Future Research Directions in Chronic Obstructive
NHLBI Workshop Summary
Published in Am J Respir Crit Care Med Vol 165. pp
838 -844, 2002 Internet address: www.atsjournals.org
THOMAS L. CROXTON, GAIL G. WEINMANN, ROBERT M.
SENIOR, and JOHN R. HOIDAL
Division of Lung Diseases, National Heart, Lung, and
Blood Institute, Bethesda, Maryland; Division of Pulmonary and Critical Care
Medicine, Department of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri;
and Department of Medicine, University of Utah Medical Center, Salt Lake City,
Between 3 and 7 million Americans are currently
diagnosed with chronic obstructive pulmonary disease (COPD), and the true
prevalence is probably greater than 16 million (1). Many of these individuals
suffer years of progressive discomfort and disability. With the number of
deaths per year attributed to this disease at approximately 100,000 and
increasing, COPD is now the fourth leading cause of death in this country (2)
and is expected to be third by the year 2020. Cigarette smoking is firmly
established as the major cause of COPD, but approximately one-quarter of
Americans continue to smoke, despite aggressive smoking prevention and
cessation efforts. Better means are clearly needed for the prevention and
treatment of COPD, and more scientific research is needed to enable
improvements in its clinical management.
Unfortunately, research progress in
this field has been slow. Most basic scientific research over the past 35 years
has focused on the pathogenetic roles of cigarette smoke, inflammation, and
protease/antiprotease balance, based on the association of COPD with cigarette
smoking and the early discovery that a subgroup of patients with emphysema is
genetically deficient in an inhibitor of a neutrophil protease (3). Although
the cigarette-inflammation-protease theory captures key features of COPD
epidemiology and pathology, this approach has not yet led to a reduction in
COPD prevalence or morbidity, to the development of any therapy proven to
modify the disease process itself, or to an adequate understanding of how risk
factors other than cigarette smoking may contribute to COPD pathogenesis.
However, there are encouraging
indications for future COPD research. Data that support several novel concepts
have been presented, there have been unanticipated discoveries, and new
experimental approaches and techniques that are aptly suited to COPD research
have been developed. Furthermore, elucidation of cellular pathways that are
critically involved in COPD pathogenesis may lead rapidly to clinical trials of
potential therapeutics, given the improving capabilities of the pharmaceutical
industry for development of mechanism-specific drugs.
Because of the enormous public health
burden imposed by COPD and the urgent need for research progress in this area,
the National Heart, Lung, and Blood Institute (NHLBI, Bethesda, MD) convened a
Working Group to discuss potential directions for future investigations. This
group was charged with evaluating the current state of knowledge, identifying
critical gaps in our knowledge, and understanding, recognizing the most
promising opportunities, and developing specific recommendations to be used by
the NHLBI in planning its promotion of future COPD research. This article is a
summary of that Working Group meeting. Specific recommendations for future
research directions in COPD follow a discussion of several intriguing clinical
and epidemiological characteristics of COPD that must be accounted for in a
more complete theory of disease pathogenesis and a review of research advances
that may foreshadow important new areas of investigation.
ENIGMA OF COPD PATHOGENESIS
COPD is a collection of conditions,
including emphysema and chronic obstructive bronchitis, which are characterized
by persistent airflow limitation that is not substantially reversed by
bronchodilators. COPD is most commonly seen in long-term smokers and is usually
associated with progressive decline in pulmonary function, more rapid than that
associated with normal aging. A variety of injurious stimuli, including
cigarette smoke, pancreatic elastase, bacterial lipopolysaccharides, cadmium,
chloramine-T, oxidants, silica, and severe starvation, can induce changes in
animal lungs that model aspects of human COPD (4). Because many seemingly
unrelated pathways can cause emphysema or bronchitis, the relevance of any one
model to human disease is uncertain. Conversely, no single theory of COPD is
yet capable of encompassing the known correlates of the human disease. Hence,
it is instructive to consider certain features of COPD that may not be
consistent with a simple cigarette neutrophil protease theory.
Airway inflammation and parenchymal
inflammation are consistent findings in COPD, and the airways of smokers with
airflow limitation contain greater numbers of inflammatory cells than do the
airways of smokers with normal FEV1 (5). Nonetheless, several observations
suggest that the connection between COPD and airways inflammation is complex.
First, inflammation is observed in the lungs of smokers who do not meet
clinical criteria for diagnosis of COPD. Second, inflammation persists long
after smoking cessation (6). Third, there is overlap in the profiles of
inflammatory cells and mediators expressed in COPD and in asthma (7). Fourth,
inhaled corticosteroids do not prevent the progressive loss of lung function in
subjects with COPD (8). Fifth, the increased numbers of infiltrating
macrophages, neutrophils, and lymphocytes in the lungs of individuals with COPD
are less than those observed in other inflammatory lung conditions that are not
associated with the development of COPD. Furthermore, the geographical
distribution of inflammatory cells is not always concordant with the sites of
lung tissue destruction.
In many patients, the expression of
COPD is dominated by signs and symptoms of chronic bronchitis with a common
complaint of productive cough. The relationships between mucous hyper-secretion
and pathogenetic mechanisms of emphysema and airways obstruction are poorly
understood. Although early epidemiological studies of occupational cohorts
failed to associate mucous hypersecretion with rapid progression of COPD, some
more recent population-based studies have reported an association of chronic
mucous hypersecretion with accelerated decline in FEV1 (9). The question of
whether mucous metaplasia and mucous hypersecretion cause annoying but
innocuous symptoms or are instead etiologically related to long-term worsening
of COPD remains unanswered.
