On the progressive nature of emphysema - Roles of proteases, inflammation, and mechanical forces

Emphysema is classically defined by pathologic criteria as destruction of lung parenchyma distal to the terminal bronchioles without associated inflammation or scarring (1-3). The primary risk factors for this disease are exposure to cigarette smoke, environmental irritants, genetic factors, and indoor pollutants (4). The major mechanisms thought to be responsible for the development and progression of emphysema include the protease-antiprotease hypothesis, inflammation, oxidative stress, and matrix remodeling (4). It is likely that these are not entirely distinct processes and that each contributes to the development of this complex disease. During the last few years, considerable progress has been made in describing the nature of inflammation in emphysema (5-8). Compelling evidence now suggests that inflammation can trigger a cascade of responses that culminate in tissue destruction that is characteristic of this disease (9). It is reasonable to presume that once established, the progression of emphysema occurs through pathways that are similar to those that govern its initial development. However, disease progression is still poorly understood (4, 10) and may also be related to abnormal repair of the tissue after inflammation (11). One factor of potential importance in disease progression that is frequently overlooked is the role of mechanical forces. Clearly, the lung is a mechanical device. The alveolar walls at end expiration are under pre-existing mechanical stress (force per unit area), and breathing superimposes additional cyclic mechanical forces. Such forces are in fact capable of physically rupturing the entire alveolar wall after initial damage and repair (12). Thus, as suggested recently (13), mechanical factors may also contribute to disease progression, as measured by a decline in FEV1 (14) or by changes in computed tomography (CT) images (15). In this Perspective, we review several mechanisms relevant for disease progression and propose a coherent view of how the intricate and complex interaction of inflammation, protease activity, repair, and mechanical forces contribute to the progressive nature of emphysema.