twice that of the nonsmoking dogs. Goblet cells and
ciliated columnar cells were no longer present ; instead, the surface
was lined with columnar and cuboidal cells with stubby projections
in place of cilia. Mitotic figures were frequently observed in the
basal cells. These findings may be relevant to carcinogenesis as
well as to the development of COPD.

In a long-term experiment, carried out by the same group, dogs
were exposed to varying doses of cigarette smoke. Details of the
experimental procedure have been outlined in the section on Pul-
monary Carcinogenesis. The animals were separated into non-
smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex-
posure groups. The dogs were "smoked" for 8'75 days, or approxi-
mately 29 months. The animals which died during the experiment
and the animals sacrificed after day 875 were examined for pul-
monary parenchymal changes as well as for bronchial epithelial
alterations. As seen in figures 1 and 2, dose-related pathological
changes, including fibrosis and emphysema, were found in the lung
parenchyma of the exposed dogs. These changes were similar to
those seen in the lungs of humans with COPD.

158


TARLE 9.-Experiments concerning the effect of the inhalation of cigarette smoke ?Lpon the tmchco-bronchial tree and pulmonary
                          parenchyma of animals'
                                (Actual number of animals shown in parentheses)

Author,               A. Type of
  Yes=.
country,   A::Y        exposure
                    B. Duration                                    Results
reference     strain       C. Material

Leuchten~  603 CF1      A. Inhalation.
berger,    female mice.  B. Up to 8 ciga-               Number

et al.,
1960,
U.S.A.
(1.w).

r&es/day for
"Pto2yeaI-s.
C. Cigarette smoke.

Number of mica showing specified chnngca
   Number

Months
c?zposu+e
  0
l-3
4-R
9-23
l-23

  Of           of          NO         Mild
cigarettes         mice        ehangr      bronchitis
  0            150         146          2
10&200           36          20          9
260-600           36          19         10
600-1600          34          19          7
25-1526          151          xx         33

Severe bronchitis
with atyptin
2 (no atypism)
7

7

8
30

Holland
et al..
1963,
(121).

60 rabbits.

A. Inhalation.
R. Up to 20 ciga-
  rettes/day for
  2-5.
C. "Normal ciga-
  rette smoke".

N0tTld
Controls  
Exposed  

          Cytology of tmchcobrouchial murosa

                      Focal hypcrplnaia
  (30)21/30         6/30
  (30) 7/30         10130

Gcnerdired
hyyerplaaia
  3/30
  I)/30

Hernander Adult Grey-   A. Inhalation.
et al..     hound      B. Twice daily/
I!lf,f,      doas.         5 per week.
U.S.A.             C. Cigarette
(111).                smoke.

                Number of
                  sections
I. Controls    (8)112
II. All exposed  (15) 205
III. Exposed <l year    (7) 98
IV. Exposed >l year  CR)107

Mm )s
number of
mo,zths
   
10.50
  4.60
14.74

  Mmn
pnrrnchymal    Groups
disruption/dog   W?IlpilTHl       P-U&O
  O.il.50        I-111       insignificnnt
  0.!)58:1        II-I        insignificant
  0.6421       III-IV       P <0.05
  I.2350       IV-I        P <0.02


TABLE 9.--Experiments concerning the effect of the inhalation of ciga,rctte smoke U~O?L tltc tmcheo-l~roncl~ial twc and pulmonary
                        parcncll,z/ttia of animals' (cont.)

(Actual number of nnimnls shown in parentheses)

huerbach
et al..
1967,
U.S.A.
(f&16).

Results

                 ~-
Beagle dogs.   A. Active inhalation  Controls (lo)-No evidence of pulmonnrv fibrosis or s&al rupture.
           via tracheostomy. Exposed (lo)-Early (sacrificed) :
         B. Up to 12 cigRrcttes                1. Alveolar space dilatarion.
            per day for up                 2. I'ad-like attachments to alveolar septa.
            to 423 days.                Medium czpo.wm: Septal wall thickening.
         C. Cigarette smoke.              Latest crposarc:
                                    1. Focal subpleuriil pulmonary fibrosis.
                                     2. Ruptured alveolar septa.
                                     3. Granrtlomata.

