Buist, et al. (22) followed a group of `75 smokers attending a smoking
cessation clinic and observed significant improvement in closing
volume, closing capacity, and the slope of the alveolar plateau at 6 and
12 months in subjects who stopped smoking. McCarthy, et al. (105)
found similar improvement in 131 subjects who stopped smoking;
resumption of smoking led to subsequent development of abnormali-
ties in the slope of the alveolar plateau and closing capacity. These
findings are especially pertinent in view of the suggestion by Cosio, et
al. (313 that some of the pathologic changes present when tests of small
airway functions are abnormal can be reversed.
As a group, ex-smokers usually perform better on conventional
pulmonary function testing than smokers, but they do not perform as
well as nonsmokers (67). Several studies have confirmed that there is
improvement in performance on standard spirometric function tests
following cessation of smoking in small numbers of patients (85, 115,
159), but there is still debate as to whether the normal decline in
ventilatory function (i.e., FEV) is accelerated in ex-smokers as
compared to nonsmokers. In the Framingham study, Ashley, et al. (8)
observed that men and women who continued to smoke had a greater
decline in forced vital capacity (FVC) than those who stopped;
however, they could not demonstrate consistent changes in the FEVl
following smoking cessation. They attributed this to the impreciseness
and insensitivity of the FEVi measurement. In women ex-smokers, the
decline in FVC was similar to that of female nonsmokers; in male ex-
smokers, the decline in FVC was slightly greater than that of male
nonsmokers. Fletcher, et al. (57) observed that cessation of smoking
halved the rate of loss of FEV and returned the rate of decline in FEV
to normal in "susceptible" smokers. However, the lost FEV was not
recovered. Smoking cessation had no effect on the normal rate of
decline in "unsusceptible" individuals. Similarly, in a two-year
followup of 118 continuing ex-smokers, aged 27 to 56, Manfreda, et al.
(100) noted that subjects who continued to refrain from smoking had a
smaller decline in FEV&FVC ratio than did smokers; in the male ex-
smokers, the decline in ventilatory function fell at about the same rate
as that for nonsmokers.
In summary, it is clear that smoking cessation leads to improved
Performance on standard pulmonary function tests. However there is
still debate as to whether the normal decline in ventilatory function is
accelerated in ex-smokers as compared to nonsmokers.

Lung Pathology
Auerbach, et al. (10) studied the relationship between age, smoking
habits, and emphysematous changes in whole lung sections obtained at
autopsy from 1,443 males and 333 females. A total of `7,324 sections 1


mm thick were graded on a scale of 0 to 9 according to the severity of
emphysema. No distinction was made between centrilobular and
panlobular emphysema. The men were classified by age, type of
smoking (pipe, cigar, or cigarette), and amount of cigarette smoking.
Smoking habits were ascertained by interviews with relatives. Within
each of the six smoking categories, the mean degree of emphysema
increased with age. Adjusting the data for age revealed that the mean
degree of emphysema was lowest among men who never smoked, was
higher in pipe or cigar smokers, and highest among regular cigarette
smokers. A dose-response relationship was found for the number of
cigarettes smoked per day and the severity of emphysema. These data
are presented in Tables 5 and 6.

In a subsequent histologic study of tissue from 1,582 men and 368
women, Auerbach, et al. (9) were able to show that rupture of alveolar
septa (emphysema) and fibrosis and thickening of the small arteries
and arterioles were far greater in smokers than in nonsmokers and
increased with increasing amount smoked (Tables 7 and 8).

When these researchers examined former cigarette smokers, they
found that those who had stopped more than 10 years prior to death
had less marked pathologic changes than those who had stopped less
than 10 years before death. But even in those who had stopped for
more than 10 years, there was a greater degree of pathological change
in those who had been smoking more than one pack per day than in
those who had been smoking less than one pack per day (Table 9).

In a clinicopathologic study of 196 men and 46 women, Mitchell, et
al. (107') found that the total exposure to cigarettes was related to
clinical symptoms of chronic airway obstruction and to both alveolar
and airway pathologic features. The severity of pathologic change was
related to the amount of smoking.

Several recent studies have shown evidence of small airway
abnormalities in young smokers. Casio, et al. (37) found squamous
metaplasia of the airway epithelium as well as chronic inflammatory
infiltrate and a slight increase in the connective tissue in the walls of
the small airways. Kleinerman and Rice (83) found significantly more
emphysema, parenchymal pigment, and chronic bronchiolitis in the
lungs of smokers as compared to age-matched nonsmokers (median age
27.5 years).

In summary, cigarette smokers demonstrate more frequent abnor-
malities in macroscopic and microscopic lung sections at autopsy than
do nonsmokers. Furthermore, there is a dose-response relationship
between these changes and the intensity of smoking. Histologic
evidence of small airways pathology was more common in cigarette
smokers than in age-matched nonsmokers in an autopsy study of
sudden-death victims.

6-24


TABLE 5.-Degree of emphysema in current smokew and in
     nonsmokers according to age groups

Subjects      CUlTWIt
who never    pipe or
smoked      cigar
regularly      smokem

   Current cigarette
     smoke&



< "zt  +1t   l-2t   2+ t

70 or
older

co.75
l-1.75
22.75
u.75
p4.75
5-6.75
7-9.00

Totals

Mean
SD

         a4l.75
         l-l.75
         2275
m-69       3-3.75
      .   44.75
         rx.75
         7-9.00

