RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULR INJURY

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Previous studies from this laboratory suggest that the administration of either endotoxin or complement activated plasma to animals in vivo results in activation of prostaglandin biosynthesis with significant hemodynamic consequences and effects on microvascular integrity. The objective of the proposed research is to characterize the relationship between gram negative bacterial endotoxin, the complement system and products of the arachidonic acid cascade. The present studies will be undertaken in three different models representing three levels of physiologic organization. Investigations of 14C arachidonic acid metabolism in isolated liver slice and granulocyte preparations wil characterize the in vitro response of the arachidonic cascade to endotoxin and complement treatment. The pattern and magnitude of both cyclo-oxygenase and lipoxygenase pathways will be characterized. Further studies will be carried out in vitro in an isolated, perfused rabbit liver model to characterize the direct effect of activated complement on cellular prostanoid production. In addition, studies will be undertaken to determine the mechanism of complement activation of the arachidonic acid cascade. These will include studies using calcium influx inhibitors, phospholipase inhibitors and free radical scavangers. In vivo studies will also be carried out in a rabbit model to establish the sequence of physiologic events related to endotoxin induced cellular injury, complement activation, and prostanoid production. Studies will include activation of the complement system with cobra venom factor with concurrent measurement of endogeneous prostanoid production; stimulation of endogenous prostanoid production by substrate supplementation with concurrent assessment of the CH50 complement titer, and endotoxin administration to complement replete and depleted animals with prostanoid quantitation. Results from these in vitro and in vivo studies will characterize the previously unrecognized relationship between endogenous complement activation, prostanoid production and subsequent pathophysiology. This data will be of value in not only understanding the pathophysiology of endotoxic shock, but should also be of value in understanding and managing other complement related disease states such as hemodialysis induced lung injury, Felty's Syndrome, systemic lupus erythematosus and glomerulonephritis.