IMPAIRMENT OF PEROXISOMAL STRUCTURE AND FUNCTION IN RAT-LIVER ALLOGRAFT-REJECTION - PREVENTION BY CYCLOSPORINE

Background, During allograft rejection, cytokines and lipid mediators contribute to cell injury and organ failure. Peroxisomes play a crucia l role in lipid metabolism, including the degradation of lipid mediato rs by peroxisomal beta-oxidation, Therefore, we investigated the alter ations of hepatic peroxisomes after allogeneic rat liver transplantati on, Methods. MHC-incompatible Dark Agouti (RT1(a)) donor rats and Lewi s (RT1(1)) recipient rats were used for allogeneic transplantation. Fo r immunosuppression, a group of these animals received cyclosporine (C sA) intraperitoneally (1 mg/kg body weight per day). Lewis rats were u sed for isogeneic transplant combination. Ten days after transplantati on, livers were investigated using morphometrical methods for determin ation of peroxisomal diameter and volume density. The activities of pe roxisomal catalase (CAT) and acylcoenzyme A oxidase (AOX) were determi ned, and the corresponding proteins were evaluated by quantitative imm unocytochemistry and immunoblotting, The expressions of mRNAs encoding CAT and AOX were investigated by Northern blotting, Results. The volu me density and diameter of peroxisomes were significantly decreased in allogeneic transplanted livers hut were unchanged in CsA-treated anim als, Both the activities of CAT and AOX and their protein levels were significantly reduced in liver allografts. Moreover, the corresponding mRNA levels of CAT and AOX were decreased significantly in liver allo grafts, whereas CsA treatment led to an increase of those mRNAs. Isoge neic transplanted livers showed only a slight reduction of the corresp onding enzyme values, Conclusions. Peroxisomes are severely affected b oth morphologically and functionally after allogeneic liver transplant ation, These results suggest that, impairment of peroxisomal lipid bet a-oxidation could contribute to the pathogenesis of the rejection proc ess by decreased catabolism of lipid mediators involved in the regulat ion of the inflammatory response. CsA, in addition to its immunosuppre ssive effects, may contribute to allograft survival by maintenance of those important peroxisomal functions.