Parenchymal deposition of fibrin is common in acute lung injury. It has been proposed that fibrin-related products contribute to lung injury and augment physiologic impairment. While many interactions between inflammatory and coagulation mechanisms are described, the processes predisposing to fibrin deposition and clearance in the injured lung are not defined. It is our hypothesis that the pulmonary macrophage is an important mediator of these processes, as 1) they are present in large numbers at the site of fibrin deposition, and 2) mononuclear phagocytes exhibit both procoagulant and fibrinolytic capabilities. Further, current evidence suggests that macrophages can exert a predominance of either procoagulant or fibrinolytic activity. We therefore propose that certain undefined regulatory mechanisms may direct these cells to promote either the formation of fibrin or its clearance. The present proposal is designed to test this hypothesis with respect to the procoagulant and fibrinolytic activities of rabbit alveolar macrophages. Rabbit alveolar macrophages will be obtained by bronchoalveolar lavage. The procoagulant and fibrinolytic activities of unstimulated cells and cells stimulated in vitro by bacterial endotoxin, C5a des Arg, f-MET-LEU-PHE, and immune complexes will be characterized. We will then examine several factors which may influence the expression of these activities, including the effects of macrophage heterogeneity, arachidonic acid metabolites, and various pharmacologic agents. The in vivo expression of macrophage procoagulant and fibrinolytic activities will then be studied in acute alveolar injuries induced by C5a des Arg, f-MET-LEU-PHE, and immune complexes. The expression of these activities will be compared to pulmonary deposition of fibrin-related materials during the course of the injury reaction. The presence of macrophage heterogeneity and the effects of pharmacologic agents on these macrophage activities will be studied in vivo. If differences in cellular mechanisms governing the expression of procoagulant and fibrinolytic activities can be defined, and if a relationship can be established between these macrophage functions and the course of pulmonary fibrin deposition, then these observations will expand our current understanding of the potential interactions between pulmonary macrophages and local coagulation and fibrinolysis in acute lung injury.