FrWX&
et al..
1968.
U.S.A.
(88).

Beagle dogs.

A, Active inhalation Electron microscopic results:
  via tracheostomy. After 44 days -   Increased number of goblet cells.
B. Up to 12 ciaarettes             Decreased number of cilia on surface lining cells.
  per dny for "P   After 420 dsys-   Increased number of epithelial cell layers.
  to 423 days.                Loss of ciliated columnnr cells.
C. Cigarette smoke.              Frequent interruptions in basement membrane.

lNumerous experiments detailing changes in bronchial epithelium aredetailed tabularly in the Cancer Chapter


80 -

20

                                12.9

                    5.7        '.

0
     GROUP N:      GROUP F:      GROUP L:      GROUP Ii:
    NONSMOKING    FILTER-TIP     NO FILTER     NO FILTER
                      (% as many cigmttes)
                             as Group H

FIGURE l.-Percent of lung sections with grade IV or V fibrosis.

SOURCES: Hammond, et al. (104).

Several investigative groups have exposed rodents to various
ambient concentrations of nitrogen dioxide over prolonged periods
of time. This gas is found in cigarette smoke and in some indus-
trially polluted air. The results of these studies are outlined in
table AlO. It is clear that chronic exposure to low levels of NO, is
capable of inducing lesions in the bronchial tree although the rela-
tionship between these changes, cigarette smoking, and the devel-
opment of COPD remains to be determined.

Rosenkrantz, et al. (196, 1.97) have recently undertaken experi-
ments dealing with pulmonary cellular metabolism. They exposed
Swiss albino mice to cigarette smoke or its vapor phase for varying
lengths of time. On autopsy, animals exposed to cigarette smoke
showed elevations in the levels of lung DNA, lactate, and glycogen
which the authors conclude reflect hyperplasia and macrophage
infiltration. Similarly, a dose-related increase in lung hydi*oxypro-
line was observed. This was considered to be due to increased fi-
broblastic collagen synthesis.

161


98.6

80 -

60 -

24.3

GROUP N:
NONSMOKING

GROUP F:      GROUP L:      GROUP H:
FILTER-TIP      NO FILTER     NO FILTER
        (% ss msny cigarettes)
           ss Group H

FIGURE 2.-Percent of lung sections with grade II or III emphysema.
SOURCES Hammond, et al. (10.4).

Aviado and coworkers have performed a series of experiments
on live animals and in heart-lung preparations to study the effect
of cigarette smoke on pulmonary physiology and structure (18,1g,
20,21,22,179,180,199, 200,201,202). The authors observed that
cigarette smoke causes acute bronchoconstriction both by the re-
lease of histamine and the stimulation of parasympathetic nerve
pathways in the lung. Bronchial arterial injections of nicotine were
found to cause reactions similar to those observed after cigarette
smoke inhalation. The bronchoconstriction was usually followed by
bronchodilatation which the authors attributed to sympathetic
stimulation. As mentioned in the Chapter on Cardiovascular Dis-
eases, nicotine has been shown to induce the release of catechola-
mines.

Experiments by Aviado and coworkers as well as other authors
(66, 99) using guinea pigs showed that exposure to cigarette
smoke was associated with increased bronchopulmonary resistance
and decreased pulmonary compliance. The authors related these
changes to the bronchoconstriction of terminal ventilatory units.

162


Similar experiments in dogs showed that the increase in resistance
following either cigarette smoke exposure or intravenous nicotine
could be blocked by pretreatment with atropine. As a parasympa-
thetic blocker, atropine would decrease the acute bronchoconstric-
tive phase.

Most recently, Aviado and his colleagues (20, 130) have at-
tempted to induce physiologic and anatomic changes similar to
those found in the lungs of patients with emphysema. They ex-
posed male rats to cigarette smoke, the introduction of the enzyme
papain, as well as to partial tracheal ligation. In 10 rats exposed
to cigarette smoke twice daily for 30 minutes over a period of 10
weeks, no changes in pulmonary compliance or resistance were
noted. Also, no abnormal histological changes were observed in the
group exposed only to cigarette smoke. However, animals who
underwent tracheal ligation as well as smoke exposure showed in-
creased numbers of enlarged air spaces and increased pulmonary
resistance when compared with animals who underwent only
tracheal ligation.

