This application seeks funding for continuation and extension of my studies concerning activated granulocytes as effectors of tissue injury in a variety of disease states. Specifically, several potential modulating factors will be studied for their ability to influence the amount of tissue injury resulting when PMNs are activated. These include (a) the presence of a chronic inflammatory state antecedent to complement and granulocyte activation; (b) the state of induction of clearance mechanisms for PMN activating substances; (c) the presence of plasma lipid abnormalities; (d) the presence and function of platelets when PMNs are activated. Pursuing preliminary observations, at least two models of C/PMN tissue injury (skin edema and pulmonary dysfunction) will be tested in naive animals and in animals harboring sterile turpentine or croton oil abscesses (a). In response to unusually severe symptoms on cross-over from weakly to more potently C-activating hemodialysis equipment, we have postulated induction of anaphylatoxin clearance. Using T-1/2 for C3a-desarg as a marker, we will attempt in experimental animals to induce more rapid clearance by repeated exposure to activated C, and T-1/2 for C3a-desarg will be measured in patients using dialyzers of differing C-activation potency (b). Studies of the mechanism of augmentation of PMN response to activated C in the presence of platelets will be pursued (d), especially in patients with lipoprotein abnormalities known to be associated with PMN and/or platelet hyperfunction (c); since a group of such patients is being placed on omega-3 PUFA supplementation at this University, the effect of such supplementation---known to blunt platelet responsiveness---will also be studied.
