Chronic Obstructive Pulmonary Disease (COPD)

ROBERT M. SENIOR and NICHOLAS R. ANTHONISEN

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; and Faculty of Medicine,
The University of Manitoba, Winnepeg, Manitoba, Canada

Recognition of chronic obstructive pulmonary disease (COPD)
as a major health problem is approximately 50 years old, coin-
cident with the 50th anniversary of the National Heart, Lung,
and Blood Institute (NHLBI). Research in COPD was greatly
stimulated by formation of the Division of Lung Diseases
(DLD) nearly 30 years ago. In this presentation we cover some
clinical aspects of COPD and aspects of the pathogenesis of em-
physema, with emphasis on findings attributed to support from
the DLD.
CLINICAL ASPECTS OF COPD
COPD is generally defined as slowly progressive airflow ob-
struction, which is only partially reversible (1). It typically oc-
curs in individuals with substantial smoking histories (at least
20 pack-yr). It is associated with three general types of lesions:
emphysema, small airways inflammation and fibrosis, and mu-
cus gland hyperplasia, most obvious in larger airways. All of
the lesions are uncommon in nonsmokers, and all may be
present in patients with COPD, but this is not always the case.
Smokers without dyspnea frequently have one or more of
these lesions.
At present, there are major difficulties with the quantifica-
tion of emphysema and small airways disease during life, so
clinical investigators study COPD by measuring the degree of
lung function abnormality, notably the impairment in FEV1.
This is justified on the basis that both emphysema and small
airways obstruction reduce maximum expiratory flow, so that
the FEV1 represents some kind of sum of the two influences.
Further, the work of the Burrows group (2–6) showed that in
patients with COPD, the FEV1 is, besides age, the single best
predictor of mortality. This finding has been independently
verified by numerous other groups. The tendency to regard
COPD as best assessed by measurement of FEV1 was power-
fully supported by the work of Fletcher and colleagues (7),
who studied a group of working men in London over 8 years.
Fletcher and colleagues found that the average rate of decline
of FEV1 was 0.03 L/yr in nonsmokers, and that decline was
twice as fast in smokers. However, given a rate of decline of
FEV1 of 0.06 L/yr, it was unlikely that the average smoker
would live long enough to develop symptomatic airways ob-
struction as signified by an FEV1 , 1.5 L. It followed that peo-
ple who developed COPD were a subset of smokers whose de-
cline in FEV1 was considerably larger than the average.
The Fletcher study produced other findings of great inter-
est. Smokers who spontaneously quit the habit had a normal
The writers regret that it was not possible in this short, selective review to ac-
knowledge the many contributions and contributors to understanding COPD
and the pathogenesis of emphysema.
Correspondence and requests for reprints should be addressed to Robert M. Se-
nior, M.D., Pulmonary and Critical Care Medicine, Barnes–Jewish Hospital (North
Campus), 216 South Kingshighway, St. Louis, MO 63110. E-mail: rsenior@imgate.
wustl.edu
Am J Respir Crit Care Med Vol 157. pp S139–S147, 1998
rate of fall of FEV1 thereafter, although their FEV1 values did
not increase to levels that would have existed had they never
smoked. These observations have been supported and ampli-
fied recently by the DLD-sponsored Lung Health Study (8), in
which smokers were randomly assigned to control or smoking
cessation groups. Smoking cessation had a beneficial effect
(Figure 1) that was, if anything, larger than that described by
Fletcher and colleagues (7).
Fletcher and colleagues also found that chronic cough and
sputum (chronic bronchitis, chronic mucus hypersecretion)
predicted the number of acute exacerbations of cough and
sputum thought to represent airways infection, but did not
predict rate of decline of FEV1. Moreover, there was no dis-
cernible effect of exacerbations on long-term fall in FEV1.
These findings essentially refuted the “British hypothesis”
concerning the pathogenesis of COPD, which was that COPD
resulted from repetitive airways infections. This conclusion, in
turn, tended to incriminate tobacco smoke as the direct cause
of the lung damage of COPD.
Fletcher did not try to test the alternative “Dutch hypothe-
sis” of the pathogenesis of COPD (9). This hypothesis was
based on the observation that asthma and COPD had many
common features, including airways hyperreactivity and other
evidence of allergy. To oversimplify, patients with COPD
were potential asthmatics who smoked. This approach in-
volved lumping people with asthma and COPD and did not
become popular in the United Kingdom or North America,
where most investigators believed that asthma and COPD
were different diseases that could be readily distinguished in
the vast majority of cases. It is only within the last 5–10 years
that some rapprochement between these views has become
evident.
