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Mechanisms of COPD*: Conference Summary FREE TO VIEW

Robert M. Senior, MD
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*From Pulmonary and Critical Care Medicine, Department of Medicine, Barnes-Jewish Hospital at Washington University Medical Center, St. Louis, MO.

Correspondence to: Robert M. Senior, MD, Pulmonary and Critical Care Medicine, Department of Medicine, Barnes-Jewish Hospital, 216 S. Kingshighway, St. Louis, MO 63110; e-mail: Seniorr@msnotes.wustl.edu

Chest. 2000;117(5_suppl_1):320S-323S. doi:10.1378/chest.117.5_suppl_1.320S-a
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Abbreviations: MMP = matrix metalloproteinase; VEGF = vascular endothelial growth factor

To begin, I want to thank Tom Petty and Steve Rennard for inviting me to be the Conference Summarizer. This is a great honor and a great challenge.

Having listened to the speakers and the discussions these past few days, I have two overriding impressions. The first is that research into the mechanisms of COPD is alive and well. The second is that the letter “C” in the acronym COPD might well stand for both “chronic” and “complex,” because it so evident that COPD has enormous complexity when one thinks about the pathophysiology at the cellular and molecular levels.

Considering the impact of COPD on human health and on the utilization of health care resources in the United States and many other countries, I was surprised to learn that the last conference on COPD here at Aspen was in 1983. Shortly before coming to Aspen, I reviewed the published proceedings of the 1983 conference and found it to be remarkably contemporary in many aspects. Using that document as a reference point in contemplating what major changes have occurred in the COPD landscape over the past 16 years, I think that there have been at least four advances: (1) the development of chest CT as a tool to identify, quantify, and monitor emphysema noninvasively; (2) the National Institutes of Health-sponsored Lung Health Study, because it is providing a large amount of confirmatory and new data about the natural history of COPD due to smoking, airway reactivity in COPD, differences in COPD between men and women, and other basic epidemiologic information about COPD; (3) the development of lung transplantation and lung volume reduction surgery as treatments for emphysema; and (4) the application of cell and molecular biology to COPD. Reflecting on all that has happened, I feel that the last 16 years have been a productive period for COPD in terms of diagnosis, treatment, and uncovering pathogenetic mechanisms.

It should not be surprising to hear that the mechanisms of COPD must be complex. The diverse pathologic changes in the airways and the lung parenchyma in COPD point to many processes. Between individuals with COPD and even within the same person with COPD, more than one type of lesion is usually responsible for airflow limitation. The histopathology of emphysema is a noteworthy example of the complexity of COPD. The different histologic features of panacinar and centriacinar emphysema suggest different pathophysiologic mechanisms, yet the majority of individuals with emphysema have both panacinar and centriacinar pathology.

Judging from the topics covered in this conference, I think that contemporary research into mechanisms of COPD is clearly trying to deal with many big questions. These include the following. What genetic factors contribute to the large differences in risk of developing COPD between smokers? What is the nature of the inflammatory process in COPD, and how does chronic inflammation in the lung parenchyma and the airways due to smoking translate into COPD? What is the basis for the cellular disappearance in the lung parenchyma in emphysema? Can emphysema be reversed? In my summary, I will comment on five of the areas covered in the conference: proteinases and emphysema, experimental models of emphysema, the nature of the inflammation in the airways and lungs in COPD, the disappearance of lung cells in emphysema, and the possibility that drugs might reverse emphysema. Many other important topics discussed at the conference, such as oxidant/antioxidant balance, might have been included, but choices were necessary to keep this summary to a manageable length.

Ever since the discovery of an association between α1-antitrypsin deficiency and emphysema and the development of animal models of emphysema using elastolytic proteinases, there has been great interest in proteolytic enzymes in the causation of emphysema. For many years, neutrophil elastase and the neutrophil were considered the most likely enzyme and cell responsible for emphysema. This view is undergoing revision as data about other elastases and other cells has emerged. Besides neutrophil elastase, neutrophils release gelatinase B (matrix metalloproteinase [MMP]-9) that has elastase activity, and macrophages produce several elastolytic enzymes, including macrophage elastase, gelatinase B, and cathepsins S and L. All of these elastases are potentially involved in the development of emphysema.

The finding that mice lacking macrophage elastase as a result of targeted mutagenesis (“knockout”) resist the development of cigarette smoke-induced emphysema has kindled great interest in this enzyme, and in the potential importance of enzymes other than neutrophil elastase generally.1 In contrast to macrophage elastase, data presented at this meeting indicate that knockout of neutrophil elastase affords only slight protection against the development of emphysema associated with exposure to cigarette smoke and that knockout of gelatinase B has no protective effect. Accordingly, these other elastases from inflammatory cells appear to be less important than macrophage elastase in the pathogenesis of emphysema, but the extent to which these findings in mice can be extrapolated to people remains to be determined. Another reason for the diminishing role of neutrophil elastase as the enzyme responsible for emphysema is findings of increases in other matrix-degrading enzymes, especially collagenolytic MMPs, in the lungs of people with COPD.