STUDIES IN HUMANS

The acute effects of cigarette smoke inhalation on bronchopul-
monary function in man have been investigated by a number of
workers. The results of these studies are presented in table 11. The
majority of studies, particularly the more recent ones, found that
the inhalation of cigarette smoke is associated with an acute in-
crease in pulmonary resistance and a decrease in pulmonary com-
pliance. Chapman (48) also observed decreases in pulmonary dif-
fusing capacity and arterial O? tension. Chiang and Wang (51)
noted changes in nitrogen washout time and alveolar dilution fac-
tor, alterations which reflect impaired alveolar ventilation and gas
mixing.

James (1.~1) examined the effect of prior smoking on the mul-
tiple breath nitrogen washout test in 41 pneumoconiotic miners and
5 normal young males. Prior smoking of a cigarette in the subject's
normal manner was found to adversely affect the indices of dis-
tribution in 20 percent of the miners and in all of the 5 normals
who smoked within one hour of testing. The author suggests that
smoking be prohibited prior to any series of pulmonary function
studies.

Anderson and Williams (9) studied the acute effect of cigarette
smoke inhaIation upon the ventilation-perfusion (V/Q) measure-
ments in the lung in normals and in patients with COPD. Cigarette
smoking was observed to cause acute changes in the V/Q measure-
ments, and the COPD patients were found to be particularly liable
to these changes.

163


Finally, Robertson, et al. (194) studied the effect of unfiltered
and filtered cigarette smoke and cigar smoke upon bronchial re-
activity in 19 of the most reactive persons in a group of 91 heavy
smokers. They observed that bronchial reactivity was significantly
reduced by increasing he retention efficiency of the filter and that
reactivity to inhaled cigar tobacco was no less than that to cigarette
smoke. They concluded that differences in inhalation account for
the difference in COPD prevalence observed between cigarette and
cigar smokers.

STUDIES CONCERNING PULMONARY CLEARANCE

Overa. Clecirance

The ability of the lung to rid itself of inhaled particles that can-
not be easily exhaled is dependent upon a number of physiologic
mechanisms including ciliary activity, the mucous sheath, and the
pulmonary alveolar macrophage. Studies concerning the effect of
human cigarette smoking and the exposure of animals to cigarette
smoke on this clearance system are presented in table A13. LaBelle,
et al. (115) and Bair and Dilley (23) observed no change in clear-
ance following the exposure of rats, rabbits, or dogs to cigarette
smoke. The latter authors noted, however, that normal clearance
rates obtained prior to smoking were too low to reflect any sig-
nificant change except complete cessation.

Albert, et al. (3) exposed donkeys to cigarette smoke via nasal
catheter and observed impairment of clearance times. Holma (125)
obtained similar results in rabbits.

In a relat.ed study, Albert, et al. (2) studied the bronchial clear-
ance times of 9 nonsmokers and 13 cigarette smokers in a total pop-
ulation of 36 subjects. The rates of bronchial clearance were slower
on the average in the cigarette smokers when compared with the
nonsmokers, although a wide variation was present in each group.
In relation to their study mentioned above, they also noted that the
shape of the whole lung clearance curves seen in smokers (with
markedly prolonged 50 percent clearance times) was similar to that
developed in the donkey following acute exposures to sulfur dioxide
or cigarette smoke.             .
                             . .

Numerous experiments have shown that cigarette smoke or cer-
tain constit.uents of cigarette smoke adversely affect and can even
bring about a cessation of ciliary activity in respiratory epithelium
it/ ~`i?*o and it) ~it,,o in cultures of ciliated microorganisms. The re-
sults of a number of these experiments are presented in table 12.

164


Ciliary activity has been shown to be affected by particulate matte1
as well as by the gas phase components of cigarette smoke. The rel-
ative importance of these two large classes of components of smoke
in producing ciliastasis is presently a matter of some discussion.
Dalhamn and Rylander (63, 61) consider the particulate phase to
be of greater importance while Battista and Kensler (28, 29) con-
clude that gas phase components are more important in the induc-
tion of ciliastasis.