Totals

Mean
SD

o-O.75
l-l.75
22.75
3-3.75
4-4.75
5-6.75
7-9.00

Totals

Mean
SD

53
2
-
-
-
-
-
-
55


0.10
0.04


35
1
2
2
-
-
-
-
40


0.39
0.13


68
4
5
4
-
-
-
-
81


0.50
0.39

18       12
11       4
1       2
1       5
-       -
-       -
-       -

-
31

23

0.83
0.13

129
026

17       4
8       1
3       4
2       2
-       1
-       -
-       -

-
30

12

0.95
0.16

1.90
0.34

21       2
28       10
22       13
8       5
2       1
1       -
-       -

-
a


1.66
0.11

31

215
0.17

-
45

2
24
130
50
8
4
3
iii

237
0.16

256
0.07

-    -
-     4
5     37
9     42
3     11
1     8
1     5
-    -
19    107

3.53
0.35

ii


293
020

3.33
0.15


-
2
40
38
11
9
12
112


3.63
0.17

-
5
56
38
7
5
1
-
112

2.86
0.10

-
1
23
24
9
1
4
-ii

3.37
0.20

-
44


3.91
0.27

*Subjecta who amoked regularly up to time of terminal illnear
W=kagw&y.
~LHtCX Auerbsch. 0. (10)

b3king and the Pathogenesis of Lung Damage
In recent years, numerous investigators have examined the mecha-
nisms by which smoking might induce lung damage. Three major
Pathogenetic possibilities by which smoking may damage the lungs

6-25


TABLE C.-Age-standardized percentage distribution of male
     subjects in each of four smoking categories according
     to degree of emphysema

Degree of
emphysema

Subjects    current
who never   pipe or
smoked     Gw
regularly    smokem
(W      cv

Current
cigarette
smokers (%)

                                     <I'      1+ o


O-6.75 (none)                     90.0       46.5       13.1       0.3
l-l.75 (minimal)                     3.8       33.0       16.4       5.2
2-2.75 (slight)                     3.3       13.0       33.7      42.6
3-3.75 (moderate)                    2.9       6.3       25.1       32.7
44.00 (advanced to far advanced)          0        1.2       11.7       19.2

                            -              -
Totals              loo.0 Ko      100.0   lao.0

`Packages/day.
SOURCE: Auerbach. 0. (10)

TABLE 7.-Means of the numerical values given lung sections at
     autopsy of male current smokers and nonsmokers,
     standardized for age                     .

         Subjects who Current pipe
           never smoked   or cigar       Current cigarette smokers
          reguldy     smoket3


                             <.5      5-l      l-2     >2
                               Pk.      Pk.      Pk.      Pk.

Number of subjects     175        141       66      115      440      216

Emphysema
Fibrosis
Thickening of
Wt.&Ok3
Thickening of
arteries

0.09       0.90       1.43      1.92      2.17     227
0.40       1.1      278      3.73     4.06     4.26


0.10       1.11       1.35      1.66     1.82     1.89


0.02       0.23      0.42     0.68      0.83     0.90

NOTE: Numerical value8 were determined by rating each lung section on 841% of C-4 for emphysema urd
thickening of arterioles. LL? for fibrosis, and CL3 for thickening of art&en.
SOURCE: Auerbach, 0. (9)

have been scrutinized. They are: (1) altering protease-antiprotease
balance in the lungs, (2) compromising immune mechanisms, and (3)
interfering with pulmonary clearance mechanisms.

Proteolytic Lung Damage

Emphysema is characterized by irreversible destruction of alveolar
septal tissue. If severe, this disruption may result in loss of elastic

6-26


TABLE S.-Means of the numerical values given lung sections at
     autopsy of female current smokers and nonsmokers,
      standardized for age

Subjects who
never smoked
regularly

Current cigarette
  smokers

<l Pk.     11 Pk

Number oc subjects                 262              33         64

Emphywma                      0.&5             1.37        1.70
Fibrosis                        0.37             239        3.46
Thickening of arterioles               0.06             1.26        1.57
Thickening of arteries                0.01             0.40        0.64

NOTE: Numerical value. were determined by rating each lung section on scales of @4 for emphysma and
thickening of the arteriden, O-7 for fibrosis. and Wg for tbiekening of lbe arteries.
60UFccE: Auerbch. 0. (9)

TABLE b.-Means of the numerical values given lung sections at
     autopsy of male former cigarette smokers,
     standard&l for age

Formerly Smoked

stopped 1 10 yr.

supped < 10 yr.

<1 Pk.

Pk.

<l Pk.

Pk.

Number of subjects            35         66         51         131

Emphysema                0.34        0.70        1.0s        1.63
Fibmsis                   1.14        1.74        244        3.30
lliclwling of arterides          0.57        0.93        1.25        1.56
Thickening of artwiea           0.04        0.16        0.36        0.61

NOTE: Numeriul values for each finding were determined by rating each lung section on aala, of O-4 for
~pbyaem;l and thiiening of the arimides, W7 for fibrwis, and K3 for thickening of the arteries.
SOURCE: Auerbsb. 0. (9)

recoil, enhanced collapsibility of the airways, and airflow obstruction.
The elastic properties of the lung are attributed to the appropriate
distribution of elastin in its connective tissue framework. Recent data
suggest that the lung damage observed in emphysema may be due to
injury of this elastic framework by proteolytic enzymes released (and
not inhibited) in the lung. Formulation of this hypothesis was catalyzed
by the discovery that emphysema is extremely common in individuals
who are severely deficient in alpha-1-antitrypsin (@, a glycoprotein
that inhibits several proteases. Subsequently, it was postulated that
Conditions interfering with the normal balance between protease and
antiprotease activity could give rise to an excess of free protease (i.e.,
elastase) in the lung and initiate lung destruction (109).

6-27


The proteases are a group of enzymes which probably serve a wide
range of functions in the normal host. Proteases with particular
elastolytic capability (elastases) are synthesized and released by
alveolar macrophages which are found in increased numbers in
bronchopulmonary lavage fluid of smokers. They are also present in
significant concentrations in polymorphonuclear leukocytes (PMNs).

