Renal allografts undergoing rejection metabolize arachidonic acid (AA) to a variety of cyclooxygenase and lipoxygenase products and these eicosanoids possess powerful effects on the immune system and renal function. This proposal investigates the role of altered eicosanoid production on renal allograft function and immunologic reactions occurring in the allograft. Also, the metabolism of AA by kidneys subjected to ischemia-reperfusion injury and toxic doses of cyclosporine A (CYS) will be determined and correlated with renal function. A standard dog renal allograft model will be used to study renal allograft function during pharmacologic intervention of AA metabolism. Renal allograft function will be assessed by daily measurements of total renal blood flow (implantable flow probes), cortical blood flow (H2 Washout), GFR (creatinine clearance), and electrolyte excretion (flame photometry). Concomitant immunologic monitoring of T- lymphocyte function in the renal allograft, spleen, and blood will be performed by one way mixed lymphocyte reactions, cell mediated cytotoxicity assays, and interleukin-2 production and utilization by helper and cytotoxic T-lymphocytes. The strategy will be to inhibit """"""""pro-rejection"""""""" eicosanoids (TXA2 and lipoxygenase products) and enhance production of anti-rejection eicosanoids (PGI2 and PGE2) by administering compounds that alter AA metabolism either alone or in combination. It is hypothesized that rational alterations in AA metabolism will result in improved graft function and survival. Correlation of alterations in T-cell function with changes in both renal allograft function and renal eicosanoid production during manipulation of AA metabolism should contribute to an understanding of the mechanisms involved in renal allograft rejection. In addition, renal damage occurring from ischemia-reperfusion and CYS nephrotoxicity may be associated with altered AA metabolism and maybe attenuated with agents directed at various arms of the AA cascade.
Showing the most recent 10 out of 11 publications