Risk Factors
Almost by definition, tobacco use is by far the most important
risk factor for COPD, best summarized as cumulative dose or
pack-years. However, as noted above, not all heavy smokers
develop COPD; in fact, most do not, and there has been con-
siderable interest in other risks. COPD is familial to a greater
extent than can be accounted for by the relatively few cases
of a1-antitrypsin (a1-AT) deficiency (10). It is not known
whether this familial tendency reflects genetic or environmen-
tal influences, or both. Dusty occupational environments are
well established risks (11), though probably not major factors
in North America. Childhood respiratory illnesses may render
some people susceptible to tobacco-induced lung damage
(12). All of these influences are minor compared to that of
smoking, and none satisfactorily explains the differences be-
tween smokers who develop COPD and those who do not.
There was hope that susceptibility to tobacco smoke could
be identified early, before permanent or major damage to the
lungs occurs. This was based on the finding that young smok-
ers had inflammatory and fibrotic lesions of the small airways
(13) and the probability that the conventional lung function
tests using forced expiration were relatively little influenced
S140 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Figure 1. Rates of decline of lung function in participants in the
Lung Health Study (see Reference 8). The ordinates are postbron-
chodilator FEV1; the abscissas are years. The top panel shows de-
cline in the three treatment groups, with the dashed line with
squares representing the usual care group, and the other symbols,
the groups that received an anti-smoking interventions. The bot-
tom panel shows results from participants in one of the treatment
groups and compares individuals who stopped smoking at the on-
set of the study with those who continued to smoke.
by such lesions. A variety of tests for small airways diseases,
most notably closing volume, were developed and studied in
detail with DLD support (14). However, the tests were not
nearly as reproducible as the FEV1 and were probably too
sensitive, since abnormalities were often detected in the ma-
jority of otherwise healthy tobacco users. These efforts re-
emphasized the value of careful repetitive spirometry in the
assessment of COPD.
As noted previously, for more than 30 years Dutch clinical
investigators had argued that asthma and COPD were differ-
ent points in a spectrum of obstructive disease with some risk
factors in common, most notably allergy and airways reactiv-
ity. Atopy (15) and eosinophilia (16) have been identified as
relatively minor risk factors for COPD, but the influence of
VOL 157 1998
airways reactivity on the course of COPD, as differentiated from
asthma, was unresolved until recently because there was am-
ple evidence that the degree of airways reactivity was directly
related to the degree of airways obstruction of whatever cause.
This meant that individuals with the same level of obstruction,
but differing values of airways reactivity, had to be followed
for long enough to discern differences in disease progress after
allowing for variation of potential confounders such as smoking.
The Lung Health Study (8) successfully accomplished this,
measuring methacholine reactivity in a large number of smok-
ers with subclinical airways obstruction at the beginning of a
careful 5-yr follow-up. The initial level of airways (methacho-
line) reactivity was, after smoking, the most important single
determinant of decline in FEV1, and this effect was not ex-
plained by variation in the initial level of obstruction (17).
Thus, it is reasonable to conclude that airways reactivity is an
important risk factor for COPD. On the other hand, it is not
clear what this represents in terms of biology. In particular, it
is not known whether the reactivity observed in the smokers
of the Lung Health Study has mechanisms similar to those in
patients with asthma.
The Lung Health Study also found that airways reactivity
was greater in women than men smokers, and FEV1 may de-
cline more rapidly in women when allowances are made for
lung size and degree of smoking (18). Thus, the female gender
may be a risk for COPD, an influence previously obscured by
the preponderance of tobacco use by men.
Therapy
General. The DLD has been very active in supporting studies
of the treatment of COPD. Indeed, most of the long-term
therapy trials have been done with DLD sponsorship, and
DLD-sponsored trials have established the gold standard for
this kind of research.
Generally speaking, COPD therapy has two aims: amelio-
rating the course of the disease and/or improving the quality
of life. Neither of these aims or end points is easy to assess,
and in both cases statistically significant differences may be of
little clinical significance, or achieved at inordinate cost. At
present, changing the course of COPD implies changing the
rate of decline of FEV1 or prolonging life. Study of the first re-
quires large patient samples with at least 3–5 yr follow-up, and
study of mortality requires either a much longer follow-up or
selection of end-stage patients. Both approaches are laborious
and expensive. We need alterative end points that are more
easily evaluable, but comparably robust, and justifiable in
terms of cost.
Measures of quality of life include assessment of symp-
toms, exercise performance, and health care utilization. None
is easy to measure in reproducible fashion, and all have sub-
jective aspects that make things like standardization between
different centers difficult. Further, quality of life measured in
the short term may or may not apply in the longer term, and
long-term studies are expensive and difficult. Some COPD ther-
apies have been justified on the basis of short-term changes in
lung function. Improvements in FEV1 have been related to
improvements in quality of life in the short term, so that FEV1
can function as a surrogate for quality of life. On the other hand,
the use of short-term studies as the rationale for long-term ther-
apy carries a number of assumptions that are seldom justified.