The antiproteases, of which alpha-1-antitrypsin is the most abun-
dant, are found primarily in blood although alveolar macrophages and
bronchial secretions are additional sources of antiproteases. An excess
of protease within the lung may arise from any circumstances in which
there is increased release of protease which is not matched by
availability of antiprotease activity at the site of such release. Various
types of experimental support for the proteolytically mediated
hypothesis of lung damage have been presented in recent years (15, 75,
77,132).

Crude leukocyte extracts can digest lung tissue (76, 92) and
homogenates of leukocytes can produce emphysema (101, 103) when
instilled into the lungs of animals. The degree of damage depends on
the proteolytic activity of the instillate (82). Recently, Senior, et al.
(129) instilled purified human leukocyte elastase into the tracheas of
hamsters. At two months the lungs of the animals showed mild, patchy
-emphysema. In a related study, Schuyler, et al. (226) administered
elastase to hamsters intravenously and demonstrated significant loss
of elastic recoil at low lung volumes when their lung histology was
normal. The authors suggested that submicroscopic lesions may
antedate obvious morphologic evidence of emphysema.

The mechanisms by which cigarette smoking may alter the protease-
antiprotease balance have-been the subject of several recent investiga-
tions. Janoff and Carp (744 demonstrated .that unfractionated
cigarette smoke condensate suppressed antiprotease activity in vitro.
Elastin-agarose gels were impregnated with cigarette smoke conden-
sate. Elastases were then allowed to diffuse through the gels toward a
counterdiffusing sample of antiproteases. The effectiveness of the
antiproteases in blocking-the enzyme washet&nined by the elitent of
elastin destruction in the plates. -F&Wins, proteases, and antiproteases
from different sources, inc!llding purified human leukocyte elastase
and human alpha-1-antitrypsin, were tested. In all situations, .t.he
-cigarette smoke condensate suppressed the inhibitory activity of the
antiprotease. In a followup study, Carp and Janoff (26) demonstrated
that fresh cigarette smoke also Suppressed elastase-inhibitory activity
of human serum. In addition, treatment of serum with model oxidants
caused a similar suppression of elastase inhibition. These in vitro
observations suggested to the researchersthat emphysema in cigarette
smokers might be due in part to the suppression of- antipro&%
activity by oxidizing agents`present in cigarette smoke.

6-B


In another study from the same laboratory, Blue and Janoff (16)
demonstrated that cigarette smoke condensates elicited the release of
elastase from human PMNs. When human PMNs were incubated in
vitro with cigarette smoke condensate, three enzymes were released:
beta-glucuronidase, acid phosphatase, and elastase. The elastase was
active in digesting elastin, even in the continuing presence of cigarette
smoke condensate. When mixtures of human PMNs and cigarette
smoke condensate were instilled into rat lung in F&O, elastase was
released and could be traced to connective tissue targets using
immunohistochemical and enzyme-histochemical techniques. This
study appears to be particularly relevant in view of previous studies
demonstrating that cigarette smoke recruits leukocytes into the lung
airways (81, 124), immobilizes them (46), and inhibits their chemotaxis
in vitro (17).

The role of the pulmonary macrophage in proteolytic lung damage
has been evaluated by several investigators. Alveolar macrophages are
normally important in cleansing the lower airways by phagocytising
and digesting foreign particulate matter. Bronchopulmonary lavage
studies have documented increased total numbers of macrophages in
lavage fluid of smokers as compared to nonsmokers (65, 156). Keast
and Holt (79) exposed mice to smoke via a special apparatus and found
sustained elevations in bronchopulmonary macrophage populations.

Changes in the ultrastructure of macrophages have been reported in
smokers. Pratt, et al. (116) observed pigmented cytoplasmic inclusions
in macrophages from cigarette smokers, Brody and Craighead (18)
observed that the pigmentation appeared to be due, at least in part, to
an increased number of lysosomes and phagolysosomes. In addition,
distinctive "smoker's" inclusions were observed within these cyto-
plasmic organelles which appeared plate-like and crystallographically
consistent with kaolin&e. The authors presented some preliminary
evidence that these particles are derived from inhaled tobacco smoke.
Kaolinite is a common clay mineral found in the soil in many tobacco
growing regions and is sometimes used as a tobacco additive in the
production of cigarettes for the purpose of reducing tar content. A few
studies have shown that when macrophages engulf kaolinite they
release beta-gulcuronidase and lactic acid dehydrogenase, lysosomal
enzymes believed to play a role in cell death and fibrogenesis in tiuo (3,
66, 157). In a recent study, Matulionis and Traurig (104) exposed
Pulmonary macrophages of mice in situ to cigarette smoke and found:
(I) an increase in number, variety, and size of lysosome-like bodies in
the macrophage; (2) the appearance of multinucleation; and (3) an
increased size of the macrophages. After cessation of smoke exposure,
macrophage morphology and population size returned toward normal.
A considerable increase in elastase-like e&erase and protease
activity was demonstrated by Harris, et al. (64) in human alveolar
macrophages in smokers as compared to nonsmokers. In a subsequent

6-B


study, Rodriguez, et al. (119) demonstrated that human alveolar
macrophages from smokers released elastase into serum-free culture
medium, unlike those from nonsmokers. Elastase was not detectable in
cell homogenates from either smokers or nonsmokers, implying that
this enzyme is not stored. The authors suggested that cigarette
smokers have the potential for a 20-fold increase in elastase released in
the lungs when the increased number of macrophages in lungs of
smokers also is considered.

Potentially important effects of cigarette smoke also have been
demonstrated on alveolar macrophage pinocytosis (164), cell adhesion
(61), cell migration (154), and protein synthesis (94, 95, 163). The data
relating the effect of cigarette smoke to alveolar macrophage
phagoocytosis and bacteriocidal activity are conflicting (61, 130, 135,
1%`) but generally have shown cigarette smoke to have a suppressant
effect. At least some of the toxic effects of the gas phase of cigarette
smoke on macrophage activity may be due to the oxidant, acrolein (74).