Acute Exacerbations and Bacterial
The slow progression of COPD is
typically punctuated by acute exacerbations characterized by increased dyspnea,
cough, and mucous production often with a change in mucus color. Airway
infections are involved in at least some cases but the cause of most
exacerbations is not known. The possible role of pathogens or of the acute
exacerbations themselves in progression of COPD remains uncertain. One
suggestion is that cigarette smoking predisposes to bacterial colonization and
that bacterial products then contribute to inflammation, activation of
proteases, and alteration in subsequent host responses to inhaled toxicants
Despite striking differences between
COPD and asthma, several facts demand continued consideration of the
relationship between these diseases. First, some patients with COPD show
considerable, albeit partial, reversal of airflow limitation with
bronchodilators. Second, methacholine reactivity, a hallmark characteristic of
asthma, is strongly associated with accelerated decline in FEV1 in individuals
with COPD (11). Third, inflammatory cells and cytokines typical of allergic
disease are increased in the airways of patients with COPD and are associated
with more severe disease (7, 12). Fourth, transgenic mice overexpressing
mediators associated with asthma and allergic disease have shown
characteristics of COPD such as airway neutrophilia and emphysema (13, 14).
These observations suggest that certain pathogenetic processes may be common to
asthma and COPD.
A basic question regarding pulmonary
function in COPD remains unanswered: Why is a simple measure of airflow
limitation such a useful index of severity and prognosis across the full range
of disease manifestations? Although it is well established that individuals
with low FEV1 are more likely to show rapid decline in pulmonary function and
are more likely to die from COPD (15, 16), the connection between specific
disease mechanisms and impairment in pulmonary function remains unclear. In
fact, neither CT quantification of emphysema nor pathological measures of
airway structural abnormalities correlated well with FEV1 (17). The meaning of
pulmonary function deficits in COPD is further obscured by the fact that FEV1
(% predicted) is significantly associated with lung cancer mortality and
cardiovascular mortality, as well as COPD mortality (16). Finally, although
FEV1 is an essential measure in COPD research, its usefulness is limited by its
inability to reveal regional variations in disease within the lungs or to
distinguish between a wide range of pathophysiological processes, including
smooth muscle hypertrophy, fibrosis, mucous metaplasia, inflammation, and loss
of bronchiolar tethering with alveolar destruction.
Variation in Susceptibility to
COPD and Disease Progression
Cigarette smoking is by far the most
important causative factor for COPD; and in population studies the amount of
smoking correlates with loss of lung function. Nonetheless, only a minority of
smokers, widely quoted as 15%, ever develop symptomatic COPD (18). Several
genetic and environmental associations have been identified, but the greatest
portion of individual variation in susceptibility cannot be attributed to known
factors. Understanding why only certain smokers develop COPD is important not
only for understanding the true mechanisms of disease development, but also
because such knowledge might allow targeting of intensive smoking interventions
to individuals at highest risk and might enhance the effectiveness of those
interventions. Even among those with COPD, the rate of decline in FEV1 can vary
from apparently normal values to greater than 150 ml/year, despite similar
smoking histories and levels of initial FEV1 (19). Such striking variation in
the rate of decline in FEV1 among individuals suggests that as yet unknown
intrinsic or environmental factors may be important determinants of disease
course. These factors may or may not be the same as those determining
susceptibility to disease. There is also remarkable unexplained variation in
the manifestations of COPD with regard to the severity of bronchitic symptoms,
the extent of emphysema, and the distribution of emphysematous changes in the
lung (centrilobular vs. panlobular patterns).
Other Lung Diseases Associated
with Cigarette Smoking
Several interstitial lung disorders
may be relevant to COPD pathogenesis because they typically occur in current or
former smokers: idiopathic pulmonary fibrosis (including both usual
interstitial pneumonitis and desquamative interstitial pneumonitis),
respiratory bronchiolitis-associated interstitial lung disease, and pulmonary
histiocytosis X (20). Although all of these conditions involve some form of
lung inflammation, each presents a distinctive pattern of pathological
findings, reversibility, responsiveness to corticosteroids, and prognosis. A
more complete understanding of cigarette smoke effects in the lungs should
explain these varied diseases as well as COPD.
NEW RESULTS, CONCEPTS, AND
OPPORTUNITIES IN COPD RESEARCH
COPD researchers have presented a
number of unexpected results, novel ideas, and promising approaches for further
research. This section briefly describes some innovative concepts identified by
the Working Group that may prove important in COPD pathogenesis and some more
recent methodological advances that will likely be of value to research in this
Diversity of Protease Functions
In addition to degradation of
elastic fibers and other components of the extracellular matrix, it is now
appreciated that proteases have many other pathophysiological actions that may
be relevant to COPD pathogenesis (21). Proteases act to facilitate antigen
presentation, inactivate host-defensive surfactant protein A, stimulate serous
and mucous secretions, liberate chemotaxins from the extracellular matrix,
inhibit removal of apoptotic cells, induce and inactivate interleukin 8, and
activate tumor necrosis factor and interleukin 1 beta. Rational therapeutic
agents may possibly be developed by clarification of which alpha protease
actions are of importance in COPD, identification of which of the many
proteases elaborated by inflammatory and lung septal (endothelial, epithelial,
smooth muscle, and fibroblast) cells perform those actions, and design of small
molecules with an appropriate spectrum of protease inhibitory activity.
