Protective Effect And Mechanism Of Pretreatment Rat Donors After Cardiac Death With Simvastatin On Liver Ischemia Reperfusion Injury

Part ? Simvastatin ameliorates total liver ischemia/reperfusion injury via KLF2-mediated mechanism in ratsAim The total hepatic ischemia/reperfusion injury(IRI)involves the fact that both liver and gut are subjected to warm ischemia,which is a complex unavoidable process encountered during liver transplantation and a serious threat to graft outcome.The ways to improve hepatic IRI are currently limited.The aim of the present study was to explore the protective effect of simvastatin on total hepatic IRI and examine the underlying mechanisms.Methods Male Sprague Dawley rats were subjected to total(100%)hepatic warm ischemia to induce hepatic IRI.Thirty-six male rats(250-300g)were randomly divided into three groups: sham,IRI control and simvastatin(1 mg/kg)pretreatment 0.5 h before surgery.Serum samples and liver tissues were collected after reperfusion at 6 and 24 h for further studies.Results Simvastatin pretreatment significantly decreased the values of the transaminases alanine aminotransferase and aspartate aminotransferase and improved histological alterations according to improved Suzuki's score(P< 0.05).Moreover,simvastatin upregulated the expression of Kruppel-like factor 2(KLF2),phosphorylated endothelial nitric oxide synthase and thrombomodulin(P< 0.05).Furthermore,simvastatin pretreatment affected superoxide dismutase and malondialdehyde activities(P< 0.05)to reduce oxidative stress,and inhibited levels of high mobility group box-1,CD68,toll-like receptor 4,tumor necrosis factor ?,interleukin-1? and interleukin-6(P< 0.05)to suppress inflammatory response.Conclusion Simvastatin pretreatment ameliorates total hepatic IRI via a KLF2-mediated protective mechanism.Simvastatin may be used as a potential prophylactic treatment strategy for clinical trials against hepatic IRI.Part? Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury Through a KLF2-dependent Mechanism in RatAim Severe hepatic ischemia reperfusion injury(IRI)can result in poor short and long-term graft outcome after transplantation.The way to improve the viability of livers from donors after cardiac death(DCD)is currently limited.The aim of the present study was to explore the protective effect of simvastatin on DCD livers and investigate the underlying mechanism.Methods 24 male rats were randomly received simvastatin or its vehicle.30 min later,rat livers were exposed to warm ischemia in situ for 30 min.Livers were removed and cold stored in UW solution for 24 h,subsequently reperfused for 60 min with an isolated perfused rat liver system.Liver injury was evaluated during and after warm reperfusion.Results Pretreatment of DCD donors with simvastatin significantly decreased IRI liver enzyme release,increased bile output and ATP and ameliorated hepatic pathological changes.Simvastatin maintained the expression of KLF2 and its protective target genes(e NOS,TM,HO-1),reduced oxidative stress,inhibited innate immune responses and inflammatory,and increased the expression of Bcl-2/Bax to suppress hepatocyte apoptosis compared to DCD control group.Conclusion Pretreatment of DCD donors with simvastatin improves DCD livers functional recover probably through a KLF2-dependent mechanism.These data suggest that simvastatin may provide a potential benefit for clinical DCD livers transplantation.