Does sirolimus attenuate the damage induced by partial warm ischemia/reperfusion injury in rat livers?

Abstract

Ischemia/reperfusion (I/R) injury of liver occurs in a number of clinical settings as hepatic resection surgery. In this study we have addressed the possible protective effect of sirolimus, a potent novel immunosuppressant which acts on signal transduction pathways in CD4+ T-cells, and could potentially modulate immune/inflammatory cellular reactions involved in hepatic injury induced by I/R in rats. Rat livers were subjected to partial warm hepatic ischemia for 30 min followed by 0, 1, 3 and 7 days reperfusion. I/R-induced liver damage was characterized both histologically and biochemically. Histologically I/R induced necrosis and inflammatory cell infiltration during different reperfusion time intervals. Moreover, biochemical investigation showed significant elevation in serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and lactate dehydrogenase levels as compared with sham-operated group. Pretreatment with sirolimus (1mg/kg/day for 4 days before I/R) did not improve histological manifestations but caused gradual improvement of liver function tests. To evaluate the possible mechanisms involved in I/R injury myeloperoxidase (MPO) malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and reduced glutathione (GSH) were measured in liver homogenates. I/R disturbed the redox state, increased neutrophil infiltration and raised TNF-α. Sirolimus improved MDA, MPO and TNF-α, but did not induce any change in GSH level. It might be concluded from the current study that sirolimus exerts some degree of hepatic protection and improved hepatocyte membrane integrity. This effect may be attributed to its immunosuppressive action through modulating the release of the inflammatory cytokine TNF-α rather than its antioxidant property.