Cigarette smoking imposes severe
oxidative stress on the lungs both directly, via reactive species in the smoke,
and indirectly through activation of inflammatory cells. Oxidative stress may
contribute to COPD through many biological actions, including cellular injury,
oxidation and nitration of proteins, changes in gene expression, stimulation of
mucous secretion, inactivation of antiproteases, expression of proinflammatory
mediators, remodeling of blood vessels, and enhancement of apoptosis (22).
Markers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane, and lipid
peroxides) are elevated in the breath or serum of subjects with COPD, and
epidemiological studies have demonstrated negative associations of dietary
antioxidant intake with pulmonary function and with obstructive airway disease
A plausible risk factor for the
development of COPD is the presence of latent viral infection in the lung. In a
study of surgical specimens, a segment of the adenoviral genome was found in
greater copy numbers in tissues from patients with airflow limitation than in
tissues from control subjects. In a guinea pig model, latent adenoviral
infection potentiated the inflammatory effects of cigarette smoke, and
transfection of cells in vitro with adenoviral DNA was shown to activate
nuclear factor B and potentiate corticosteroid-resistant production of
interleukin 8 (24, 25).
Chronic bronchitis is associated
with hyperplasia of both epithelial goblet cells and submucosal glands in the
airways. Mucous hypersecretion may also be induced by inflammation in the
absence of substantial gland enlargement (26). Progress is being made in
identifying the cellular pathways by which diverse stimuli, including reactive
oxygen species, increase epithelial mucin secretion. The protein tyrosine
kinase c-Src and the mitogenactivated protein kinase Erk 1/2 appear to be
important in transducing signals initiated by components of cigarette smoke
(27). Less is known about the regulation of submucosal glands, despite the fact
that these are the source for most of the mucus in the airways (28).
Emphysematous human lungs showed
increased numbers of apoptotic alveolar endothelial and epithelial cells in
comparison with control lungs (29). Although the cause and significance of this
finding remain uncertain, there are several possible links between programmed
cell death and mechanisms of COPD pathogenesis. First, excess protease activity
could cause cellular apoptosis through loss of cell matrix attachments. Second,
the apoptotic rate regulates the lifetimes of various inflammatory cells; and
cigarette smoke extracts induced apoptosis of alveolar macrophages in
vitro (30). Third, neutrophil elastase can inactivate a phosphatidylserine
receptor involved in cellular uptake and removal of apoptotic cells (31),
possibly enhancing inflammation through diminished release of transforming
growth factor beta or through the release of inflammatory mediators from
neutrophils that are not properly removed.
Role of Blood Vessels
Treatment of rats with a blocker of
the vascular endothelial growth factor (VEGF) type 2 receptor caused emphysema
that was associated with endothelial cell apoptosis and with markers of oxidant
stress but was not accompanied by inflammation (32). The relevance of this
process to COPD is supported by observations that oxidant stress decreases VEGF
levels and that expression of both VEGF and its receptor are decreased in
emphysema (29). Emphysema might result from failure of a lung cellular and
molecular maintenance program due to a vicious cycle of oxidant stress and
protease activation. Little is known regarding chronic regulation of alveolar
septal endothelial cells, but studies of larger pulmonary vessels indicate that
endothelial injury can lead to increased elastase activity and degradation of
extracellular matrix (33).
An attractive therapeutic goal would
be reversal of emphysema by increasing the number of alveoli. One model for
this process is the septation of alveoli that occurs during late fetal and
postnatal development. Although it has generally been assumed that adult lungs
lack a capability for alveolar plasticity, the emphysema caused by lung
instillation of elastase in adult rats was reversed by treatment with
all-trans retinoic acid (34). A feasibility study of retinoic acid is
underway in subjects with COPD.
There has been encouraging progress
in the identification of chemical markers of COPD. Subjects with stable COPD
were shown to have elevated markers of oxidant stress in exhaled air (35), of
inflammation in serum and sputum (36, 37), and of elastin degradation in urine
(38). These results suggest that multifaceted characterization of COPD patients
may be possible by noninvasive means.
Pulmonary function is influenced by
heredity (39, 40). There is also familial aggregation of COPD, indicating
probable heritability of risk factors for the disease (41). Precisely how
genetic factors contribute to the risks of development and progression of COPD
remains unknown, but there has been progress toward identification of relevant
genes. Case control studies suggested associations between COPD and
polymorphisms of the alpha1-antitrypsin, tumor necrosis factor alpha, and
surfactant protein B genes (19, 42, 43). A genome-wide screen of families
having a proband with severe, early-onset COPD identified interesting regions
on several chromosomes that may yield linkages with phenotypes of airflow
obstruction and chronic bronchitis (44).
Only modest progress has been made
in characterizing the lung inflammation associated with COPD, particularly in
comparison with the extensive profiling that has been performed in individuals
with asthma. There are increased numbers of CD8+ T cells
in the airways and lung parenchyma of smoking subjects with COPD, and there is
a negative correlation between FEV1 (% predicted) and CD8+ T cell number (45).