Studies investigating the effect of cigarette smoke on the
morphology of the tracheobronchial tree in animals have noted a
decrease or absence in the number of cilia in smoke-exposed ani-
mals. Recently, Kennedy and Elliot (131) studied the effect of the
direct exposure of cigarette smoke upon the electron microscopic
structure of protozoan mitochondria. After 42 minutes of exposure
to mainstream smoke, they noted destruction of the internal mem-
brane structure of the mitochondria.

Thus, cigarette smoke has been shown to be toxic to ciliary func-
tion by pathological (including electron microscopic) and physio-
logical methods.

Phugocytosis

The effect of cigarette smoke upon pulmonary alveolar phago-
cytosis, one part of the clearance mechanism, has been studied by
several authors. Masin and Masin (162) observed increased varia-
tion in the size of lipid inclusions in sputum macrophages obtained
from smokers as compared to those obtained from nonsmokers.
They attributed these differences to a combined effect of irritation
of the alveolar lining, increased turnover of alveolar cells., and in-
creased injury to the macrophages. Green and Carolin (96) noted
that cigarette smoke inhibited the ability of rabbit alveolar macro-
phages to clear cultures of S. a?ATeus. This effect was noticeably
reduced by filtration. Similarly, Yeager (239) exposed rabbit
alveolar macrophages which had been induced by M. bovis to cigar-
ette smoke and observed a dose-dependent decrease in protein syn-
thesis. This alteration occurred at smoke solution concentrations
that did not affect cell viability. The alteration was only partly re-
versible and was due mainly to gas phase components. Myrvik and
Evans (175) observed similar protein synthesis alterations in
macrophages exposed to NO,.

Roque and Pickren (195) obtained alveolar macrophages at
thoracotomy from 17 smokers and 4 nonsmokers, They found a
decrease in the activity of oxidoreductases and hydrolases in the
macrophages of smokers. The reduction in the enzymatic activity
was directly proportional to the amount of stored fluorescent ma-
terial present in the macrophages. This material was thought t.o

165


TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function

Author,
Y-u-,
country.
reference

Bickerman
and
Barach,
1954,
U.S.A.
(31).

Number and
type of

A. Method =
B. Material 1
C. Duration of

RemIta

   population

I. 66 male and
   25 female
   patients
   with chronic
   nontuberculous
   respiratory
   disenws
   ( swrage age
   50).
II. 20 male and
   7 female
   normal suh-
   jects (average
   age20).

      smoking

A. Pulmonary
   function.
B. 3 cigarettes.
C. 30 minutes.

   Vital capacity ( VC)
I. lo/91 decrease.
II. No significant change.

Ma&nd breathing capacity  B/91 patients showed
IO/91 deerease.         VC incresse due to
No significant change.     clearance of secre-
                  tions. All mild or
                   moderate smokers.

Eich,
et al..
1957.
U.S.A.
(76).

I. 31 patients with
   obstructive
   PUb~OIWY
   emphysema.
II. 14 normal
   subjects.
III. 6 patients with
   respiratory
   complaints.
   All habitual
   smokers.

A. Esophageal balloon
   technique to
   mecL9ure pulmonary
   compliance and
   resistance.
B. 1 cigarette.
C. Undefined.

  Mean airway resistance
I. Statiaticslly significant
   increase.
II. No change.
III. No change.

Mean aimmu compIiance
   No change.

   No change.
   No change.


TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulnaonam function (cont.)

Author,
Ye*=,
cou"trY,
reference

Attinger
et al.,
1958,
U.S.A.
(19).

Number and
type of
population

I. 20 normal
   subjects
   (10 Sm.
   10NS).
II. 34 patients with
   various diseases;
   9 rheumatic heart
   diseases, 8 pul-
   mOn*rY mlPhY-
   sema, 7 asthma,
   5 pulmo"aly
   fibrosis,
   5 undefined.