In summary, a number of recent investigations have suggested that
a destruction of the elastic framework of the lungs seen in COLD may
result from a protease-antiprotease imba!ance. Although definitive
evidence is lacking, it appears that alveolar macrophages and PMNs
are the most important sources for the proteases. Cigarette smoke
appears to increase the rate of synthesis and release of elastase in vitro
from human alveolar macrophages and increases their numbers.
Antiproteases are inhibited from counteracting protease activity in the
presence of cigarette smoke in vitro. Possible deleterious effects of
cigarette smoke also have been demonstrated on a variety of functions
of the human alveolar macrophage.

Interference with Immune Mechanisms

The lungs have a highly developed lymphatic system and the capacity
to effect local immune responses. Inhalation of tobacco smoke produces
significant changes in cellular and humoral immunity in both animal
and man. However, the role of such changes in the pathogenesis of
lung disease remains speculative. Waldman, et al. (151) reported that
cigarette smokers of more than l/2 pack per day had an increased risk
of influenza-like illnesses although the length of illness was no
different than for nonsmokers.

Finklea, et al. (52) noted that smokers had more frequent subclinical
influenza than nonsmokers; subsequently he observed that the
serological response (hemaglutination antibody titers) to either
vaccination or natural infection with A-Z antigens was similar to that
in nonsmokers but not as long lasting (51).
Cigarette smoke appears to adversely affect the nonspecific
(phagocytosis) defense mechanisms provided by the alveolar macro-
phage. Evidence for an effect on the specific (immune) defense roles

6-30


played by both macrophages and lymphocytes has been offered by
several investigators.

The alveolar macrophage system plays an important role in the
overall immune response as an antigenic "processor." Warr and Martin
(15.4 studied alveolar macrophages lavaged from four healthy smokers
and four healthy nonsmokers. Only two members of each group were
reactive to skin tests with Candida albicans. The migration of
macrophages from nonsmokers was inhibited by migration inhibitory
factor (MIF) whereas macrophages from smokers did not respond to
MIF. The cells from smokers were noted to migrate three times faster
than those from nonsmokers. When Candida antigen was added to the
medium, cells from the nonreactive subjects (both smokers and
nonsmokers) were not inhibited. The cells from the reactive nonsmok-
ers were inhibited, but not those from reactive smokers. Thus,
macrophages from smokers did not respond normally either to MIF or
antigenic challenge.
The B and T lymphocytes participate in humoral and cell-mediated
immune mechanisms, respectively. Warr, et al. (155) noted that a
greater number of T cells and B cells were recovered by human
bronchopulmonary lavage from smokers than from nonsmokers.
Daniele, et al. (39) examined the T and B cell populations in peripheral
blood of smokers versus nonsmokers and found no difference in either
the absolute number of cells or the lymphocyte response to phytohema-
glutinin (PHA) or concanavalin A. In a lavage study of five smokers
the lymphocyte subpopulation did not differ from that in nonsmoking
subjects (n=8), but cells from smokers showed a diminished response
to PHA and concanavalin A. They concluded that cigarette smoking
may impair cellular immune defenses.
In contrast, Silverman, et al. (134 found that young smokers had an
increased number of T lymphocytes in peripheral blood and an
enhanced response to PHA. No differences were found in the response
of older smokers or those with a history of heavier cigarette
consumption as compared to controls. A number of other studies have
examined the relationship of smoking to T-cell function; these are
reviewed in the Chapter on Allergy and Immunity.
Roszman and Rogers (121) noted that both the nicotine and the
water-soluble fraction of whole cigarette smoke suppressed the
immunoglobulin response of lymphoid cell cultures to antigen chal-
lenge. When concentrations of over 200 micrograms per milliliter of
nicotine of the water-soluble fraction were added, they were able to
SuPpress completely the immunoglobulin response; this suppression
also occurred in cells exposed 2 hours prior to the antigenic challenge.
In a subsequent experiment, they found suppression of mitogen-
induced blastogenesis by cigarette smoke (120). War-r, et al. (156)
examined immunoglobulin levels in bronchopulmonary lavage fluid in

6-31


19 smokers and 36 nonsmokers. They could find no difference in IgA
levels; however, IgC levels were twice as high in smokers.

In summary, a variety of alterations in the specific immune system
have been observed that are presumably due to cigarette smoking.
Macrophages from smokers respond abnormally to MIF or antigen
challenges. T lymphocytes obtained by bronchopulmonary lavage in
smokers showed a diminished response to PHA compared to those of
nonsmokers. Cigarette smoke suppresses production of immunoglobu-
lin by B lymphocytes in lymphoid cell culture. However, the role of
these abnormalities in the pathogenesis of lung damage is unclear.

Effect on Clearance Mechanisms

The mucociliary transport system protects the lung against inhaled
particulate matter. Its two major components are the respiratory
mucus blanket (secreted by submucosal and goblet cells) and the
ciliated columnar epithelial cells lining the larger airways. Denudation
of epithelium, an increased number of goblet cells, and squamous
metaplasia have been demonstrated by Auerbach, et al. (11) in dogs
exposed to cigarette smoke via a tracheostoma, and by Leuchtenber-
ger, et al. (91) and Rylander (12.4) in mice and guinea pigs exposed to
cigarette smoke via their upper airway passages. Similar morphologic
abnormalities have been observed in human cigarette smokers (58).

A number of investigators have examined the effects of cigarette
smoke on mucociliary function, employing a wide variety of experi-
mental techniques. These studies have scrutinized the effects of gas
and particulate elements of cigarette smoke in both acute and chronic
situations.

