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, Utah
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 Infections
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 (10).
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 field.
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 (23).
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 clinical efficacy.
RECOMMENDATIONS FOR FUTURE RESEARCH
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 histopathological methods.
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 candidate genes.
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 disease monitoring.
Acknowledgment : 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. O'Connor, 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, CT).
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(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 Bethesda, Maryland.
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: firstname.lastname@example.org