    A. Method 1
   B. Material 1
   C. Duration of
      smoking

A. Esophagal balloon

I. No change.

Ftesulta                     CO"l"E"ts

      No change.

  technique to meas"re
  pulmonsry compliance
   and resistance.
B. l-4 cigarettes.       II. Expiratory resistance rose        No change.
C. 10 minute interval         signiticantly only among
   between              patients with
   cigarettes.             emphysema.

Motley and  125 males and         A. Pulmonary           41 smokers             Pulmomrg~ compliance     Various groups of
KUZ"l*",   16 females             function.           (8 "ornlals,                                normals and cardio-
1968.     (24-70 years of       I%. 2 cigarettes.          33 patients           Significant decrease after     pulmonary patients
U.S.A.    age-"ormals        C Undefined.            with cardio-             smoking.              showed little or no
(f74).    and patients).                           pUl"lO"*lY                              change in arterial
                                          disease).                       p02 during exercise
                                                                           and at rest follow-
                                                                          ing cigarette smoke
                                                                           inhalation.
                                                                      .-.
Nadel and   I. 22 patients with     A. Body plethy-             Airwev cmdvctance/thoracic gas vdumC        Nicotine hitsrtrate
CO"VO&      cardiopulmonary      smography.       I. 18/22 significant decrease (inhibited by pretreatment       aerosol evoked no
1961,        disease--all       B. 15puffs.             with isoproterenol aerosol).                     change.
U.S.A.       smokers.        C. 5 minutes.       II. 31/36 significant decrease (inhibited by pretreatment with
(176).   II. 36 normals (21                        isopmtercnol aerosol).
           smokers, 16
           nonsmokers).


Author,
war,
countlY,
reference

Number and
type of
population

A. Method 1
B. Material '
C D;a&a$";gof

   -                          -..

Results                     Comments

Sim""ss"",
1962,
Sweden.
(207).

Zll"ld
et al.,
1963.
England,
(240).

I. 9 male and 7
   female normals
   (most smokers).
II. 15 male nnd 1
   female pulmonary
   disease patients
   (most smokers).
~
I. 6 male and G
   female nonsmokers.
II. 6 male and 6
   female smokers
   (18-32 years
   of age.)

A. Pulmonary
   function.
B. l-2 cigarettes.
C 5-6 minutes
   PCP cigarette.

   MmnFEVl o
  (immediately ejtcr)
I. Significant decrease.
II. Significant decrease.

   McanFEVl o
   (45 minutes letcr)
No significant decrease.
Significant decrcnse.

No siunifirnnt changes
ohserved in FEV/FVC.

A. Body plethy-
   smography.
B. 1 cigarette.
C. Undefined.

Airway resistance
I. Significant increase.
II. Significant increase.

1965.
Ireland
(48).

__-
McDermott
and
Collins,
1965,
Wales
(160).

I. 12 normal
   v"lu"teers
   (all smokem).
11. G patients with
   chronic "on-
   specific lung
   disease.

I. 32 normals.
II. 2X with chronic
   bronchitis
   (All ciga-
   rette smokers
   35-GO years
   of age.)

A. Pulmonary function
   Arterial blood
   studies.
B. 1 cigarette.
C. Undetined.

I. All showed a decrease in diffusing capacity.
II. 4/6-significant decrease in arterial O2 tension.
   No change in vital capacity or FEV.

A. Body plethy-
   smography.
B. Cigarette.
C. Undefined.

Mean airway resiatancc              Light smokers showed
I. Significant increase.               greater changes than
II. Significant increase.               heavy smokers.


Miller and   10 normal
SProule,    cigarette
1966,     smokers
U.S.A.     (40 years
(1GG).    ofage).

A. Esophaeeal ballwn
   technique.
B. 1 cigarette.
C. One inhalation
   Pc3-Y ao-FO
   seconds.

FEvo.5
No significant
change

Dynamic
compliance
Significant
decrease.

Inspiretory and
erp,iratory rceistmca
   Significant
    increase

Sterling.   11 normal adults
1967.     (E smnkers,
England   3 nonsmokers)
(219).

Chiang and 7 male normal
W*nEC.    nonsmokers
1970.      (L-43 years
Formosa   of age).
(51).