As indicated above, smoking cessation is the best way to change
the course of the disease (7, 8). Nicotine substitution improves
cessation success rates, but as illustrated by the Lung Health
Study, most “good” cessation programs are expensive and pro-
duce long-term quit rates on the order of 25% (8).
Senior and Anthonisen: Chronic Obstructive Pulmonary Disease
Bronchodilators. As is perhaps best illustrated by data
from the DLD-sponsored IPPB trial (19, 20), most patients
with COPD have a measurable increase in FEV1 with the in-
halation of beta-agonists, and in some the change is substan-
tial (Figure 2). Responses to anticholinergic agents are at least
comparable, and these agents have been shown to improve
quality of life over the short term. The method of delivery of
inhaled bronchodilators has not been shown to influence their
effect in a clinically significant way. Though there were sug-
gestions that regular, inhaled bronchodilator therapy might al-
ter the long-term course of COPD, this issue was studied in
the Lung Health Study and no long-term effect was found (8).
Systemically administered bronchodilators, particularly
aminophylline, have been extensively studied, with differing
results. In general, they add relatively little to inhaled bron-
chodilator therapy in the short term. On average, there is a
10% improvement in FEV1, with some reduction by dyspnea.
The size of the effect varies from patient to patient and in-
cludes some who benefit more than others. Though systemic
administration is likely to affect airways not reached by in-
haled agents, this is apparently of little clinical significance.
The use of intravenous aminophylline in COPD exacerbations
is probably not justifiable (21). Use of aminophylline for pur-
poses other than bronchodilation in COPD has not been stud-
ied in large numbers of patients in the long term.
Corticosteroids. Numerous studies show that some patients
with stable COPD have improvements in lung function when
given anti-inflammatory corticosteroids. Responses are sub-
stantial in a minority of patients and are most common when
steroids are given systemically in large doses (22). The long-
term therapeutic implications of these findings have not been
explored adequately. It is not clear how reproducible steroid
responses are in a given patient with COPD nor whether ste-
Figure 2. Frequency distribution of bronchodilator response in pa-
tients with COPD enrolled in the Intermittent Positive Pressure
Breathing Trial (see References 19 and 20). The ordinate is percent
of patients, and the abscissa is postbronchodilator FEV 1 as a per-
centage of the prebronchodilator value. There were 985 patients
included, with a mean prebronchodilator FEV 1 of 36.1% of pre-
dicted normal.
S141
roids change the course of COPD in steroid responders or un-
selected patients. The advent of high-dose inhaled steroids has
made steroid therapy safe and practical, and at present there
are at least three major clinical trials of these agents in COPD,
one of them sponsored by DLD. The results of these trials will
be of great practical and theoretical interest.
Steroid responsiveness in COPD raises the issue of overlap
between COPD and asthma. Some investigators have found
that patients with COPD who respond to steroids have other
features reminiscent of asthma, while other investigators have
not. It has been argued that people who respond to steroids
should be designated asthmatic, and the diagnosis of COPD
reserved for those who do not. This argument assumes that
steroid responsiveness is an immutable patient characteristic,
which has not been demonstrated. Indeed, there is inferential
evidence that this is not the case. Albert and coworkers (23)
showed that systemic steroids improved lung function in unse-
lected patients with COPD in acute exacerbations; others
have confirmed these results (24). These findings suggest that
all or most COPD patients are “steroid responders” during acute
exacerbations, which is not the case in stable COPD. It is pos-
sible, therefore, that patients who do not respond to steroids
when stable do so when in exacerbation. This hypothesis war-
rants further investigation.
Antibiotics for exacerbations. Acute exacerbations of symp-
toms of COPD are often accompanied by increased sputum
volume and purulence that suggest infection of the airways.
Treatment of exacerbations with broad spectrum antibiotics is
common, and the balance of the evidence indicates that such
treatment improves the quality of life by speeding symptom-
atic recovery (25). However, the effect is by no means dra-
matic and it is difficult to use these data to argue a purely bac-
terial origin of exacerbations. Most of the acceptable studies
of this issue were completed more than 10 years ago and used
relatively unsophisticated agents. It is not known whether the
organisms involved in exacerbations have changed or whether
newer antibiotics offer advantages.
It is worth noting that neither the causes nor the conse-
quences of COPD exacerbations are known. The effects of an-
tibiotics and of immunostimulatory agents (26) suggest that
exacerbations are in part infectious, a hypothesis supported by
the benefits of flu vaccine. However, steroid responses in ex-
acerbations may imply other mechanisms. As to consequences,
the studies of Fletcher and colleagues (7), mentioned previ-
ously, showed that exacerbations did not alter the long-term
course of COPD in a relatively normal population. They did
not study individuals with severe airways obstruction, among
whom it is axiomatic that some will develop respiratory failure
and die during exacerbations.