Besides uncertainty about the specific proteinases that are involved in producing emphysema, there is also uncertainty as to whether inflammatory cells are the only source of destructive enzymes in emphysematous lungs. Information to be mentioned below points to structural cells of the lungs as possible producers of enzymes that degrade lung tissue in emphysema.

My idea about proteinases and the pathogenesis of emphysema is that we should avoid thinking that there is necessarily one proteinase and one cell type that is responsible. Based on the papers presented here at Aspen and work reported elsewhere, it seems more likely that a variety of proteolytic enzymes participate in the alveolar destruction that leads to emphysema and that the profile of enzymes may change in the same individual at different times during the course of the disease, as for example, during acute exacerbations compared to periods of clinical stability. Interesting data in this regard were the reports at this meeting of increased collagenase activity associated with emphysema. MMP-1, an interstitial collagenase, was found in lung tissue obtained at volume reduction surgery, clearly a terminal stage of emphysema. In contrast, MMP-8, another MMP that is the neutrophil collagenase, was found in BAL fluid obtained from asymptomatic smokers with emphysema by chest CT. Is this evidence that different collagenases are important at different stages of COPD? The findings with volume reduction tissue were also noteworthy because in situ hybridization indicated that MMP-1 messenger RNA was expressed by alveolar structural cells rather than inflammatory cells, raising the possibility that focusing exclusively on inflammatory cells as the sources of proteinases responsible for emphysema may be too restrictive.

Reports at this meeting showed convincingly that chronic tobacco smoke exposure produces emphysema in mice. This discovery is important because it means that mice, about which there is a great deal of genetic information and in which genetic manipulation is convenient, can be used to study mechanisms of emphysema induced by the same means as the human disease. I think that the days are over of instilling pancreatic elastase or other agents into the lungs to produce emphysema quickly.

One of the great attractions of the mouse model of emphysema due to cigarette smoke is that it gives an opportunity to study the early stages of alveolar injury associated with cigarette smoke exposure in an animal in which many genetic alterations are possible. Thus, the effects of underexpression and overexpression of proteinases, cytokines, and other factors can be evaluated beginning with the first cigarette. Events in lung tissue that precede overt changes in alveolar structure may be particularly instructive from the standpoint of uncovering pathogenetic mechanisms. Besides the conceptual appeal of looking at the early stages of injury, study of the initial phase of the pathologic process has the practical advantage that experiments can be completed in less time and at less cost than if experiments are extended for several months or longer to get full-blown emphysema.

Two other models of emphysema, neither related to exposure to cigarette smoke, were presented at this conference. These were surfactant protein-D deficiency in mice and blockade of one of the vascular endothelial growth factor (VEGF) receptors in rats. Unlike models where emphysema was the intended outcome, these models were surprises and underscore the idea that the lung remodeling called emphysema may be triggered in unexpected ways. Emphysema that develops in mice with knockout of surfactant protein-D is associated with abnormal appearing alveolar macrophages so that inflammatory cell proteinases may be involved. More novel from a mechanistic standpoint is emphysema due to VEGF receptor blockade, because the primary lesion appears to be endothelial cell apoptosis and the lung remodeling occurs without obvious inflammation. This model will be discussed again below.

Chronic inflammation of the lung parenchyma and airways has long been viewed as central to the pathogenesis of COPD. Early findings indicative of inflammation in COPD were more alveolar macrophages and neutrophils in BAL fluid from smokers than lavage fluid from nonsmokers and accumulations of alveolar macrophages in respiratory bronchioles of young adult smokers. As presented during the conference, inflammation is not only prominent during the evolution of COPD, but it persists even at the advanced stages as shown by high numbers of inflammatory cells in lung tissue removed at volume reduction surgery.

One of the surprising and yet consistent findings of recent years is that neutrophils are not prominent in airway mucosal biopsies or surgical specimens of COPD lung tissue, even though they may be increased in lavage fluid. Emphysematous tissues contain large numbers of lymphocytes and other mononuclear inflammatory cells, and a positive correlation of tissue lymphocytes with emphysema was first reported several years ago.2 Accordingly, just as neutrophil elastase is being displaced as the principal proteinase most likely causing emphysema, the neutrophil is also getting displaced by alveolar macrophages and lymphocytes.

An intriguing finding noted in recent years, and reported again at this conference, is that the lymphocyte subtypes found in COPD tissues are different from those seen in asthmatic airway tissue. In COPD the ratio of CD4+ T cells to CD8+ T cells favors CD8+ T cells, whereas the opposite is true in asthma. At this time, one can only speculate about the role that CD8+ T cells in alveolar and airway tissue play in the development and progression of COPD. It will be of interest to see whether the mouse model of smoking-induced emphysema replicates the human profile of inflammatory cells.

A provocative report at this meeting raised the possibility that the inflammatory response to exposure to cigarette smoke may be strongly influenced by the status of resident lung cells. Specifically, data were presented suggesting that lung cells containing the E1A domain of the adenovirus genome have heightened cytokine production in responses to stimuli such as cigarette smoke. Coupled with earlier results showing that E1A is more common in COPD tissue, these findings suggest that pulmonary tissue responses to cigarette smoke may be established early in life as a result of an adenoviral or other infection. Clearly, more needs to be learned about the relationships between cytokine and chemokine production by lung cells and the risk of COPD among smokers. I think the question of how the inflammatory process gets started in the smoker’s lung and why is it so much more exuberant in some smokers than others has to be important and deserving of vigorous investigation.

