Prolonged or repeated intravascular complement activation has been proposed as a mechanism contributing to development of the adult respiratory distress syndrome. In sheep, intravascular complement activation results in severe pulmonary hypertension and hypoxemia and increased lung vascular permeability. These events are associated with sequestration of granulocytes and lymphocytes as well as intrapulmonary release of thromboxane. Completed pharmacologic studies indicate that thromboxane is the primary mediator of the hypoxemia, but not the pulmonary hypertension. The increase in permeability is related to the release of toxic oxygen radicals by complement stimulated leukocytes. The purpose of this proposal is to improve understanding of the cellular mechanisms responsible for the pulmonary dysfunction and the increase in lung vascular permeability. The first hypothesis is that the pathophysiology is the result of interactions of complement anaphylatoxins with granulocytes, lymphocytes, and endothelial cells. Specifically, activated granulocytes participate by releasing oxygen-derived free radicals and leukotriene B4. Activated lymphocytes participate by release of proinflammatory eicosanoids including thromboxane and sulfidopeptide leukotrienes. The second hypothesis is that through manipulation of the fatty acid substrate available for metabolism through the arachidonic acid cascade, eicosanoids with little biological activity can be substituted for the proinflammatory metabolites. The third hypothesis is that migration of granulocytes and monocytes through the air-blood barrier contributes to increases in endothelial and epithelial protein permeability through creation of gap junctions between cells. Successful completion of the proposed experiments will provide significant new information necessary to understanding cell-cell interactions during intravascular complement activation and to propose new hypotheses concerning the role of intravascular complement activation as an effector mechanism in the development of the adult respiratory distress syndrome.
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