Oxygen. The first DLD-sponsored multicenter clinical trial
in COPD concerned home oxygen therapy (27), comparing
nocturnal treatment (about 12 h/d) with continuous treatment
(about 19 h/d). This trial, known as NOTT (Nocturnal Oxygen
Therapy Trial), concluded at about the same time as a British
Medical Research Council (MRC)-sponsored trial (28) that
compared 15 h/d of oxygen therapy with none at all. Entry cri-
teria for the two trials were similar, involving COPD patients
with chronic, stable hypoxemia, and the results were strikingly
congruent. Oxygen therapy prolonged life, and the more con-
tinuous the therapy the larger the effect (Figure 3).
These trials had a major impact upon the treatment of pa-
tients with COPD. They established oxygen therapy for ad-
vanced COPD as state of the art, and the DLD entry criteria
were widely adopted as requirements by third-party payers for
oxygen therapy.
The success of NOTT gave both the pulmonary community
S142 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Figure 3. Results of North American and British trials of home oxy-
gen therapy in hypoxemic chronic obstructive pulmonary disease.
In both cases, survival is plotted against time of follow-up. The
British trial (top panel) (see Reference 28) compared no oxygen
with 15 h of oxygen per day. The North American trial (bottom
panel) (see Reference 27) compared 12 h of nocturnal oxygen
(squares) with an average of 19 h per day (circles).
and DLD confidence to initiate other multicenter trials in
COPD. Finally, it is remarkable how well the results of the
MRC and National Institutes of Health (NIH) trials have stood
up. Indeed, although they were accomplished nearly 20 years
ago, little of importance in regard to oxygen therapy has been
learned since. The role of oxygen therapy has not been well
worked out in episodic hypoxemia, such as that occurring dur-
ing sleep and exercise. A recent Polish trial re-examined oxygen
therapy in COPD patients with less severe hypoxemia than
those of the original trials, and found no survival benefit (29).
Nonpharmacologic therapy. Pulmonary rehabilitation for
patients with COPD has a long and controversial history.
Broadly speaking, the term refers to patient education and ex-
ercise training, and its supporters believe that it improves ex-
ercise tolerance and quality of life (30). There is little doubt
that these benefits can occur, and that they can outlast the
program (31). There are problems, however, in assessing the
cost-effectiveness of such programs, since the benefits are
VOL 157 1998
modest on average and the therapeutic effort may be large
(32). Further, it is not entirely clear which component(s) of a
particular program are responsible for the improvement, al-
though most believe it is the exercise training. If an inexpen-
sive variety of pulmonary rehabilitation could be shown to be
effective, it would be widely adopted.
The ground-breaking work of Macklem drew attention to
the fact that COPD compromises the function of the muscles
of inspiration and that the state of these muscles may deter-
mine quality of life and survival. Two therapeutic avenues
were suggested: training the inspiratory muscles so that they
performed better, and resting them on the assumption that
they were fatigued. Many investigations of inspiratory muscle
training using a wide variety of techniques showed that task-
specific improvements in inspiratory muscle function were at-
tainable, but that these did not translate well into improve-
ments in the quality of life (33), rather as if the disease itself
trained the muscles for breathing. Resting the inspiratory
muscles was the subject of a DLD-sponsored clinical trial.
Stable patients with COPD were given daily periods of nega-
tive pressure (tank) ventilation. Results showed that it is ex-
tremely difficult to accomplish this in the home and that it had
no discernible benefit (34). Thus, it appeared that inspiratory
muscle fatigue was not an important feature of stable COPD,
though in other situations such fatigue might be crucial.
Two surgical procedures have been recommended for COPD:
lung transplantion and volume reduction. The former is imprac-
tical in the vast majority of patients with COPD, who are elderly
and infirm. Volume reduction surgery offers promise in that it
appears capable of effecting improvements in ventilatory func-
tion that are not achieved by medical management (35). Patient
selection and surgical technique have not been standardized,
however, and results are not predictable. Much important data
will doubtless emerge from the current multicenter study, Na-
tional Emphysema Treatment Trial (NETT), sponsored jointly
by NHLBI and Health Care Finance Administration.
PATHOGENESIS OF EMPHYSEMA
Definition of Emphysema
A workshop of the DLD provided the generally accepted def-
inition of emphysema as “a condition of the lung character-
ized by abnormal, permanent enlargement of airspaces distal
to the terminal bronchiole, accompanied by destruction of
their walls, and without obvious fibrosis” (36). This definition
is useful, but several aspects merit comment. First, emphy-
sema appears to begin as an increased number and size of
holes in alveolar walls so that destruction of entire alveolar
septa must be a process that occurs in stages (37). Second, dis-
ruption of alveolar attachments to small airways is an impor-
tant additional site of tissue destruction occurring during the
loss of alveolar septal tissue, and likely important in the mech-
anism of reduced maximal airflow associated with emphysema
(38). Third, the relationship between enlarged airspaces and
lung function is not clear-cut. Increased lung compliance and
decreased diffusing capacity correlate more closely with mi-
croscopic abnormalities of alveolar walls than with the pres-
ence of enlarged airspaces (39). Fourth, increased collagen in
both human emphysema (40, 41) and smoke-induced experi-
mental emphysema (42) suggests that the evolution of emphy-
sema involves both destruction and synthesis of extracellular
matrix.