The fate of alveolar parenchymal cells during the evolution of emphysema has largely been ignored by everyone working on the basic mechanisms of COPD. Conventional thinking has been that these cells “disappear” as a result of damage to the parenchymal extracellular matrix because normal cell-matrix interactions are disrupted.

At this meeting, data were presented suggesting that apoptosis of pulmonary microvascular cells may precede the development of emphysema and may be linked to loss of signaling through one of the VEGF receptors on endothelial cells. Several pieces of evidence for this hypothesis were shown, of which perhaps the most compelling was, as mentioned above, the development of microvascular apoptosis and emphysema in rats given an agent that blocks VEGF signaling through one of its two receptors. These studies are interesting to me because this model of emphysema does not appear to involve inflammatory cells, so that the mechanism of emphysema is not obvious, and because the results suggest that parenchymal lung cells may enter a death cycle in emphysema prior to overt damage to the parenchymal extracellular matrix.

Whether apoptosis turns out to be a feature of garden-variety human emphysema awaits much further study, but these initial observations are provocative. They raise many other questions, such as whether other parenchymal lung cells have signaling pathways linked to cell survival that are perturbed by exposure to tobacco smoke. The abundance of lymphocytes in emphysematous tissue together with the expression of Fas by bronchiolar and alveolar epithelium makes one wonder whether the Fas-Fas ligand system is operative in emphysema resulting in excessive apoptosis of structural cells of the lungs, analogous to what may be an important feature of the pathogenesis of pulmonary fibrosis.3

In June 1997, the COPD research community was startled by data showing that treatment with retinoic acid reversed pancreatic elastase-induced emphysema in rats.4 These results fit with earlier work showing that retinoic acid increased the number of alveoli in normal rats, apparently by stimulating alveolar septation. These tantalizing data are now being tested in other species.

The possibility that normal alveoli can grow in the adult lung is not without precedent. Lung growth occurs postpneumonectomy in rodents, and the resultant lung shows normal architecture with normal deposition of extracellular matrix. Although there are major gaps in understanding how alveolar septation is controlled, trials of retinoic acid therapy for people with emphysema are about to begin. From the standpoint of the limited knowledge about the regulation of alveolar septation, retinoic acid trials seem somewhat premature, but they should prove valuable because they will lead to the design of protocols and new means of assessing alveolar growth.

An article published earlier this year reported the findings of using complementary DNA chip technology to assess the expression of 8,600 genes in fibroblasts in culture when they are exposed to serum after a period of serum starvation.5 In terms of experimental design, this is about as simple as one can imagine, yet the results were quite remarkable. Besides the expected activation of genes involved in cell proliferation and matrix production, there was activation of many other genes, including ones whose products are involved in clotting and immunity. The message for lung cell biologists is clear. Just as the days are over of squirting pancreatic elastase into the lungs as a model of emphysema, the days of putting lung cells in culture and testing them for one or a few responses are also waning rapidly. If a fibroblast has such an extraordinary repertoire of responses, we have a lot of work ahead of us to figure out what is happening in the lung that leads to COPD.

It has been 16 years since the last Aspen Lung Conference on COPD. What is the COPD landscape going to be like 16 years from now? I will make two predictions. First, I am certain that COPD will still be an important clinical problem, because smoking shows no sign of abating in the United States or other parts of the world. Indeed, it is on the increase in developing countries. Second, I am sure that we will know much more about the mechanisms of COPD than we do now, but not everything.

Hautemaki, RD, Kobayashi, DK, Senior, RM, et al (1997) Requirement for macrophage elastase for cigarette smoke induced emphysema in mice.Science277,2002-2004
Finkelstein, R, Fraser, RS, Ghezzo, H, et al Alveolar inflammation and its relation to emphysema in smokers.Am J Respir Crit Care Med1995;152,1666-1672
Kuwano, K, Hagimoto, N, Kawasaki, M, et al Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.J Clin Invest1999;104,13-19
Massaro, GD, Massaro, D Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.Nature Med1997;3,675-677
Iyer, VR, Eisen, MB, Ross, DT, et al The transcriptional program in the response of human fibroblasts to serum.Science1999;283,83-87




Hautemaki, RD, Kobayashi, DK, Senior, RM, et al (1997) Requirement for macrophage elastase for cigarette smoke induced emphysema in mice.Science277,2002-2004
Finkelstein, R, Fraser, RS, Ghezzo, H, et al Alveolar inflammation and its relation to emphysema in smokers.Am J Respir Crit Care Med1995;152,1666-1672
Kuwano, K, Hagimoto, N, Kawasaki, M, et al Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.J Clin Invest1999;104,13-19
Massaro, GD, Massaro, D Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.Nature Med1997;3,675-677
Iyer, VR, Eisen, MB, Ross, DT, et al The transcriptional program in the response of human fibroblasts to serum.Science1999;283,83-87
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