A. Body plethy-
   smography.
B. 15 inhalations.
C. 5 minutes.

  Airway rcsiatancc
Significant increase (Return
to normal in 30 minutes).

A. Pulmonary function    Nitrogetr roaskcwt      L1my clcnrancc      Aleeolar dilution All luna volumes,

   Nitrogen washout.
B. 2 cigarettes.
C. Undefined.

tima
Significant
increase.

A. Body plethy-
   smography.
B. 1 cigarette.
C. Undefined.

Guvatt    110 subjects;
et al..     50X smoked
1970.     between meas-
England   ures 202
(lml).    did not fimoke.

-

  ' All the experiments listed concern studies of sulmonary function be-
fore and after smoking the epecified number of cigarettes (unless other-
wise specified).

illll,.L!
Significnnt
increase.

factor     excrpt for residual
Significant    \-olumr showed no
decrense.    significant change.
        No significant
         change in any of
         the flow rates.

    Brunckoconstrictio?~       On the avernge. non-
Significant increase with smoking.    smokers and es-smokers
                       sh<,wed tnonchodilation
                       and nm<,kers showed
                       I,~~rnch~~constriction.
                       Thr authors postulate
                       that the result among
                       nonsmokers is due to
                       the> rclcnsc of ndrenal
                       hoymonrs in these sub-
                       pxts.
        ~-_- __


TABLE 12.--Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance

Author,
Yea=.
countru,
reference

Subjects         Method

RBUkS                           Comments

Laurenzi   Swiss-Webster     Mice exposed to    Significant increase in S. aureu8 retention in mice expceed to:
et al..     male mice.        aerosol of s. au7euuB   (a) hypoxia-retention ratio 2.5 (10 percent Oa).
1963,                  and sacrificed at      (b) cigarette smoke-retention ratio 4.5.
U.S.A.                 intervals following
(149).                 exposure to various
                      stimuli.

LaBelle
et al..
1966,
U.S.A.
(145).

Albino female
rabbits.

Silver iodide or
colloidal gold
intratrachesllu.

17-30 hours of exposure to cigarette smoke caused no change in pulmonary
clearance as compared with controls breathing room air.

Bair and   Sprague-Dawley    Radioactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic
Dilley,    female rats.                 exposure to cigarette smoke (up to 18-20 cigarettes/? hour day/5 day week
1967.     male beagle dogs.   Radioactive aerosol.   for UP to 420 days) had no observable effects. The authors noted, however,
U.S.A.                         that normal clearance rates were too low to reflect anything but complete
(2.9).                               cessation.

Albert
et al.,
1969.
U.S.A.
(9).

--

36 subjects
undergoing 117
experiments.

                                              so perct?nt   90 percent t Approximate values.
                                              clearance    clearance  None of 9 nonsmokers
Radioactive tagged                   Number of   Average    time       time    had 60 percent times
FeOZ particles                      eubjects     age    (minutes)   (minutes )  over 200 minutes or
measured with    Nonsmokers  .   9       28        88        367    90 percent times over
Scintillation      All smokers  . . . . . .  14       33       172       t496    600 minutes while
counter.       20-29 cigarettes/day . . . .   7       29       191       ts19    6/14 smokers exceeded
            30-40 cigarettes/day   I       36       163       t414    both these limits.
             Uranium miners . .   3       62       310        580
           Cigar and pipe smokers   4       46        81        316
            Emphysema patiats .   2       66       330        676


TABLE 12.-Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.)

Author,

year.
country,
reference

Subjects

Method

Results

Commenta

Albert
et al.,
1969,
U.S.A.
(8).

Holma,
1969,
U.S.A.
(125).

Donkeys exposed
to cigarette
smoke by nasal
cstheter.

Rsdiosetive tagged    Average                                Trachael transit  Those donkeys exposed
Fe02 particles      number                                   time      to the greatest
measured with    cigarettes in    Perrent clearance   Halftime clearance                amount of smoke
Scintillation     .%hour period   Control  Cigarsttc Control  Cigarette  Control  Cigarette showed residual
counter.          1X-24       58      69     1.2      1.9      0.6      1.2    impairment of
               36         58      64     1.0      3.4      0.4      6.8    clearance for et least
                                                             2 months after acute
                                                              exposure.