Short-term exposure to cigarette smoke causes ciliostasis and
decreased mucociliary transport in most animals (152). The ciliotoxic
effects of cigarette smoke are not peculiar to tobacco cigarettes; they
have been observed in protozoans following exposure to smoke from
lettuce and grass cigarettes (60). The data relating these effects to
specific particulate or gas phase elements of cigarette smoke are
conflicting (38). Moreover, the relevance to human conditions of animal
models demonstrating altered mucociliary function in "smoking"
(tracheostomized) animals has been questioned, since, in humans,
cigarette smoke passes the upper airways which might alter its
ciliotoxic capacity for the lower airways (152). Data regarding the
effects of acute cigarette exposure on mucociliary clearance in man
also are conflicting (2.51).

Long-term exposure to cigarette smoke has been examined in
animals and in man. Tracheal mucous velocity has been shown to be
decreased in purebred beagle dogs (153) exposed to 100 cigarettes per
week for 13.5 months. In donkeys (.2), low level exposure to whole
cigarette smoke accelerated tracheobronchial clearance; at intermedi-


ate and high levels whole cigarette smoke had twice the effect of
filtered smoke in decreasing clearance.
The long-term effects of cigarette smoking on mucociliary function
in man are unclear. Most of the evidence indicates that long-term
smoking reduces mucociliary transport (152). Animal and human
studies have suggested that cessation of smoking may allow partial
recovery of mucociliary function (1,25).

interaction of Smoking with Other Risk Factors for COLD
Alpha-l-antitrypsin Deficiency

It would be useful to identify the populations at special risk of
developing COLD from smoking so that such populations might be
made aware of the risk. Persons with significant deficiencies of alpha-
1-antitrypsin may be such a population.
Eriksson (~8) was the first investigator to observe a relationship
between the presence of markedly decreased serum trypsin inhibitory
capacity and panlobular emphysema. Since Eriksson's paper, much
research has been published concerning this intriguing observation.
Severe alpha-1-antitrypsin deficiency is due to a rare genetic trait
which occurs in approximately 1 in 2,000 people (49). Less severe
reductions are found in approximately 2 to 10 percent of the
population. Alpha-1-antitrypsin inheritance patterns indicate multiple
codominant alleles at one gene locus. Some alleles (notably Z, S, and
"null") are associated with substantially reduced serum levels of alpha-
1-antitrypsin. The autosomal codominant inheritance allows multiple
combinations of alleles associated with low or normal serum levels of
the antiprotease. For example, extremely low levels are associated
with the ZZ homozygous state, intermediate levels with the MZ
heterozygous state, and normal levels with the MM state. Thus, a wide
range of serum levels may be encountered which depend upon the
Particular alleles involved. The particular phenotype of a given patient
can be identified by antigen-antibody crossed gel electrophoresis but
not by measurement of serum levels alone, because alpha-1-antitrypsin
is an acute phase reactant. The pathophysiologic implications of a
reduction in antiprotease activity have been discussed in previous
sections.
Severe deficiency of alpha-1-antitrypsin has been associated 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 (63, 136, 158).
PoPulations with this genetically related form of emphysema have a
greater percentage of females than is usually observed in the general
emphysema population. Their disease begins earlier, is more severe, is
characterized by dyspnea rather than cough, and frequently is

6-33


unassociated with a history of preceding bronchitis (63, 136, 158).
Radiographic studies of alpha-1-antitrypsin deficient patients have
revealed decreased vascularization of the lower lobes (134).

Several retrospective studies in patients with severe deficiency have
demonstrated an association between smoking and the age at which
emphysema becomes manifest. However, control nonsmoking subjects
with a similar phenotype have not been included. Black and Kueppers
(14) evaluated 18 patients with alpha-1-antitrypsin deficiency who had
never smoked and had little or no exposure to occupational or urban air
pollution and compared them to 36 individuals with similar phenotype
(PiZZ) who were (or had been) smokers. A larger percentage of
individuals who smoked had impaired lung function early in life.
However, there was considerable variability as to clinical course,
degree of pulmonary function abnormality, and appearance of the
roentgenogram among the nonsmokers. The authors recognized that
their study was biased in favor of individuals with symptomatic
disease; however, they noted that the rarity of the PiZZ phenotype and
the need to identify nonsmokers with no other exposure to respiratory
irritants would have required an enormous screening program
Prospective studies scrutinizing these relationships are lacking.

The natural history of the states with less severe deficiencies of
alpha-1-antitrypsin is unclear (86). Cross-sectional studies have found
such a deficiency more frequently in patients with COLD than would
be expected by chance alone (87, 93). However, several other reports
obtained from population studies have suggested that mild forms of
antitrypsin deficiency are not important risk factors for emphysema
(30, 34, 111). Mittman (108) recently reviewed the controversy as to
whether the MZ phenotype is a significant risk factor for COLD but
could not resolve the issue based on current evidence. Longitudinal
studies in such individuals have not been reported. Because the natural
history of the mild deficiency state is unclear, the effect of smoking on
such individuals remains unsettled.

In summary, individuals with severe alpha-1-antitrypsin deficiency
have an excessive risk for developing COLD; the onset of symptomatic
COLD is probably abbreviated by smoking. The natural history of
individuals with mild deficiency states for alpha-1-antitrypsin is
unclear, as is the question of whether they represent a group at special
risk from cigarette smoking.

Other Genetic Factors

Continued interest has been shown in the possible contribution of
genetic factors (other than alpha-1-antitrypsin deficiency) to the
pathogenesis of COLD. In earlier studies (71, 88, 89), the existence of
kindreds with a high incidence of COLD had been noted, but the
relative importance of genetic factors and smoking habits was unclear.

6-34


TABLE lO.-Expected and observed prevalence rate (percent) of
     "cough" among smoking partners to co-twins who
     either had or had not the symptom "cough"
      Monozygotic pairs

"Coughing" status in
non-smoking partner

No. at risk

Prevalence rate for "coughing" among
  smoking co-twins. percent

                          EXpXtd          OtkWrVd

No "cough"               497              4              12
`Tough"                 41             24              37

SOURCE: cederlof. R (es,

Cohen, et al. (32, SS), in a family study in Baltimore, Maryland, found
an increased prevalence of pulmonary function abnormalities in first-
degree relatives of COLD cases as compared to first-degree relatives of
nonpulmonary cases, even when Pi variant relatives were excluded. In
all groups, smokers demonstrated a higher frequency of function
abnormalities. The authors suggested that there is some interaction of
familial factors with smoking. In a similar study in rural areas outside
Rochester, Minnesota, Miller, et al. (106) found a twofold increased
prevalence of functional abnormalities in family members of subjects
with COLD as compared to families of controls matched for age, sex,
occupation, and smoking exposure.

