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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery and Bioengineering Study Section (SB)
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Washington University
Schools of Medicine
Saint Louis
United States
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Mangino, M J; Zografakis, J; Murphy, M K et al. (1992) Improved and simplified tissue extraction method for quantitating long-chain acyl-coenzyme A thioesters with picomolar detection using high-performance liquid chromatography. J Chromatogr 577:157-62
Turk, J; Bohrer, A; Stump, W T et al. (1992) Quantification of distinct molecular species of the 2-lyso metabolite of platelet-activating factor by gas chromatography-negative-ion chemical ionization mass spectrometry. J Chromatogr 575:183-96
Callery, M P; Mangino, M J; Flye, M W (1991) A biologic basis for limited Kupffer cell reactivity to portal-derived endotoxin. Surgery 110:221-30
Callery, M P; Kamei, T; Mangino, M J et al. (1991) Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis. Arch Surg 126:28-32
Mangino, M J; Anderson, C B; Murphy, M K et al. (1991) Renal allograft platelet activating factor synthesis during acute cellular rejection. J Lipid Mediat 4:69-81
Anderson, C B; Mangino, M J (1991) Arachidonate 5-lipoxygenase inhibition and acute renal allograft rejection. Transplant Proc 23:640-2
Mangino, M J; Murphy, M K; Grabau, G G et al. (1991) Protective effects of glycine during hypothermic renal ischemia-reperfusion injury. Am J Physiol 261:F841-8
Callery, M P; Mangino, M J; Kamei, T et al. (1990) Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2. J Surg Res 48:523-7
Mangino, M J; Jendrisak, M D; Murphy, M K et al. (1990) Prostanoids and hypothermic renal preservation injury. Prostaglandins Leukot Essent Fatty Acids 41:173-9
Mangino, M J; Jendrisak, M D; Sicard, G A et al. (1989) Renal eicosanoid synthesis in patients with renovascular hypertension. Prostaglandins Leukot Essent Fatty Acids 38:127-8

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