The plasminogen activation system in lung disease.

The importance of the plasminogen activator (PA) system in multiple pulmonary disorders has become increasingly apparent as methods to analyze its components have improved. Early investigations discovered that the pulmonary alveolar space is normally a pro-fibrinolytic environment that is diminished in a variety of lung diseases. Interest in these observations was greatly increased when animal experiments revealed that manipulations of the PA system significantly modulated the tissue fibrosis that follows many types of lung injury. In particular, enhancement of PA activity was found to consistently decrease the extent of scarring induced by lung damage. Based upon these early observations, it was hypothesized that fibrin was necessary for the pathogenesis of lung fibrosis, and that an increase in PA activity would reduce collagen accumulation by accelerating the clearance of fibrin from the provisional matrix. However, as is often the case with simple hypotheses, subsequent studies revealed that the actual role of the PA system in pulmonary disease is much more complex. Possible mechanisms beyond fibrinolysis include degradation of other matrix proteins, activation of protease cascades including those involving matrix metalloproteinases, activation and release of growth factors from sites of production and sequestration, and modulation of cell adhesion and motility. In each of these processes, the serpin plasminogen activator inhibitor-1 (PAI-1) plays a central role. For these reasons, it has become apparent that PAI-1 presents an attractive target to influence multiple disease processes within the lung, particularly those that lead to lung fibrosis.