ROLE OF COMPLEMENT AND INFLAMMATORY CELLS IN LUNG INJURY

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Complement (C5)-derived peptides have been implicated as being mediators of acute lung injury (i.e. adult respiratory distress syndrome, ARDS), by virtue of their ability to cause sequestration of polymorphonuclear leukocytes (PMN) in the pulmonary vasculature and subsequent damage to endothelium. Neither the precise identity of the responsible C5-derived peptide nor the mechanism of PMN-mediated injury has yet been determined. The objective of the proposed research is to test the hypothesis that platelet-derived factors and/or metabolites of arachidonic acid together with C5a- and/or C5a des Arg-stimulated PMN alter the integrity of pulmonary microvascular endothelial cells. The proposed studies will involve purification and characterization of rabbit C5a and C5a des Arg as well as experiments designed to examine interaction between rabbit C5-derived peptides, rabbit PMN and rabbit endothelial cells. Synergistic effects betwee peptide-stimulated PMN, prostanoids and/or platelet factors on increased vascular permeability and PMN emigration into alveoli will be assessed in animal models of acute lung injury. The role of naturally occurring regulatory proteins (i.e. carboxypeptidase N, cochemotaxin, and chemotactic factor inhibitor) in modulating these interactions will also be determined in animal models and in vitro. Results from these studies should provide new information concerning interaction of the complement system, neutrophils, platelets and vascular endothelium in the pathogenesis of ARDS. Results of these studies should also provide clues to the rational investigation of prophylactic and therapeutic measures for ARDS.