is currently the sixth leading cause of death and the 12th
leading cause of morbidity worldwide. (1) Among the leading
causes of death and disability, COPD is the one that is rising
the most rapidly. By the year 2020, COPD is expected to be
the third leading cause of death and the fifth leading cause
of disability. (2) Cigarette smoking is the most important
cause of COPD, and the current epidemic is in large part due
to smoking behavior over the last several decades.
Although smoking cessation reduces the accelerated loss of
lung function that is associated with smoking/lung function
unfortunately continues to decline in former smokers. As a
result, many ex-smokers, who are not currently symptomatic,
will develop symptoms of COPD as a loss of pulmonary function
associated with aging, which further compromises lungs that
have been damaged previously by smoking. As a result, the
COPD epidemic will continue for the next several decades,
even if major advances are made in controlling tobacco use.
Current treatments for COPD can be extremely helpful in improving
symptoms and the quality of life for affected individuals.
(4) Patients with COPD, however, restrict their activities
in order to avoid sensations of dyspnea, and the disease remains
undiagnosed in many patients. A diagnosis of COPD can be made
relatively easily using simple physiologic measures such as
spirometry. There is, therefore, a significant need for the
implementation of the proper diagnosis and management of COPD
Current therapies, however, are limited in important ways.
The most effective drugs that are available currently, the
bronchodilators that were developed originally for the treatment
of asthma, exploit the small degrees of smooth muscle tone
that are present in COPD patients. By inducing smooth muscle
relaxation, airflow can be improved, but only very modestly.
These small gains, perhaps surprisingly, can be exceedingly
meaningful for some COPD patients. Dyspnea can decrease, exercise
tolerance can improve, and a clinically meaningful and statistically
significant improvement in health status, sometimes termed
quality of life, may result. While current therapies can clearly
be beneficial in treating the symptoms of COPD, new treatments
are desperately needed. In particular, the development of
novel drugs that ameliorate the inflammatory and abnormal
airways secretory responses initiated in response to chronic
irritation from inhaled tobacco smoke may provide useful steps
toward reduction of the ongoing destruction of the lung parenchyma
and the progressive, relentless deterioration in pulmonary
function that culminates in respiratory failure and death,
which comprise the "holy grail" of therapy in patients
COPD SYMPOSIUM IN LUND
An international symposium, which was sponsored by AstraZeneca
in Lund, Sweden, in April 2001, and which is documented in
this supplement, was instigated to explore and discuss COPD
with the intent of highlighting the new understanding of the
basic biology underlying this complex syndrome. An increased
understanding of the mechanistic bases of COPD has identified
a number of potential novel therapeutic targets in this disorder.
This understanding, moreover, has underscored the need for
novel means with which to assess COPD patients both clinically
and for the purposes of evaluating new mechanism-based treatments.
Since the 1960s, the roles of inflammatory cells and the
mediators derived from those cells have played an important
role in models designed to explain the pathogenesis of COPD.
Excessive proteolytic activity of neutrophil elastase in excess
of endogenous antielastase protection, the so-called protease/antiprotease
model, has long been prominent among these. (5) This model,
however, has now been extended to include a variety of other
serine and metalloproteases as well as other mediators released
by inflammatory cells, including reactive oxidants and cytokines.
(6) Moreover, it is now recognized that inflammatory cells,
in addition to neutrophils, likely also contribute in important
ways to the pathogenesis of COPD. The symposium included discussions
of the potential roles of macrophages and lymphocytes, particularly
because these cells may be key in determining why the inflammation
induced by toxic exposures like cigarette smoke leads to the
development of COPD in some individuals but not in others.
A number of features may account for varied individual susceptibility.
Genetic factors clearly play a role, although only one specific
gene related to COPD, [[alpha].sub.1]-protease inhibitor (also
known as [[alpha].sub.1]-antitrypsin) deficiency, has been
identified to date. (7) Thus, individuals who are homozygous
for [[alpha].sub.1]-antitrypsin deficiency have increased
susceptibility for developing pulmonary emphysema, especially
if they also smoke. It is also possible, however, that susceptibility
can be related to acquired features. Viral infections, for
example, can lead to the chronic expression of viral genes
that can greatly modulate subsequent inflammatory responses.
Inflammatory responses can, moreover, be associated with the
development of autoimmunity, which also can modulate subsequent
inflammatory processes. Both of these topics were specifically
addressed in the symposium.
It is also becoming increasingly clear that the pathogenetic
processes initiated in COPD can have multiple effects on target
tissues. Airflow limitation likely develops from several processes
causing a variety of distinct lesions. (6) These include peribronchiolar
fibrosis and narrowing of, as well as destruction of, alveolar
walls with loss of lung elastic recoil. COPD also is characterized
by alterations of the airways epithelial surface, by phenotypic,
proinflammatory changes in epithelial cells, and by altered
production of airway secretions and mucus. These latter changes
likely lead to both chronic cough and mucus hypersecretion
as well as to a predisposition toward developing airway infections.
The latter often are associated with exacerbations of COPD
that are characterized by acutely increased dyspnea, cough,
and secretions. These exacerbations are, moreover, associated
with systemic inflammatory responses, which may have adverse
systemic effects and may contribute to worsened health status.
The symposium included sessions on abnormal epithelial functions,
airway secretions, and exacerbations of COPD.
The pathogenetic processes in COPD also can lead to adverse
systemic effects. These effects may account for abnormal skeletal
muscle function and total body wasting, which characterize
COPD. These latter are not directly related to airflow and,
therefore, are not directly assessed by measures such as spirometry.
Alternate means to assess these key features of COPD are needed
both in order to understand the disease process and to develop
therapies targeted at the systemic components of the disorder.
A number of novel therapies are under consideration for patients
with COPD. In this regard, agents that target specific aspects
of the inflammatory response or that target the production
and regulation of airway secretions are appealing. Agents
that modulate lung repair following injury, moreover, have
the potential for restoring lost lung function.
The symposium, which is summarized in the accompanying articles,
addressed many of these issues and served to confirm the enormous
complexity of the disorder that is COPD. COPD is characterized
by embarrassing and distressful symptoms such as persistent
cough, excessive sputum production, and dyspnea. Furthermore,
this syndrome is associated with slowly progressive, irreversible
declines in lung function, repeated pulmonary infections,
and muscle weakness. These chronic manifestations of COPD
are accompanied by breathlessness, often with only mild exertion,
decreased mobility, repeated hospitalizations, reduced quality
of life, and ultimately, due to unrelenting respiratory failure,
death. Since COPD is usually a result of long-term smoking,
patients often have comorbidity associated not only with their
habit, but also with aging, including pulmonary hypertension,
coronary vascular disease, and cancer.