Cederlof, et al. (27, 28) examined the relationship of smoking to
symptom prevalence among monozygotic and dizygotic twins who
were both discordant and concordant for smoking habits. They
observed that the hypermorbidity for COLD symptoms related to
smoking persisted even after controlling for zygosity; they concluded
that a causal relationship of smoking and COLD symptoms was
supported. However, genetic factors had an appreciable influence.
In a more recent analysis of their twin data, Cederlof, et al. (29)
examined the prevalence of cough among monozygotic pairs discordant
for smoking. The results are presented in Table 10. They assumed that
the nonsmoking symptomatic co-twin had a predisposition to cough.
The smoking co-twin had a threefold increase in prevalence of cough
compared to his asymptomatic nonsmoking co-twin-a l-112 times
increase compared to the symptomatic nonsmoking co-twin. The
Prevalence rates were higher in the smoking groups than in non-
smoking groups but highest in the "predisposed" smoker. The authors
suggested that hereditary factors were equally as important as
smoking for the development of cough in the smaller "predisposed"
group.
These findings lend support to earlier suspicions that genetic factors
may play a role in determining the risk for COLD. Kazazian (78) haq

6-35


suggested that common lung diseases may be due to a combination of
risk factors, varying from one individual to another, and that this risk
may be modulated by different genes in combination and by different
environmental factors (e.g., smoking). Long-term prospective studies
are necessary to answer these questions.

Occupational Exposures

Exposure to certain occupational environments has been shown to be
associated with several forms of non-neoplastic bronchopulmonary
disease. An increased prevalence of COLD is found with exposures to
coal and granite dust and cotton fiber. This risk is increased further by
cigarette smoking. However, in none of these studies is the relationship
of COLD to occupation as strong as that to smoking.

A discussion on the proposed modes by which smoking interacts with
occupational exposures is presented in the Chapter on the Interaction
Between Smoking and Occupational Exposures.

Air Pollution

The relationships among air pollution, smoking, and COLD remain
controversial. Reasons for this controversy include difficulties in
controlling such variables as socioeconomic class, degree of crowding,
ethnic differences, and age distribution, as well as in determining the
exact type and amount of individual pollution exposure. Measuring
individual pollution exposure, even within a small area, is difficult
since both amount and type can vary dramatically from street to street
(e.g., proximity of a street to a heavily traveled expressway).

In an effort to control as many of these variables as possible, two
basic approaches in study design have been utilized. The first approach
has been to find areas where different pollution levels have been well-
measured and then to select populations that are as similar as possible
in these areas. Thus, a population in a low-pollution area can be
compared with a similar population in a high-pollution area. The
second approach has been to select a population that is as uniform as
possible (for example, twins), and then measure individual responses to
different pollution exposures.

Using the first approach, the Community Health and Environmental
Surveillance System evaluated the excess COLD (i.e., rate of COLD
experienced above that of nonsmokers) in subjects in two communities
of differing air pollution: Salt Lake City (high), and the Becky
Mountain Area (low). Finklea, et al. (5.3) commenting on the data,
noted that smoking was the most important risk factor in developing
abnormal pulmonary function but that smoking and exposure to air
pollution had a synergistic effect.

The relationship among smoking, air pollution, and COLD were
analyzed in an autopsy study of tissue samples from St. Louis, Missouri
(high pollution) and Winnipeg, Canada (low pollution) (162). Three

6-36


hundred lungs were evaluated as to the extent and degree of
emphysema; urban groups were matched for smoking habits, length of
residence, age at immigration, and employment history; 25 to 26
percent of each group were nonsmokers. In nonsmokers, emphysema
was more frequent and severe in the St. Louis than in the Winnipeg
group. In male smokers the incidence of severe emphysema was
fourfold higher in the St. Louis than in the Winnipeg group. The
author concluded that tobacco smoke may have a cumulative or
synergistic action with air-pollution exposure.

Increased prevalence of COLD has been demonstrated in areas of
high pollution in the Netherlands (ISO), Yokkaichi, Japan (113), and
Cracow, Poland (125). However, these studies were poorly controlled
for socioeconomic status.

Several studies have used the second major method of investigating
the relationship between smoking, air pollution, and COLD, i.e., to
select a uniform population and then to measure individual differences
to pollution exposure. Cornstock, et al. (36), in an attempt to control for
occupational exposure and socioeconomic class, studied three separate,
uniform populations of telephone workers and used as a measure of
pollution the location of the place of work and residence. The
populations studied were telephone installers and repairmen in
Baltimore, New York City, Washington, D.C., and rural Westchester
County, New York, in 1962 (survey 1) and in 1967 (survey 2), and
telephone installers and repairmen in Tokyo in 1967 (survey 3). The
researchers were unable to find any relation between pulmonary
symptoms and degree of urbanization of place of work or place of
residence (either current or past). They were, however,, able to
establish a strong correlation between smoking habits and pulmonary
symptoms. Given the crude estimation of pollution exposure used in
this study (all workers in each city were treated as though they
received the same exposure), a small difference in symptoms due to air
pollution could have been missed, whereas the difference due to
smoking could be detected both because it was larger and because it
Was possible to determine individual exposure more exactly.