Historic Note
Emphysema has been known for two centuries at least, but
plausible ideas about its pathogenesis did not appear until the
Senior and Anthonisen: Chronic Obstructive Pulmonary Disease
early 1960s, when researchers in Sweden and the United
States made discoveries that have become the cornerstone of
current thinking. One was discovering a1-AT deficiency and
its association with emphysema. The other was finding that le-
sions resembling human emphysema could be induced with
proteolytic enzymes in experimental animals.
a1-Antitrypsin deficiency. While surveying serum protein
electrophoresis patterns of about 1,500 clinical specimens in
Malmo, Laurell and Ericksson (43) noticed five without the
usual distinctive band in the a1 zone. Because a1-AT accounts
for the sharply staining band in the a1 zone, although it is not
the only protein there, they reasoned and demonstrated that
these five samples were deficient in a1-AT. Three of the sub-
jects had emphysema, leading them to comment, “The clinical
material is too small to warrant any definite conclusions con-
cerning possible connections between the a1-AT deficiency
and the patient’s clinical pictures. It is, however, striking that
three of the patients had widespread pulmonary lesions and
that the sister of one had the same lung disease and obviously
the same plasma protein deficiency.”
Shortly after the initial report, Eriksson (44) demonstrated
three groups of values of a1-AT: values corresponding to nor-
mal; values about 60% of normal; and values less than 10% of
normal in a single family. These findings pointed definitively
to genetic inheritance of the deficiency and to heterozygous
and homozygous states. In two of the individuals with marked
deficiency, aged 38 and 48, there was COPD with hyperinfla-
tion. In a large series of deficient subjects and their families,
reported in 1965, Eriksson (45) confirmed the trimodal distri-
bution of a1-AT and conclusively linked the deficiency with
early-onset COPD.
The first five deficient subjects revealed the pulmonary
spectrum of a1-AT deficiency. Symptomatic emphysema was
present in three, who were 35, 38, and 44 yr of age. Early-
onset emphysema has become one of the leading clues to the
presence of the deficiency. On the other hand, two subjects
did not have clinical lung disease, including a woman in her
seventies. Similar variability in the occurrence of COPD has
been observed ever since (46). Marked a1-AT deficiency is
not necessarily associated with emphysema and a shortened
life span. Because smoking is now known to accelerate COPD
in a1-AT deficiency, it seems likely that the first elderly, as-
ymptomatic individual never smoked. The Registry for Pa-
tients with Severe Deficiency of Alpha-1-Antitrypsin, spon-
sored by the NHLBI, has completed its data collection and
will be reporting on the clinical and laboratory course of this
group of 1,129 individuals, the largest cohort with the defi-
ciency (47).
Besides discovering a1-AT deficiency and recognizing the
clinical features, Laurell and Ericksson (43) also concluded
that the deficiency is not rare, that it is probably an inherited
defect, and that the a1-AT protein in deficient subjects has a
structural abnormality because it migrated slower than the
normal protein upon electrophoresis. They have been proven
correct in each of these conclusions.
Papain-induced emphysema. In 1964, Gross and colleagues
(48) in Pittsburgh reported enzymatically produced emphy-
sema. This result was uncovered in a project designed to test
the effects of proteolytic enzymes on developing silicotic pul-
monary nodules. Papain, a plant-derived proteinase, or chy-
motrypsin was injected intratracheally into rats exposed to
quartz dust in inhalation chambers. Animals that received pa-
pain developed centriacinar emphysema; the other animals
did not. Emphysema developed quickly after papain and with-
out apparent inflammation, suggesting a direct proteolytic ef-
fect on lung tissue. Within a few years, other researchers re-
S143
ported marked changes in the appearance of lung elastic fibers
in enzyme-induced emphysema (49).
These initial studies linking emphysema to a1-AT defi-
ciency and intrapulmonary proteolytic enzymes triggered a
burst of research activity, and an international symposium
convened on the topic of pulmonary emphysema and proteol-
ysis in 1971. The participants accepted a connection between
proteases and emphysema and agreed that a1-AT deficiency
presented an important model to dissect the pathogenesis of
emphysema, even though most individuals with emphysema
do not have the deficiency. Eugene Robin, the conference
summarizer, noted “the growing maturity of the discipline of
chest disease as one capable of assimilating and using all the
basic disciplines of biology” (50). Indeed, studies into the
pathogenesis of emphysema have helped with the entry of
modern cell and molecular biology into lung research gener-
ally. The DLD has played a major role in these developments
in many ways, including support of the first international
meeting on elastin and its successor, the Gordon Research
Conference on Elastin and Elastic Tissue, that has been held
every 2 years over the past two decades.