The large airways of smokers with severe COPD show increased numbers of
neutrophils, macrophages, and natural killer lymphocytes in comparison with
smokers without clinically defined COPD; and each of these cell types is
negatively associated with FEV1 (5). Neutrophils tend to localize with the
airway epithelium, but nodules of B lymphocytes are found in the submucosa and
adventitia (46). Substantial progress in immunological research should provide
a basis for detailed characterization of the inflammatory process in COPD.
Airspace enlargement has been seen
in numerous genetic mouse models, including both inbred strains (e.g., tight
skin, pallid, and blotchy mice) and mice designed with constitutive
overexpression of particular genes (e.g., collagenase or platelet-derived
growth factor B). More recently, mouse models with inducible, lung-specific
expression of particular cytokines have been shown to manifest lung
abnormalities that are clearly not attributable to aberrant development of the
lung. Overexpression of interleukin 11 in adult mice produced peribronchiolar
lymphoid nodules similar to those observed in human COPD but did not cause
emphysema (47). Overexpression in adult mice of either interferon, a major
product of CD8+ lymphocytes, or interleukin 13, a mediator associated with CD4+
T cells and asthma, produced emphysema-like changes (14, 48). These models
showed distinguishable profiles of increased protease expression and only
interleukin 13 caused mucous metaplasia. Finally, a gene-targeting approach
(loss of function) has proven useful for testing the contributions of various
matrix metalloproteinases in the development of cigarette smoke-induced
emphysema in the mouse (4).
Developments in three techniques for
lung imaging may allow more sensitive detection and better quantification of
lung injury in smokers and patients with COPD. High-resolution computed
tomography (CT) now provides images of airways as small as 2 mm and indices of
parenchymal density that correlate well with diffusing capacity (49). Magnetic
resonance imaging (MRI) of tracer gases in the lungs can demonstrate
ventilation in real time (50) and may provide a measure of alveolar size (51).
Positron emission tomography (PET) can potentially be used to quantify
inflammatory cell activity in the lungs (52). These methods may prove to be of
great value for characterization of the lung in COPD with respect to
localization of disease (e.g., pattern of emphysema by CT), physiological
sequelae (e.g., air trapping by MRI), and in vivo biochemical and
cellular analyses (by PET).
Molecular Characterization of
Diseased Tissues and Cells
The identification of most human
genes paves the way for characterization of diseased tissues at an
unprecedented level of molecular detail. The expression levels of a multitude
of genes in a tissue can be assayed with microarrays of gene-specific probes,
whereas reverse transcription in histological sections can be used to show the
distribution of expression of a particular gene at high spatial resolution.
Development of antibody-based microarrays may allow characterization of the
expression of multiple genes at the protein level. Of particular interest to
COPD research, given the multiplicity of cell types in the lung, are methods
such as laser capture microdissection for isolation of RNA from single cells
(53) and techniques for reverse transcription and cDNA amplification in
situ. Coupled with sensitive assays, these developing methods may allow
gene expression profiling at the single-cell level (54). Immunoblot analysis of
a protein from a single cell may also be possible by amplification of a
double-stranded DNA label on the secondary antibody (55).
Classes of pharmaceuticals of
potential usefulness in COPD that are either available now or are anticipated
in the near future include long-acting M3-selective muscarinic antagonists,
leukotriene B4 inhibitors, 5-lipoxygenase inhibitors, phosphodiesterase 4
inhibitors, thromboxane antagonists, endothelin antagonists, adenosine A2a
agonists, antioxidants, nuclear factor kappa B inhibitors, adhesion molecule
antagonists, p38 mitogen-activated protein kinase inhibitors, interleukin 8
antagonists, tumor necrosis factor antagonists, neutrophil elastase inhibitors,
matrix metalloproteinase inhibitors, tachykinin antagonists, mucolytics,
antiapoptotic compounds, and enhancers of mucociliary clearance. Even when
proof of principle is established, the ability of any of these agents to alter
outcomes in COPD remains speculative because the critical pathogenetic pathways
for this disease have not yet been determined. An important limiting factor in
development of drug treatments for COPD is the lack of efficient and economical
means to identify which drugs are most likely to be of value and to test their
RECOMMENDATIONS FOR FUTURE
There was consensus among members of
the Working Group that the following objectives are important to COPD research
and are feasible within approximately five years. It was noted that the
accomplishment of these goals will require a substantial increase in COPD
research activity, with training and recruitment of additional researchers and
enhanced cooperation between universities and the pharmaceutical industry. In
many cases, the need has long been recognized, but the opportunity to
accomplish the research has come about as a result of the development of new
experimental tools and techniques.
Description of the Disease Process
Characterization of human lung
tissues by advanced molecular, biochemical, microbiological, and
Research progress in COPD is hampered
by a lack of fundamental knowledge regarding the pathology of this disease,
particularly with regard to small airways. Changes with COPD in the structure,
cellular composition, inflammatory status, and chemical milieu of the lung are
poorly defined, as are the relationships of these changes to clinical
manifestations of the disease. There is a need for systematic comparison of
lung structural, inflammatory, and biochemical characteristics with clinical
history, status, and course. Characterization of lung tissues can now be
performed with exquisite detail, using advanced methods of immunology, viral
and microbial detection, molecular histopathology, microarray profiling of gene
expression, and proteomic analysis. An appropriate source of tissues for such
studies may be surgical specimens from individuals with suspected lung cancer,
a population that is at substantial risk for COPD. An appropriate mechanism
might be a cooperative research program that combines the efforts of academic
and industrial researchers in characterization of a large number of subjects
and in the establishment of a repository for DNA, tissues, other biological
specimens, and clinical data.