Hrubec, et al. (70), in a study of twins from the U.S. Veterans
Registry, were unable to show a difference in respiratory symptoms
either between individuals with different exposures to air pollution or
between members of twin pairs with different air-pollution exposures.
However, they too used a crude measure of air-pollution exposure (by
each zip code area), and so could have missed a small difference due to
air pollution despite being able to relate respiratory symptoms to
smoking, socioeconomic status, and alcohol intake.
Volley, et al. (35). in a study of 3,899 persons (2%year-olds born
during the last week of March, 1946, in the United Kingdom), were also
unable to show a relation between COLD and air pollution. As
estimates of air-pollution exposure, they used the domestic coal

6-37


consumption in the towns where the subjects lived. This method of
estimating air pollution is subject to the same limitations cited for the
previous two studies, i.e., limited sensitivity to small risks due to air
pollution.

In summary, if an increased risk of COLD due to air pollution exists,
it is small compared to that due to cigarette smoking under conditions
of air pollution to which the average person is exposed. The possibility
remains that the two kinds of exposure may interact to increase the
total effect beyond that contributed by each exposure separately.

Socioeconomic Status

In a morbidity survey (117) of the non-institutionalized population of
the United States (1964), socioeconomic status appeared to be an
important risk factor in determining rates of reporting chronic
bronchitis, asthma, and emphysema. Rates were higher among those in
lower socioeconomic classes. This relationship had been previously
recognized in the United Kingdom (118).

In a recent study, the relationship of smoking to socioeconomic
status and chronic respiratory diseases was examined in 9,226 residents
of Tecumseh, Michigan, observed from 1962 to 1965 (68). The
prevalence of chronic bronchitis was higher in cigarette smokers than
in nonsmokers, higher in blue-collar workers than in white-collar
workers, and least among men with the most education (Table 11).
There was no significant association between the prevalence of asthma
and smoking habits, occupation, education, or income. Most of the
differences in the prevalence of chronic bronchitis in subjects of
differing occupational, educational, or income classes were attributable
to differences in smoking habits. Compared with smoking, poor
occupations, educational background, and economic circumstances
have only a weak deleterious effect.

Childhood Respiratory Illness and Adult Respiratory Disease
A connection between pediatric respiratory illness and adult respira-
tory disease has long been suspected on clinical grounds. Burrows, et
al. (24 recently reported that physician-confirmed chronic bronchitis
and/or emphysema and abnormalities in measures of expiratory flow
are more common in older subjects with such history. They suggested
that childhood respiratory illness leads to an increased susceptibility to
the effects of bronchial irritants and respiratory infections.

In a prospective study of lo-year&Is followed since age 2 (n=3699),
Colley, et al. (85) found that subjects with a history of respiratory tract
illness before age 2 had an increased likelihood of developing
respiratory symptoms by age 20. However, cigarette smoking appeared
to be an even more important factor in increasing risk for developing
these symptoms (Table 12).

6-38


TABLE Il.-The age-adjusted* prevalence (percent) of chronic
      bronchitis score by occupation and smoking habits
      in men 25 to 64 years of age, Tecumseh, 1962-65

Chronic bronchitis

Occupation

No. ,
examined

All

Non-     Cigarette
smokem      sowken

F'rofesaional and
managerial
FWlM?TB
Clerical and sales
Craftsmen and
OperatiVeJ
service
Labom2

421         123         4.9         26.1
41         162         -         -
114         16.1         5.4         32.0


782         18.2         5.3         31.5
33         28.1         -         -
35         30.0         -         -

whitezollar                 53.5        x29         4.9        27.1
BIue-collar                 850         18.9         5.4         31.6
Agricultural                 48        19.4         -

*Adjusted to the age distribution of men and women in Tecumseh !25 to 64 yeara of agx. Includes 7 farm labwen
SOURCE: BiggIna. 116. W. (68)

TABLE 12.-Prevalence (%) for cough day or night in both sexes
      in winter by cigarette smoking and by cheat illness
      before age 2* (Figures in parenthesis are
      population)

Cheat iilness under 2 ye. of age

Cigarette smoking

Never

Present

No cheat iilneas                     5.2 (1361)        13.7 (1141)
Ow or more cheat illness                 9.1 (397)         16.5 (423)

o hIodea 577 petsons-exmnokera and thaw where history of cigarette smoking and of cheat illnem before age 2
~6 history ?? an& day and night ate unknown.
3f)URCE: C&y, J&T. (35)

In a followup study of the same cohort (80), the association of cough
prevalence with current smoking habits and with childhood respiratory
tract illness was confirmed and strengthened.

Summary

cigarette smoking,-even in young age groups, produces lung damage.
Cessation of smoking leads to at least partial resolution of symptoms.
Pulmonary function and histologic abnormalities have been observed
in young smokers, confirming clinical suspicions of lung damage in this
group.

6-B


A variety of pulmonary functional abnormalities believed to
represent small airway dysfunction occurs in smokers. Many such
individuals demonstrate normal expiratory flow as measured by
conventional spirometry. In one prospective study, abnormalities in
tests of small airway function appeared to correlate well with
pathologic abnormalities of the peripheral airways. It has been
suggested that such changes may be precursors of more extensive
anatomic-functional abnormalities if smoking were continued. How-
ever, prospective studies relating small airway physiological and/or
pathological abnormalities to the development of COLD are lacking.

Adult cigarette smokers have respiratory symptoms more frequently
than do nonsmokers; some symptoms (i.e., cough and sputum
production) increase with a greater dosage of cigarettes. While it is
clear that COLD is more common in men than in women, it is uncertain
whether men and women with equivalent smoking histories have a
similar increase in the prevalence of respiratory symptoms and COLD.