Proteinase–Antiproteinase Hypothesis
The idea that emphysema results from proteolytic injury to al-
veolar septa has been the prevailing hypothesis about the
pathogenesis of emphysema for the past three decades. Ac-
cording to the proteinase–antiproteinase hypothesis, there is a
steady or episodic release of proteinases into the lung tissue
capable of digesting structural proteins of the lung. Normally,
lung tissue is protected by a shield of proteinase inhibitors,
principally from the blood, but also synthesized locally. Em-
physema results when the proteinase-antiproteinase balance
favors proteolytic activity. The importance of elastin destruc-
tion followed recognition that elastolytic activity was required
for proteolytic induction of emphysema and by the finding
that the capacity of different papain preparations to cause em-
physema correlated with their elastase activity (51). The fact
that neutrophil elastase was shown to be the principal target
of a1-AT (52) further strengthened the connection between
elastin and emphysema. Janoff (53) prepared a comprehen-
sive review of this topic in 1985.
Lung elastin and elastic fibers. Emphysematous lung tissue
has aberrant-looking elastic fibers (54) and contains less elas-
tin than normal lung tissue (40). Elastin is the principal com-
ponent of elastic fibers. Encoded by a gene on human chromo-
some 7, elastin is secreted from several cell types as a soluble
monomer precursor of approximately 70 kilodalton (kD) called
tropoelastin. In the extracellular space tropoelastin molecules
align on a “scaffold” of microfibrils, which consist of a number
of constituents including fibrillins and microfibril-associated
proteins. Under the action of lysyl oxidase, most of the lysine
residues in tropoelastin become modified, causing the tro-
poelastin monomers to crosslink and form elastin, a highly in-
soluble, rubber-like polymer. The lysine-derived crosslinks are
known as desmosines.
Under normal circumstances, the synthesis of lung elastin
begins late in fetal life, peaks in the early neonatal period,
continues to a much lesser degree during adolescence, and
stops in adult life, although the tropoelastin gene may remain
transcriptionally active (55). Elastic fibers in the lung normally
last a human life span (56). Elastic fibers are not distributed
uniformly in the lung parenchyma. They loop around alveolar
ducts, form rings at the mouths of alveoli, and penetrate as
wisps into alveolar septa, where they are concentrated at
bends and junctions (57). Therefore, destruction of entire al-
veolar septa must affect matrix components besides elastin.
S144 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Important in thinking about the role of elastases in producing
emphysema is that all elastases degrade multiple components
of the extracellular matrix in addition to elastin.
Because they are unique to elastin, desmosines have been
used to quantify elastin in tissues and as markers of elastin de-
gradation in biologic fluids. Recently, in smokers with marked
variability in annual deterioration of FEV1, urinary excretion
of desmosine was found to correlate with the rate of decline in
FEV1 (58). There was, however, no correlation between em-
physema as determined by computed tomography (CT) and
desmosine excretion. Although the sensitivity of CT to micro-
scopic indices of emphysema may be a limiting factor, these
data suggest that desmosines can originate from breakdown of
elastin in small airways as well as lung parenchyma. Other stud-
ies, however, using plasma peptides of elastin as the marker
and indices of elastic recoil, do show a relationship between in-
creased elastin breakdown and emphysema (59).
What little is known about repair of lung elastic fibers in
vivo is primarily from studies in animals given intratracheal
elastases. After intratracheal instillation of elastase, much of
the lung elastin is depleted within hours to a few days (60).
This phase is followed by a burst of elastin synthesis so that
over the next few weeks the elastin content of the lungs is re-
stored. Yet, the lung is emphysematous and the alveolar elas-
tic fibers look abnormal (61), resembling the aberrant alveolar
elastic fibers in human emphysema (54). Accordingly, restor-
ing the elastin content of the lung does not restore normal
lung architecture in this experimental model. This result is not
surprising considering that production of an elastic fiber is
complex, involving temporal and physical coordination of ex-
pression of tropoelastin, microfibrillar proteins, and lysyl oxi-
dase.
An intriguing recent finding was restoration of normal al-
veoli in elastase-induced emphysema by treatment with retin-
oic acid (62). This result was achieved in adult male rats, an
animal that has continued lung growth throughout life, unlike
people. Verification in other species and elucidation of the
mechanisms involved in producing alveolar repair in adult
lungs could prove extremely valuable.
