Emphysema, a common form of chronic obstructive lung disease, affects between 1.5 and 2 million Americans, and 3-4 times that many individuals worldwide. Based largely on the classic paradigm of disease progression in patients with inherited alpha-1 anti-protease deficiency, it is postulated that tissue destruction in emphysema is a consequence of an imbalance between opposing factors that promote and inhibit enzymatic destruction of lung tissue. This imbalance causes damage to the elastin-collagen network in emphysema, and is thought, in most instances, to be due to smoking-related inflammation which causes release of proteolytic enzymes by neutrophils and mononuclear cells. While there is little doubt that inflammation plays a central role in the initial development of emphysema, recent experimental and clinical observations suggest that other factors may be important in causing disease progression. Here we hypothesize that mechanical stress promotes disease progression by causing rupture of alveolar walls in remodeled tissues that are mechanically weakened. Our research group has shown that mechanical forces generated during tidal breathing can rupture the elastin-collagen fiber network or remodeled emphysema tissues in vitro. Although no evidence exists to support such a direct role for mechanical force in vivo, the accelerated rate of decline in FEV1 observed in patients following lung volume reduction surgery or single lung transplantation is consistent with this notion. The present study will examine this hypothesis in a well characterized sheep model of heterogeneous emphysema that possesses many features of advanced human disease. The results of these experiments will provide new insight into the role of mechanical forces in promoting injury in the intact emphysema lung, and the effect of mechanical forces on tissue remodeling. ? ?