Rabbits
(anesthetized).

C+* monodisperse   Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 nuffs/X minutes) caused
polystyrene      a "significant" increase in lung retention 10 minutes following cessation of
aerosol.         exposure.


originate in tobacco smoke. The authors suggested that the tobacco
smoke may have induced abnormalities in the mitochondria of the
macrophage. In a study of pulmonary macrophages harvested by
endobronchial lavage from smokers and nonsmokers, Pratt, et al.
(187) observed that the macrophages of smokers contained an ab-
normal pigment.

These studies indicate that the function of pulmonary clearance
carried on by the macrophage and ciliary systems is adversely af-
fected by cigarette smoke.

STUDIES CONCERNING THE SURFACTANT SYSTEM

The surfactant system of the lung consists of various biologically
active compounds such as phospholipids and mucopolysaccharides
which are present in the alveolar lining. Normal pulmonary func-
tion is influenced and partly determined by the integrity of this
system (203). The purpose of the surfactant system is to main-
tain the proper amount of surface tension in the alveoli so that the
expansion and contraction of the alveoli are facilitated.

Studies concerning the effect of cigarette smoke upon the sur-
factant system and the surface tension of the pulmonary alveoli
are presented in table A14. Exposure of rat and dog lung extracts
to cigarette smoke has been found to induce a notable decrease in
the maximal surface tension demonstrated by the extracts (94,
165, 2.24). Cook and Webb (57) observed that surfactant activity
was diminished in smokers and in patients with pulmonary disease
when compared with healthy nonsmokers.

Scarpelli (203) in a recent review, concluded that the lowering
of maximal surface tension by cigarette smoke has been demon-
strated reasonably well. The relationship of these findings to the
pathogenesis of emphysema is unclear at this time.

OTHER RESPIRATORY DISORDERS

INFECTIOUS RESPIRATORY DISEASES

Several studies have examined the question of whether ciga-
rette smokers are at an increased risk of developing infectious res-
piratory and bronchopulmonar~ disease. Table Al.5 presents a
summary of these studies. Lowe (1.57) observed an excess of
smokers among `i0.5 tuberculosis patients, but Brown and Campbell
(43) in a similar study found that the difference was not present
lvhen the cases and controls were matched for alcohol intake. More
recent studies have been concerned with the frequency of upper
respiratory infections among groups of smokers and nonsmokers.
A number of investigators (lOS,181, 183) have reported increased

172


-ates of respiratory illnesses among smokers. Finklea, et al. (83)
studied a male college population (prospectively) during the
1968-69 influenza epidemic. They found that smokers of all amounts
experienced more clinical illness than did nonsmokers and that this
relation was dose-dependent. Similarly, smokers required more bed
rest than nonsmokers.

A survey conducted by the National Center for Health Statistics
(220), involving approximately 134,000 persons, showed that male
cigarette smokers reported 54 percent more cases of acute bron-
chitis than males who had never smoked cigarettes, while female
smokers reported 74 percent more acute bronchitis than did females
who had never smoked. Male cigarette smokers reported 22 percent
more cases of influenza than did males who had never smoked cigar-
ettes, while the female smokers reported an excess of 9 percent.

Experimental evidence in support of this relationship has been
noted by Spurgash, et al. (211). Mice were challenged with
Klebsiellu pneumoniae or Diplococcus pneumoniae before or after
a single exposure to cigarette smoke. They observed that those ani-
mals exposed to smoke exhibited a decrease in resistance to respira-
tory infection, as shown by an increase in mortality and a decrease
in survival time. Preexposure to cigarette smoke was found to have
no significant effect on resistance of mice to influenza infection
initiated by aerosol exposure. However, exposure of infected mice
to smoke resulted in significantly higher mortality, thus suggest-
ing that cigarette smoke can aggravate an existing respiratory
viral infection.

In the light of the experimental evidence presented above con-
cerning the effect of cigarette smoke on pulmonary clearance,
phagocytosis, and ciliary function, it seems reasonable to conclude
that such changes in tracheobronchial physiologic function would
predispose a person to respiratory infections or aggravate already
existing ones.