In the majority of epidemiological surveys, a higher prevalence of
functional abnormalities has been found in smokers as compared to
nonsmokers. There are conflicting data as to the effect of smoking on
pulmonary function in different racial groups and whether men and
women with equivalent smoking habits have similar reductions in
pulmonary function. It is clear that cigarette smoking produces a more
rapid decline in FEV and a higher prevalence of productive cough.
However, it is unclear whether the presence of productive cough by
itself predicts the risk for a more rapid decline in FEV independent of
that increased risk associated with cigarette smoking. It has been
suggested that there may be a "susceptible" group of smokers whose
rate of decline in FEV is much greater than that in both "unsuscepti-
ble" smokers and nonsmokers and that "unsusceptible" smokers and
nonsmokers have similar rates of decline in FEV. Therefore, preva-
lence surveys of functional abnormalities in all smokers may underesti-
mate the impact of cigarette smoking in the "susceptible" population.

Several studies have confirmed that there is improvement in
standard spirometric function tests following cessation of smoking, but
there is still debate as to whether the normal decline in ventilatory
function is accelerated in ex-smokers aa compared to nonsmokers.

Cigarette smokers demonstrate more frequent abnormalities in
macroscopic and microscopic lung sections at autopsy than do
nonsmokers. Furthermore, there is a dose-response relationship
between these changes and the intensity of smoking. Histologic
evidence of small airways pathology is more common in cigarette
smokers than in age-matched nonsmokers in one autopsy study of
sudden death victims.

A number of recent investigations have suggested that destructive
lung changes seen in the emphysematous form of COLD may result
from excess liberation of, or failure to inhibit, proteases in the lung.

6-40


Although definitive evidence is lacking, it appears that PMNs and
alveolar macrophages are the most important sources for the
proteases. Cigarette smoke appears to increase the rate of synthesis
and release of elastase in vitro by human alveolar macrophages.
Antiproteases are inhibited in the presence of cigarette smoke in vitro.
Cigarette smoke also has been demonstrated to impair a variety of
functions of the human alveolar macrophage.

Inhalation of tobacco smoke produces detectable changes in compo-
nents of the cellular and humoral immune systems in both animal and
man. Macrophages obtained by lung lavage from smokers respond
abnormally to MIF or antigen challenge. T lymphocytes obtained from
bronchopulmonary lavage show a diminished response to PHA in
smokers. Cigarette smoke suppresses production of immunoglobulin by
B lymphocytes in lymphoid cell culture. However, the role of these
abnormalities in the pathogenesis of lung damage is unclear.

Individuals with severe alpha-1-antitrypsin deficiency have an
excessive risk for developing COLD; the onset of symptomatic COLD
is probably accelerated by smoking. The natural history of individuals
with mild or moderate alpha-1-antitrypsin deficiencies is unclear, as is
the effect of smoking on such individuals.

Genetic factors other than alpha-1-antitrypsin deficiency appear to
play a role in determining the risk for COLD. Common lung diseases
may be due to a combination of risk factors varying from one
individual to another. The risk may be modulated by different genes in
combination and by different environmental factors (e.g., smoking).
A recent study examined the relationship of smoking to socioeco-
nomic status and chronic respiratory disease. The prevalence of chronic
bronchitis was higher in cigarette smokers than in nonsmokers, higher
in blue-collar workers than white-collar workers, and least among men
with the most education. However, most of the differences in the
prevalence of chronic bronchitis in subjects of differing occupational,
educational, or income classes was attributable to differences in
smoking habits. Compared with smoking, poor occupations, educational
background, and economic circumstances have only a weak deleterious
effect.

Childhood respiratory disease appears to be a risk factor for
respiratory symptoms as an adult. However, cigarette smoking appears
te be a more important factor in increasing risk for developing these
symptoms.

bearch Recommendations

The extensive studies already performed have identified several areas
that merit particular investigational attention because of their promise
in elucidating the effects of smoking and other risk factors upon the
development of COLD:

6-41


(1) Current data suggest that early detection of pulmonary
functional and histologic changes in asymptomatic smokers may
identify populations which are particularly susceptible to COLD.
Investigations documenting the relationships between tests for small
airways dysfunction, pulmonary histology, and symptoms should be
extended. In addition, longitudinal studies are needed to (a) document
the impact of smoking cessation upon these early abnormalities, and,
most important, to (b) define the relationship of these early abnormali-
ties to the development of COLD.

(2) Similar longitudinal studies in patients with welldefined COLD
should be carried out to define the effects of smoking cessation on
clinical, physiologic, and anatomic parameters.

(3) The protease antiprotease imbalance hypothesis for the patho-
genesis of pulmonary elastic tissue injury has received substantial
support from investigations reported to date. Observations are
available which suggest mechanisms by which cigarette smoke might
promote an injury-inducing imbalance in man. Appropriate extensions
of both in. vitro and in wivo investigations which bear upon this
relationship should be performed. It would appear particularly
important to assure that in wivo research be carried out to determine
the biologic importance of the expanding body of promising in witro
research.

(4) Subjects with genetically-determined severe and mild-moderate
deficiencies of alpha-1-antitrypsin appear to be a particularly promis-
ing population in which to study the natural history of COLD, the role
of cigarette smoking and other risk factors, and the mechanisms
responsible for COLD. Carefully designed studies, cross-sectional and
longitudinal, of subjects with severe and mild-moderate deficiencies
should be undertaken. Multi-center studies with pooling of data should
be encouraged.

(5) There are in vitro effects of smoking and cigarette smoke on both
the humoral and cellular components of the immune system. Extension
of relevant in vitro and in tivo investigations dealing with smoking-
immune system interactions should be encouraged.

(6) Further investigations of the relationship between cigarette
smoking and the mucociliary ("clearance") apparatus are warranted.

In all of the above areas, research planning should include attention
to the primary goal, i.e., elucidation of the mechanisms responsible for
the development of COLD in man and the manner in which smoking
impacts upon these mechanisms to promote COLD. Thus, research
support should seek a balanced program providing for in vitro and in
wivo investigations (in animal models and in man). Such a balanced
program also should provide for effective interchange of information
among investigators pursuing research in vitro, in animals, and in
man.

6-42


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