Biomarkers and intermediate end
points. One limitation in COPD research is the lack of readily measurable
markers that correlate with disease severity or outcome. Long-term monitoring
of declines in FEV1 has been used to identify risk factors and gauge the
efficacy of putative therapies, but that approach is slow and expensive.
Biomarkers of COPD would be of value for investigations of the natural history
and epidemiology of COPD, for phenotyping in genetic studies, and for
clarifying the relationships of animal models to human disease. Validated
surrogate markers of COPD might also serve as intermediate end points for
evaluations of efficacy and appropriate dosage of potential therapeutic agents
in relatively short-term studies. Markers involving noninvasive methods would
be of particular value. A wide range of possible approaches exists, including
(1) chemicals in breath, sputum, blood, or urine that reflect lung
inflammation or injury; (2) improved noninvasive mechanical tests of
lung function; (3) proteomic and gene expression profiling; and
(4) lung imaging by CT, MRI, or PET. Longitudinal and cross-sectional
studies of well characterized smokers with and without COPD are needed to
evaluate the correlation of a broad array of putative markers with COPD
susceptibility, severity, exacerbation, and progression.
Inflammation. Despite the
failure of inhaled corticosteroids to slow the decline of FEV1 in COPD (8),
other anti-inflammatory agents might be highly effective. Studies are needed to
better characterize the inflammation of COPD, to define what is appropriate
immune function in the lung, and to discover pharmacological means for ensuring
beneficial, rather than injurious, contributions of lung inflammatory cells.
Three lines of investigation may be involved. First, extensive characterization
of the inflammatory status of smokers with and without COPD is needed to define
the subtypes of inflammatory cells present, the movement and fate of immune
cells recruited to the lung, and the particular cytokines involved. Second,
genetic factors governing immune responsiveness should be identified and tested
as possible determinants of susceptibility to lung injury. Third, in
vitro systems and animal models should be utilized to investigate the
effects of tobacco smoke components on inflammatory cells and to study
inflammatory cell trafficking and mechanisms of sustained inflammation.
Genetic risk factors. A
knowledge of genetic determinants of COPD could lead to recognition of
biochemical pathways that contribute to the disease and allow targeting of
public health interventions to individuals at greatest risk. A program for
identification of genes related to COPD should consider several issues: First,
simultaneous characterization of multiple phenotypes will be necessary because
different genes may be related to different aspects of the disease (e.g.,
susceptibility, severity, propensity to exacerbation, rate of progression, and
chronic bronchitis vs. emphysema). Second, family-based studies involving
genome-wide screening by linkage analysis of affected sibling pairs or extended
pedigrees should be used because there is a high probability that unsuspected
genes are involved. Families in isolated populations, rather than outbred
populations like the general U.S. population, may be studied more efficiently.
Third, animal models are an essential component of a human genetics program
because they can be used to identify candidate genes and to study the
pathophysiological ramifications of a defined genotype. Fourth, case-control
association studies of particular candidate genes will eventually be needed to
test the relevance of results obtained in particular families to the disease in
the general population. Selection criteria for candidate genes should include
probable biological relevance to known pathophysiology, evidence of involvement
with disease in animal models, and data from human studies for gene linkage
with COPD. Fifth, although not ideal for genetic studies, clinical trials
involving large numbers of well-characterized subjects with COPD should obtain
and archive DNA samples whenever possible to allow for later analysis of
Causes and consequences of
exacerbations. Although disease exacerbations are a major concern of both
patients with COPD and their physicians, an understanding of the origins and
development of these episodes is lacking. There is a need for research directed
toward identifying the bases of COPD exacerbations and clarifying the
pathophysiological processes that contribute to worsening of symptoms. Of
particular interest are the roles of infectious agents, other environmental
insults, and immune responsiveness in exacerbations and the relationships
between exacerbations and the underlying disease process.
Mucous metaplasia and excess mucous
secretion. Mucous production is troublesome to many patients with COPD, yet
little is known regarding the mechanisms of mucous hypersecretion, the benefits
and risks associated with increased mucous production, or the means whereby
mucin secretion, mucus composition, and mucociliary clearance might be
therapeutically regulated. Research is needed to expand our understanding of
the molecular and cellular mechanisms of mucous metaplasia and excess mucous
production. Studies of the submucosal glands of small airways are especially
needed because these glands are probably of most importance in COPD and have
attracted relatively little research interest.
Animal models. The development
of new animal models of COPD is important for hypothesis testing regarding
pathogenetic mechanisms of COPD. Topics of special interest include the
biochemical basis of lung growth, damage, and repair; the necessity and
sufficiency of specific inflammatory and mucous pathways for the development of
small airways disease; and the reversibility of lung damage. Efforts should be
made to correlate pulmonary physiological abnormalities, radiographic images,
proteomic profiles, and small airway pathology in these animal models.
