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1 Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; and 2 Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
Correspondence and requests for reprints should be addressed to Amir Sharafkhaneh, M.D., F.C.C.P., Division of Pulmonary, Critical Care and Sleep Medicine, Michael E. DeBakey VAMC, Bldg 100 (111i), 2002 Holcombe Boulevard, Houston, TX 77030. E-mail: amirs{at}bcm.tmc.edu
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.
Key Words: emphysema • apoptosis • protease–antiprotease balance • oxidative stress • hypoxemia
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition characterized clinically by dyspnea, cough, and sputum production. Dyspnea is physiologically caused by expiratory flow limitation. Pathologically, COPD lungs show alveolar destruction and enlargement and inflammation of lung parenchyma and airways. The pathogenesis of emphysema is an arena of ongoing, active research, and new developments continue to arise. Emphysema can result from increased alveolar wall cell death and/or failure of alveolar wall maintenance (1). The literature indicates that chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair in emphysema. Furthermore, because only a minority of smokers develops clinically significant emphysema, genetic factors may play an important role in susceptibility or resistance to cigarette smoke (see Hersh and coworkers, pages 486–493, this symposium [25]). We briefly review a paradigm integrating these mechanisms in generating emphysema. For a detailed review of COPD pathogenesis and a description of related animal studies, readers are referred to recent comprehensive reviews (1–4).
PATHOGENIC MECHANISMS IN EMPHYSEMA
Pathologically, COPD is characterized by diffuse inflammation of lung parenchyma and airways (Figure 1). The inflammatory response in emphysema typically shows evidence of the activation of innate and acquired inflammatory processes. The accumulation of these inflammatory components contributes to the lung injury in these patients and serves as a self-perpetuating stimulus for further immune activation. The mobilization of inflammatory cells to the lung leads to the release of potentially destructive mediators, including tissue proteases and cytokines, which directly contribute to tissue remodeling and destruction. These mediators include chemoattractant factors, most notably chemokines, which serve to attract additional inflammatory cells. The overall inflammatory response serves to trigger structural cells, including vascular endothelial cells and epithelial cells, to produce substantial levels of proinflammatory cytokines, chemokines, and other mediators.
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B, which activates proinflammatory cytokine transcription (5, 6). Recent evidence suggests that cigarette smoke inhibits histone deacetylase, further promoting the release of proinflammatory cytokines (7). Therefore, oxidant injury and lung inflammation act in concert to increase alveolar destruction or compromise maintenance and repair of alveolar structure. Table 1 outlines the established and some proposed mechanisms behind COPD pathogenesis.
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1-antitrypsin deficiency is a well-described genetic risk factor for emphysema (8). Furthermore, several animal models show development of emphysema with intratracheal instillation of elastolytic enzymes (1). An animal model of matrix metalloproteinase (MMP)-12 knockout mice showed resistance to development of emphysema in mice exposed to cigarette smoke (9). Macrophages and neutrophils are main sources of proteases in lungs, and many studies have shown correlations between the degree of macrophage and neutrophil inflammation and severity of airflow obstruction (10). In addition to neutrophil elastase and MMP-12, there are other proteases that may play an important role, including MMP-8 (a collagenase), MMP-9 (a gelatinase), and cathapsins S, L (in macrophages), and G, and proteinase-3 (in neutrophils) (4). In addition to destruction of the matrix, elastin fragments generated by proteinases have a chemotactic effect on monocytes and thus increase the inflammatory and protease burden in the lung, creating a positive feedback loop that results in continuous destruction of lung parenchyma (9, 11, 12). In short, protease–antiprotease imbalance can degrade the lung matrix and affect alveolar structure maintenance by altering the matrix and cell signaling (1).
Maintenance of Alveolar Structure and Apoptosis
The neonatal lung develops from interactions between foregut endoderm and mesenchyma. This development is completed by alveolarization that continues into the neonatal period. Development and maintenance of alveolar structure depends on the concerted interaction among various elements of the alveolar wall. Massaro and Massaro suggested that this remarkable phenomenon of lung parenchymal plasticity is related to amount of oxygen consumption and nutritional status (13).
Many studies have suggested that malnutrition and starvation may contribute to the development of emphysema. Studies by Sahebjami and colleagues suggest that caloric restriction may result in loss of alveoli and lung cells and that increasing nutrition restores normal structure (14). Autopsies undertaken on starved patients during World War II revealed signs of emphysema in relatively young individuals (15). Finally, patients with anorexia nervosa have decreased diffusing capacity and increased emphysema via computed tomography (CT) imaging compared with a control group in one trial (16). In an editorial review, Massaro and Massaro differentiated the regulated alveolar loss of malnutrition from tobacco-induced emphysema (17). Massaro and Massaro suggest that malnutrition results in regulated and spontaneously reversible alveolar loss in response to an internal stimulus (calorie restriction), whereas tobacco-induced emphysema is an unregulated spontaneously irreversible process due to exposure exogenous agents (17).
The literature suggests that surfactant may play an important role in the maintenance of alveolar structure. Blockage of neutral lipid metabolism has been shown to cause emphysema, increased lung neutrophils and macrophages, increased expression of proinflammatory cytokines and MMPs, and Clara cell hypertrophy and hyperplasia in a lysosomal acid lipase knockout mouse model (18). Emphysema- and inflammation-related remodeling is also seen in the absence of surfactant proteins A, C, and D with findings similar to lysosomal acid lipase knockout mice (19). In short, the plasticity of alveoli allows constant adjustment of lung parenchyma, and interference with this process leads to enlargement and destruction of the alveolar space.
Recent studies point to the role of alveolar structure maintenance failure and apoptosis as a contributing mechanism to emphysema development (20). This failed maintenance can target one or more cell types and produce changes similar to emphysema. For example, vascular endothelial growth factor, an endothelial cell survival factor, is abundant in the lung, and its blockade results in apoptosis-dependent airspace enlargement (21–23). In contrast, apoptosis of type II pneumocytes may compromise the production of surfactant, which produces changes similar to emphysema in animal models (18, 19). Furthermore, the maintenance of the alveolar structure depends upon the interaction between different cell types and the lung's matrix. Thus, failure of one cell type may result in damage to the other cell types and failure of the overall maintenance program. Tsao and colleagues, in a mouse model of lung over expression of placental-like growth factor, reported pulmonary emphysema starting at 6 months of age, which became prominent at 12 months of age (24). The mice showed increased apoptosis of type II pneumocytes and reduced mRNA of vascular endothelial growth factor and platelet–endothelial cell adhesion molecule-1, indicating a reduced number of endothelial cells. The authors speculated that the apoptosis of type II pneumocytes may have resulted in a reduction of endothelial cells (24).
CONCLUSIONS
Ongoing inflammation and oxidative stress results in damage to airspace structure and disturbance of the normal maintenance of alveolar structure. Data strongly support a role for protease–antiprotease imbalance in the development of emphysema. Furthermore, recent studies support the additional role of apoptosis in emphysema. Identification of the cellular and molecular mechanisms involved in the development of emphysema may have important implications for the development of new targets for therapeutic intervention.
FOOTNOTES
The National Emphysema Treatment Trial (NETT) is supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119), the Centers for Medicare and Medicaid Services (CMS), and the Agency for Healthcare Research and Quality (AHRQ).
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 14, 2007; accepted in final form September 18, 2007)
REFERENCES
Related articles in Proceedings of the American Thoracic Society:
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