Elastases, elastin destruction, and the absence of fibrosis
dominate thinking about the pathogenesis of emphysema, but
experimental studies and data from human tissue point to al-
veolar septal collagen destruction and aberrant collagen re-
pair as part of the emphysematous process (63). A diet includ-
ing b-amino-proprionitrile (BAPN) to prevent crosslinking of
newly synthesized collagen, when given to hamsters along
with intratracheal elastase, resulted in worse emphysema with
giant bullae than the same dose of elastase without concomi-
TABLE 1
ELASTASES IN THE LUNG
Enzyme Cellular Source
Neutrophil elastase Neutrophil (monocyte)*
Proteinase 3 Neutrophil (monocyte)
Cathepsin G Neutrophil (monocyte) (mast cell)
Gelatinase B Macrophage, neutrophil, eosinophil
Macrophage elastase Macrophage
Cathepsin L Macrophage
Cathepsin S Macrophage
* Parenthesis denotes minor cellular source.
†
Susceptible basement membrane components include laminins, entactin, and type IV collagens.
VOL 157 1998
tant BAPN (64). Rats given intratracheal cadmium chloride
and dietary BAPN developed emphysema, but without BAPN
the pulmonary lesions resembled pulmonary fibrosis (65). In
guinea pigs exposed to cigarette smoke, emphysema was asso-
ciated with a progressive increase in septal collagen after 6
and 12 mo. These experimental studies fit with findings of in-
creased alveolar collagen and focally thickened alveolar walls
in human emphysema (41).
Elastases and anti-elastases in the lung. Recognition that
elastic fiber destruction is probably a central feature in the
pathogenesis of smoking-induced emphysema has focused at-
tention on elastolytic enzymes that might be involved. There
are numerous elastolytic enzymes in lung (Table 1). Establish-
ing their relative importance in the pathogenesis of emphy-
sema is still not resolved. Knowing which enzyme(s) is involved
is essential to develop proteinase inhibitors that may be useful
clinically, because elastases of different enzyme classes require
different inhibitors.
Although neutrophil elastase is almost surely pivotal in em-
physema associated with a1-AT deficiency, it is much less cer-
tain whether neutrophil elastase has a central role in emphy-
sema that develops in smokers with normal levels of a1-AT.
Some facts support a role for it. Increased neutrophil elastase
is detectable in bronchoalveolar lavage immediately after
smoking (66), and neutrophil elastase has been detected in
emphysematous tissue (67). The possibility that the smoker’s
lungs have a local deficiency of functional a1-AT because
smoke oxidizes a1-AT in vitro was an attractive early hypothe-
sis, but data about this subsequently have been inconclusive.
Recently, alveolar macrophages have come under increas-
ing attention to help explain emphysema in the typical smoker
who has a normal circulating level of a1-AT. Alveolar macro-
phages are strong candidates because smoker’s lungs contain a
greatly expanded number of macrophages and because they
produce several proteolytic enzymes with elastase activity, in-
cluding macrophage elastase, gelatinase B, and cathepsins L
and S. Correlations of alveolar wall destruction in smokers dem-
onstrate a relationship with the number of alveolar macrophages
and T lymphocytes, but not with neutrophils (68). Young adult
smokers have macrophage aggregations in respiratory bron-
chioles, the site where emphysema typically begins (13).
One means of pinpointing the enzymes responsible for em-
physema is targeting the genes that code for proteinases in ex-
perimental models (69). Using this approach, recent results
show an important role for macrophage elastase, a matrix met-
alloproteinase, in smoke-induced emphysema in mice. Mice
lacking a functional macrophage elastase gene as a result of
targeted mutagenesis did not develop emphysema from ciga-
Relative Elastolytic
Matrix Substrates Activity (pH 7.5)
Other Than Elastin (%)
Basement membrane† 100
Basement membrane† 40
Basement membrane† 20
Denatured collagens, types IV, V, 30
and VII collagens
Basement membrane† 35
(Inactive at pH 7.5) 0
(Unknown) 80
Senior and Anthonisen: Chronic Obstructive Pulmonary Disease S145

Figure 4. Mice with the normal expression of macrophage elastase (MME 1/1), but not mice deficient in
macrophage elastase (MME –/–), develop emphysema in response to cigarette smoke (two cigarettes/day,
6 d/wk for 6 mo). The lungs were inflated by intratracheal administration of 10% formalin under constant
pressure, 25 cm H2O. The MM 1/1 lung from a smoke-exposed mouse has centriacinar dilitation of alve-
olar ducts compared with the MME 1/1 non-smoker mouse. In contrast, the lung of the smoke-exposed
MME –/– mouse resembles the lung of the MME 2/2 non-smoker mouse. (Courtesy of Steven D. Shapiro,
M.D.) (Data adapted from Reference 70.)