Lung development and alveolar
regeneration. Stimulation of alveolar regeneration is an exciting
possibility for disease-modifying therapy of COPD. Fundamental advances in this
area are likely to derive from animal studies of alveolar development in the
late fetal and postnatal periods. Such research might include gene expression
and proteomic analyses of the developing lung, studies of the regulation of
expression of relevant genes, studies of the coordination of vascularization
and lung development and repair, use of transgenic mice to evaluate the role of
specific growth factors in the lung, and investigations of the mechanisms
whereby toxins (e.g., in utero nicotine) impair lung growth. In
addition, studies of alveolar regeneration in adults of multiple species are
needed to deter-mine the capacity of mature lungs for alveolar regrowth and the
conditions under which alveolar regeneration can occur.
Clinical studies. Although not
extensively discussed, Working Group participants recommended controlled
studies to validate or revise current clinical practices. Potential areas for
such research include, but are not limited to, indications for long-term oxygen
therapy, management of sleep disturbance in COPD, alleviation of nocturnal
hypoxemia, prevention and treatment of exacerbations, and better tools for
Participants: Chair John R. Hoidal, M.D. (Salt Lake City, UT);
Session Chairs David M. Center, M.D. (Boston, MA), Donald J. Massaro,
M.D. (Washington, DC), Robert M. Senior, M.D. (St. Louis, MO), Steven D.
Shapiro, M.D. (St. Louis, MO), and Edwin K. Silverman, M.D. (Boston, MA); and
Carol B. Basbaum, Ph.D. (San Francisco, CA), Linda B. Clerch, Ph.D.
(Washington, DC), Thomas L. Croxton, Ph.D., M.D. (Bethesda, MD), Francis M.
Cuss, M.D. (Kenilworth, NJ), James Eberwine, Ph.D. (Philadelphia, PA), Dorothy
B. Gail, Ph.D. (Bethesda, MD), Jack A. Elias, M.D. (New Haven, CT), Michael D.
Goldman, M.D., Sc.D. (Los Angeles, CA), Douglas Hay, Ph.D. (King of Prussia,
PA), Peter M. Henson, Ph.D. (Denver, CO), Jonathan Jaffe, M.D. (Kenilworth,
NJ), James P. Kiley, Ph.D. (Bethesda, MD), Talmadge E. King, M.D. (San
Francisco, CA), Barbara Knorr, M.D. (Rahway, NJ), Claude Lenfant, M.D.
(Bethesda, MD), Gloria D. Massaro, M.D. (Washington, DC), George T.
OConnor, M.D. (Boston, MA), Marlene Rabinovitch, M.D. (Toronto, Canada),
Sri Ram, Ph.D. (Bethesda, MD), Garth Rapaport, M.B.Bch., MRCP, FFPM (Greenford,
Middlesex, UK), Anuradha Ray, Ph.D. (New Haven, CT), Stephen I. Rennard, M.D.
(Omaha, NE), James R. Snapper, M.D. (Research Triangle Park, NC), Rubin M.
Tuder, M.D. (Baltimore, MD), Norbert F. Voelkel, M.D. (Denver, CO), Gail G.
Weinmann, M.D. (Bethesda, MD), Scott T. Weiss, M.D., M.S. (Boston, MA), Robert
A. Wise, M.D. (Baltimore, MD), Theodore J. Witek, Jr., Dr.P.H. (Ridgefield,
1. Stang P, Lydick E, Silberman C, Kempel A, Keating
ET. The prevalence of COPD: using smoking rates to estimate disease frequency
in the general population. Chest 2000;117:354S -359S.
2. Murphy SL. Deaths: Final data for 1998. In:
National vital statistics reports. Volume 48, no. 11. Hyattsville, Maryland:
National Center for Health Statistics; 2000. 3. Eriksson S. A 30-year
perspective on alpha1-antitrypsin deficiency. Chest 1996;110:237S -242S.
4. Shapiro SD. Animal models for COPD. Chest
5. Di Stefano A, Capelli A, Lusuardi M, Balbo P,
Vecchio C, Maestrelli P, Mapp CE, Fabbri LM, Donner CF, Saetta M. Severity of
airflow limitation is associated with severity of airway inflammation in
smokers. Am J Respir Crit Care Med 1998;158:1277 -1285.
6. Rutgers SR, Postma DS, ten Hacken NHT, Kauffman HF,
van der Mark TW, Koëter GH, Timens W. Ongoing airway inflammation in
patients with COPD who do not currently smoke. Thorax 2000;55:12 -18.
7. Jeffery PK. Lymphocytes, chronic bronchitis and
chronic obstructive pulmonary disease. In: Chadwick D and Goode JA, editors.
Chronic obstructive pulmonary disease: pathogenesis to treatment. Novartis
Foundation symposium 234. New York: John Wiley & Sons; 2001, p. 149 -161.
8. Lung Health Study Research Group. Effect of inhaled
triamcinolone on the decline in pulmonary function in chronic obstructive
pulmonary disease. N Engl J Med 2000;343:1902 -1909.
9. Vestbo J, Prescott E, Lange P. Association of
chronic mucus hypersecretion with FEV1 decline and chronic obstructive
pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir
Crit Care Med 1996;153:1530 -1535.
10. Sethi S. Bacterial infection and the pathogenesis
of COPD. Chest 2000;117:286S -291S.
11. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee
WW, Wise RA. Methacholine reactivity predicts changes in lung function over
time in smokers with early chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1996;153:1802 -1811.
12. Balzano G, Stefanelli F, Iorio C, de Felice A,
Melillo EM, Martucci M, Melillo G. Eosinophilic inflammation in stable chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1486
13. Pan Z-Z, Parkyn L, Ray A, Ray P. Inducible
lung-specific expression of RANTES: preferential recruitment of neutrophils.
Am J Physiol Lung Cell Mol Physiol 2000;279:L658 -L666.
14. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ
Jr, Chapman HA Jr, Shapiro SD, Elias JA. Inducible targeting of IL-13 to the
adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.
J Clin Invest 2000;106:1081 -1093.
15. Scanlon PD, Connett JE, Waller LA, Altose MD,
Bailey WC, Buist AS, Tashkin DP. Smoking cessation and lung function in
mild-to-moderate chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2000;161:381 -390.
16. Hole DJ, Watt GCM, Davey-Smith G, Hart CL, Gillis
CR, Hawthorne VM. Impaired lung function and mortality risk in men and women:
findings from the Renfrew and Paisley prospective population study. Br Med
J 1996;313:711 -715.
17. Gelb AF, Hogg JC, Muller NL, Schein MJ, Kuei J,
Tashkin DP, Epstein JD, Kollin J, Green RH, Zamel N, et al. Contribution
of emphysema and small airways to COPD. Chest 1996;109:353 -359.
18. Fletcher C, Peto R, Tinker C, Speizer FE. The
natural history of chronic bronchitis and emphysema: an eight-year study of
early chronic obstructive lung disease in working men in London. New York:
Oxford University Press; 1976.
19. Sandford AJ, Chagani T, Weir TD, Connett JE,
Anthonisen NR, Paré PD. Susceptibility genes for rapid decline of lung
function in the Lung Health Study. Am J Respir Crit Care Med
20. Nagai S, Hoshino Y, Hayashi M, Ito I.
Smoking-related interstitial lung diseases. Curr Opin Pulm Med
21. Chapman HA, Shi G-P. Protease injury in the
development of COPD. Chest 2000;117:295S -298S.
22. MacNee W. Oxidant/antioxidants and COPD.
Chest 2000;117:303S -317S.
23. Sargeant LA, Jaeckel A, Wareham NJ. Interaction of
vitamin C with the relation between smoking and obstructive airways disease in
EPIC Norfolk, European Prospective Investigation in Cancer and Nutrition.
Eur Respir J 2000;16:397 -403.
24. Retamales I, Elliot WM, Meshi B, Coxson HO, Pare
PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC. Amplification of inflammation in
emphysema and its association with latent adenoviral infection. Am J
Respir Crit Care Med 2001;164:469 -473.
25. Yamada K, Elliot WM, Hayashi S, Brattsand R,
Roberts C, Vitalis TZ, Hogg JC. Latent adenoviral infection modifies the
steroid response in allergic lung inflammation. J Allergy Clin Immunol
26. Saetta M, Turato G, Facchini FM, Corbino L,
Lucchini RE, Casoni G, Maestrelli P, Mapp CE, Ciaccia A, Fabbri LM.
Inflammatory cells in the bronchial glands of smokers with chronic bronchitis.
Am J Respir Crit Care Med 1997;157:1633 -1639.
27. Basbaum C, Lemjabbar H, Longphre M, Li D, Gensch
E, McNamara N. Control of mucin transcription by diverse injury-induced
signaling pathways. Am J Respir Crit Care Med 1999;160:S44 -S48.
28. Reid L. Measurement of the bronchial mucous gland
layer: a diagnostic yardstick in chronic bronchitis. Thorax 1960;15:132
29. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores
SC, Voelkel NF. Endothelial cell death and decreased expression of vascular
endothelial growth factor and vascular endothelial growth factor receptor 2 in
emphysema. Am J Respir Crit Care Med 2001;163:737 -744.
30. Aoshiba K, Yasui S, Nagai A. Apoptosis of alveolar
macrophages by cigarette smoke. Chest 2000;117:320S.
31. Fadok VA, Bratton DL, Rose DM, Pearson A,
Ezekewitz RAB, Hen-son PM. A receptor for phosphatidylserine-specific clearance
of apoptotic cells. Nature 2000;405:85 -90.
32. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le
Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF
receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;
33. Zaidi SHE, You X-M, Ciura S, OBlenes S,
Husain M, Rabinovitch M. Suppressed smooth muscle proliferation and
inflammatory cell invasion after arterial injury in elafin-overexpressing mice.
J Clin Invest 2000;105:1687 -1695.
34. Massaro GD, Massaro D. Retinoic acid treatment
abrogates elastase-induced pulmonary emphysema in rats. Nat Med
35. Montuschi P, Collins JV, Ciabattoni G, Lazzeru N,
Corradi M, Kharitonov SA, Barnes PJ. Exhaled 8-isoprostane as an in vivo
biomarker of lung oxidative stress in patients with COPD and healthy smokers.
Am J Respir Crit Care Med 2000;162:1175 -1177.