Further evidence is derived from the work of Henry, et al. (109)
and Ehrlich, et al. (7'5). These investigators exposed squirrel
monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen
dioxide. They observed that this exposure increased the suscepti-
bility of the animals to airborne Klebsiella pneumoniae as demon-
strated by increased mortality and reduced lung clearance of viable
bacteria. Infectious challenge with influenza virus 24 hours before
exposure to 10 p.p.m. was fatal to all monkeys within three days.
Infected controls showed symptoms of viral infection but did not
succumb to the infection. The extent to which the various oxides of
nitrogen present in cigarette smoke contribute to the increased SUS-
ceptibility to respiratory disease noted in smokers is presently
undefined.

173


POSTOPERATIVE COMPLICATIONS

Several studies have been published which examine the questions
of whether smokers run an increased risk of developing postopera,
tive pulmonary complications over nonsmokers undergoing similar
operations.

Morton (173) reported on a study of more than 1,100 patients
undergoing abdominal operations in which he found that cigarette
and mixed smokers were significantly more likely to develop bran.
chitis, bronchopneumonia, or atelectasis during the postoperative
period than nonsmokers (table A16).

Wiklander and Norlin (229) examined the incidence of post-
operative complications in 200 patients undergoing laparotomy in
the winter months when it was expected that pulmonary compli-
cations would be at their maximum. These authors found no sig.
nificant differences between the frequency of complications in
smokers and nonsmokers. No information about the definition of
a smoker and no data on dosage of tobacco smoke were reported.

Piper (186) observed the prevalence of postoperative pulmonary
complications in 150 patients undergoing laparotomy. Of the total
sample, 66.7 percent developed pulmonary complications during
the first postoperative week. All patients considered in the statis-
tical analysis as having pulmonary complications had radiographic
evidence of disease. Of the cigarette smokers, 73.5 percent had
complications as compared to 55.5 percent of the nonsmokers.
When the smokers were divided according to dosage, heavy smok-
ers being those consuming more than 10 cigarettes per day for the
previous six months, 55 percent of light smokers and 88 percent
of heavy smokers were considered to have postoperative compli-
cations. Piper also reported that stopping smoking for up to four
days preoperatively had no apparent effect on the incidence of
complications.

Wightman (228) reported on the incidence of postoperative pul-
monary complications in 455 patients undergoing abdominal oper-
ations and in 330 patients undergoing other operations. Of the
cigarette smokers, 14.8 percent developed complications as com-
pared to 6.3 percent of the nonsmokers. The substantial difference
between these figures and those of Piper (186) is due to the latter's
use of radiographic criteria alone. Wightman utilized only clinical
criteria.

Morton (178) has recently reported a study of postoperative
hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four
of the smokers had chronic bronchitis. He found that the smokers
had a more pronounced decrease in arterial oxygen saturation, Per-
sisting into the second postoperative day (table A17).

174


In summary, the majority of studies so far reported indicate
that cigarette smokers run a higher risk of developing postopera-
tive pulmonary complications than do nonsmokers, corroborating
a long-held clinical impression. The risk of developing such com-
plications appears to increase with increasing dosage of cigarette
smoke.

SUMMARY AND CONCLUSIONS

1. Cigarette smoking is the most important cause of chronic ob-
structive bronchopulmonary disease in the United States. Ciga-
rette smoking increases the risk of dying from pulmonary emphy-
sema and chronic bronchitis. Cigarette smokers show an increased
prevalence of respiratory symptoms, including cough, sputum pro-
duction, and breathlessness, when compared with nonsmokers.
Ventilatory function is decreased in smokers when compared with
nonsmokers.

2. Cigarette smoking does not appear to be related to death from
bronchial asthma although it may increase the frequency and se-
verity of asthmatic attacks in patients already suffering from this
disease.

3. The risk of developing or dying from COPD among pipe and/
or cigar smokers is probably higher than that among nonsmokers
while clearly less than that among cigarette smokers.
4. Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smoking
is associated with improvement in ventilatory function and with
a decrease in pulmonary symptom prevalence.
5. Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with non-
smokers of the same age.

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

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

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes charac-

175