rette smoke exposure under conditions that produced emphy- produced mainly locally in the respiratory tissues. Their rela-
sema in mice and a functional macrophage elastase gene (Fig- tive contributions to protection against alveolar septal destruc-
ure 4) (70). Macrophage elastase is not inhibited by a1-AT. tion associated with smoking is not known, but the recent data
As noted, the history of human deficiency of a1-AT began incriminating macrophage elastase in mice with smoke-induced
in 1963. Since then, the progress in understanding a1-AT over emphysema, mentioned previously, suggests that inhibitors of
the past three decades has been remarkable, and stands as a matrix metalloproteinases may prove to be important.
shining example of medical science’s capacity to unravel basic In brief, over the past 30 years a picture of the pathogenesis
aspects of human disease (71). Several rare a1-AT phenotypes of emphysema in smokers has emerged that stresses pro-
are now known to be associated with low plasma concentra-
tions and a high risk for emphysema, but the Pi Z phenotype
originally identified by Laurell and Erikkson accounts for TABLE 2
nearly all the patients with marked deficiency. Individuals PROTEINASE INHIBITORS IN THE LUNG
with the Pi Z phenotype have about 15% of the normal
Inhibitor Cellular Source Proteinases Inhibited
plasma a1-AT concentration. The Pi Z a1-AT protein has a
slower association rate with neutrophil elastase than does nor- a1-AT Hepatocyte Serine†
mal a1-AT (72), so that the Pi Z phenotype has a protein that (macrophage)*
is less effective than normal in addition to the deficiency. The SLPI Large airway epithelium, Serine‡
type II pneumocytes
threshold for the circulating level of a1-AT above which there Elafin Large airway epithelium Serine
is little increased risk for emphysema without the aggravat- a2-Macroglobulin Hepatocyte, fibroblast Matrix metalloproteinase,
ing effective smoking appears to be about 37% of normal (macrophage) serine, cysteine
(z 88 mg/dl). This value comes from finding that Pi SZ het- TIMPs Macrophage, lung Matrix metalloproteinase
erozygotes who typically have about this level of a1-AT usu- parenchymal cells
ally have FEV1 values above 80% of predicted normal if they Cystatin C Airway epithelium Cysteine
(macrophage)
have never smoked (73).
With the exception of a2-macroglobulin, each proteinase Definition of abbreviations: a1-AT 5 alpha-1-antitrypsin; SLPI 5 secreted leukocyte pro-
tease inhibitor; TIMPs 5 tissue inhibitors of metalloproteinases.
inhibitor in the lung has activity that is restricted to one class
* Parenthesis denotes minor cellular sources.
of proteolytic enzymes (Table 2). Like a1-AT, a2-macroglobu- †
a1-AT has greater affinity for NE than proteinase 3 and cathepsin G.
lin is produced primarily in the liver. The other inhibitors are ‡
SLPI does not inhibit neutrophil elastase.
S146 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
teolytic activity against extracellular matrix proteins. Damage
to elastic fibers in the lung parenchyma appears to be a critical
event, but the destruction of alveolar walls clearly affects
other extracellular matrix components in the lung paren-
chyma as well. Repair, reflected in collagen deposition, also
seems to occur coincident with alveolar septal destruction and
may help check alveolar overdistention.
CONCLUDING COMMENTS
Much of the progress in understanding and treating COPD
during the past 30 years is ascribable to the NHLBI and DLD.
It must be noted that even “negative” efforts, such as the in-
vestigation of small airways disease and the trials of artificial
ventilation and intermittent positive pressure breathing, yielded
large amounts of data of value to both clinicians and investiga-
tors. However, COPD is now the fourth leading cause of death
in the United States and exacts an enormous toll in terms of
morbidity and health care resources in industrialized countries
worldwide. Accordingly, the problem is by no means solved;
we still need better understanding of pathogenesis and more
effective therapy.
It is important to recognize that the problem is eminently
soluble simply by changing the population’s smoking habits.
This is, of course, easier said than done, but smoking is
decreasing in North America and western Europe. Though
overall mortality has not declined, the age of death from em-
physema has increased steadily, as has the age of onset of clin-
ically severe disease. People are living long enough to develop
COPD who did not do so previously, and the cohorts of men
who began smoking 50–75 yr ago, and who had very heavy ex-
posure to tobacco, are working their way through the popula-
tion. Thus, in North America and western Europe we may ex-
pect that COPD will be a less important problem in the future
than it is at present. In contrast, in developing countries where
both life expectancy and cigarette smoking are increasing,
COPD will become an important problem.
A revolution in concepts about the pathogenesis of emphy-
sema has occurred during the past 30 years. The discovery of
a1-AT deficiency led to the idea that emphysema resulted
from enzymatic digestion of lung extracellular matrix. Details
became available about the inhibitor profile of a1-AT that made
neutrophil elastase the principal candidate enzyme. More recent
studies have revealed a higher level of complexity, with sev-
eral enzymes and inhibitors present in lung tissue that might be
involved in the development of emphysema. Although clinical
emphysema is found almost exclusively among smokers, many
smokers do not develop emphysema, and the reasons remain
to be determined. Genetic factors are certain to be important,
both in the development of emphysema from smoking in some
individuals and the apparent resistance to this effect of smok-
ing in others (74). The tools of cell and molecular biology will
surely be used increasingly to identify factors involved in the
pathogenesis of emphysema.
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