36. Fiorini G, Crespi S, Rinaldi M, Oberti E,
Vigorelli R, Palmieri G. Serum ECP and MPO are increased during exacerbations
of chronic bronchitis with airway obstruction. Biomed Pharmacother
37. Keatings VM, Barnes PJ. Granulocyte activation
markers in induced sputum: comparison between chronic obstructive pulmonary
disease, asthma, and normal subjects. Am J Respir Crit Care Med
38. Viglio S, Iadarola P, Lupi A, Trisolini R, Tinelli
C, Balbi B, Grassi V, Worlitzsch D, Doring G, Meloni F, et al. MEKC of
desmosine and isodesmosine in urine of chronic destructive lung disease
patients. Eur Respir J 2000;15:1039 -1045.
39. Redline S, Tishler PV, Rosner B, Lewitter FI,
Vandenburgh M, Weiss ST, Speizer FE. Genotypic and phenotypic similarities in
pulmonary function among family members of adult monozygotic and dizygotic
twins. Am J Epidemiol 1989;129:827 -836.
40. Givelber RJ, Couropmitree NN, Gottlieb DJ, Evans
JC, Levy D, Myers RH, OConnor GT. Segregation analysis of pulmonary
function among families in the Framingham Study. Am J Respir Crit Care Med
41. Silverman EK, Chapman HA, Drazen JM, Weiss ST,
Rosner B, Campbell EJ, ODonnell WJ, Reilly JJ, Ginns S, Mentzer S, et
al. Genetic epidemiology of severe, early-onset chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 1998;157:1770 -1778.
42. Keatings VM, Cave SJ, Henry MJ, Morgan K,
OConnor CM, FitzGerald MX, Kalsheker N. A polymorphism in the tumor
necrosis factor-alpha gene promoter region may predispose to a poor prognosis
in COPD. Chest 2000;118:971 -975.
43. Guo X, Lin H-M, Lin Z, Montaño M, Sansores
R, Wang G, DiAngelo S, Pardo A, Selman M, Floros J. Polymorphisms of surfactant
protein gene A, B, D, and of SP-B-linked microsatellite markers in COPD of a
Mexican population. Chest 2000;117:249S -250S.
44. Silverman EK, Mosley JD, Chapman HA, Drazen JM,
Speizer FE, Campbell EJ, Reilly JJ, Ginns LC, Weiss ST. Genome screen linkage
analysis of severe, early-onset COPD. Am J Respir Crit Care Med
45. Saetta M, Baraldo S, Corbino L, Turato G,
Braccioni F, Rea F, Cavallesco G, Tropeano G, Mapp CE, Maestrelli P, et
al. CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1999;160:711 -717.
46. Bosken CH, Hards J, Gatter K, Hogg JC.
Characterization of the inflammatory reaction in the peripheral airways of
cigarette smokers using immunocytochemistry. Am Rev Respir Dis
47. Kuhn C III, Homer RJ, Zhu Z, Ward N, Flavell RA,
Geba GP, Elias JA. Airway hyperresponsiveness and airway obstruction in
trans-genic mice: morphologic correlates in mice overexpressing interleukin
(IL)-11 and IL-6 in the lung. Am J Respir Cell Mol Biol 2000; 22:289
48. Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ,
Chapman HA Jr, Shapiro SD, Elias JA. Interferon gamma induction of pulmonary
emphysema in the adult murine lung. J Exp Med 2000;192:1587 -1599.
49. Nakano Y, Muro S, Sakai H, Hirai T, Chin K,
Tsukino M, Nishimura K, Itoh H, Paré PD, Hogg JC, Mishima M. Computed
tomographic measurements of airway dimensions and emphysema in smokers:
correlation with lung function. Am J Respir Crit Care Med 2000;162:1102
50. de Lange EE, Mugler JP III, Brookeman JR,
Knight-Scott J, Truwit JD, Teates CD, Daniel TM, Bogorad PL, Cates GD. Lung air
spaces: MR imaging evaluation with hyperpolarized 3He gas.
51. Chen XJ, Hedlund LW, Möller HE, Chawla MS,
Maronpot RR, Johnson GA. Detection of emphysema in rat lungs by using magnetic
resonance measurements of 3He diffusion. Proc Natl Acad Sci USA
52. Jones HA, Shakur BH, Morrell NW. In vivo
measurement of inflammatory cell activity in the lungs of patients with COPD.
Am J Respir Crit Care Med 2001;163:A436.
53. Betsuyaku T, Griffin GL, Watson MA, Senior RM.
Laser capture micro-dissection and real-time reverse transcriptase/polymerase
chain reaction of bronchiolar epithelium after bleomycin. Am J Respir Cell
Mol Biol 2001;25:278 -284.
54. Ginsberg SD, Hemby SE, Lee VM, Eberwine JH,
Trojanowski JQ. Expression profile of transcripts in Alzheimer's disease
tangle-bearing CA1 neurons. Ann Neurol 2000;48:77 -87.
55. Zhang H-T, Kacharmina JA, Miyashiro K, Greene MI,
Eberwine J. Protein quantification from complex protein mixtures using a
proteomics methodology with single-cell resolution. Proc Natl Acad Sci USA
(Received in original form August
8, 2001; accepted in final form November 26, 2001)
Sponsored by the Division of Lung
Diseases, National Heart, Lung, and Blood Institute on March 5-6, 2001 in
Correspondence and requests for
reprints should be addressed to: Tom Croxton, M.D., Division of Lung Diseases,
National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Bethesda, MD
20892-7952. E-mail: email@example.com