Although prostaglandins (PG) are recognized to be regulators of renal function, their importance in renal allograft rejection has not been clearly defined. Pilot studies of acute renal allograft rejection in the dog have identified aberrations in PG metabolism, manifested by marked increases in TxB2:PGI2 ratios. This proposal investigates PG production by both the cyclooxygenase [thromboxane (TxA2), prostacyclin (PGI2), prostaglandin E (PGE2)] and lipoxygenase [hydroperoxyarachidonic acid (HPETE)] pathways during renal allograft rejection and compares levels of these arachidonate metabolites with changes in renal function and alterations in immunologic reactions. Concomitant immunologic monitoring will focus on T-lymphocyte function in the renal allograft, spleen and blood using the one way mixed lymphocyte reaction (MLR), cell mediated cytotoxicity assay (CMC) as well as interleukin 2 (IL2) production by helper T-lymphocytes (HTL) and IL2 utilization by cytotoxic T-lymphocytes (CTL). It is anticipated that increased production of lipid hydroperoxides such as HPETE (a PGI2 synthetase inhibitor), will account for a decrease in renal PGI2 levels and that the prostaglandin-eicosanoid system will be demonstrated to be an important link between the immune response and the final destruction of the kidney during acute allograft rejection. A standard dog renal allograft model will be used to study products of arachidonic acid metabolism in the kidney. Initially, studies will involve in vitro tissue slice incubation, and later in vivo renal vein and urine sampling, using chromatographic and radioimmunoassay techniques. It is hypothesized that restoration of the normal balance between TxA2 (a potent vasoconstrictor and platelet aggregator) and PGI2 (opposite effect) by increasing PGI2 production (Nafazatrom), inhibition of the lipoxygenase pathway (nor-dihydroguaiaretic acid), and/or inhibition of thromboxane synthetase (UK-38,485) will prevent, attenuate, or delay the hemodynamic and excretory changes that accompany renal allograft rejection. This has potential utility in that immunologic tolerance for the graft could develop in time with or without special immunologic manipulations if renal iability is maintained by preservation of renal blood flow during the """"""""adaptation"""""""" period. Correlation of alterations in the immunologic response (T-cell function) with changes in renal PG metabolism may contribute to an understanding of the complex entity of renal allograft rejection. Also observing the changes in arachidonate metabolism in this model of intense accelerated renal injury should provide insight about the role of the prostaglandin-thromboxane-eicosanoid system in other forms of renal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033308-03
Application #
3231712
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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; 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
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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