Mechanisms of hepatic ischemia reperfusion injury and tumor recurrence after liver transplantation

Abstract

Background and objectives: Liver transplantation is the first choice for the treatment of end-stage liver diseases and selected hepatocellular carcinoma (HCC) patients. However, hepatic ischemia reperfusion (IR) injury and tumor recurrence are the critical issues associated with liver transplantation, especially in living donor liver transplantation. To attenuate hepatic IR injury and to prevent tumor recurrence, understanding of the precise molecular mechanisms of hepatic IR injury and tumor recurrence after liver transplantation is crucial. In this study, the objectives are: (I) To explore the role and mechanism of aldose reductase (AR) in hepatic IR injury；(II) To investigate the role and mechanism of repressor and activator protein (Rap1) in hepatic IR injury；(III) To explore the role and mechanism of hepatic IR injury in regulatory T cells (Tregs) mobilization and tumor recurrence after liver transplantation for HCC patients. Materials and methods: In this project, the association of AR and Rap1 with hepatic IR injury were investigated in both human and rat liver transplantation. The roles and mechanisms of AR and Rap1 in hepatic IR injury were studied in AR-/- mice and Rap1-/- mice model with hepatic IR injury and in vitro functional studies. Furthermore, the correlation among tumor recurrence, hepatic IR injury and Tregs mobilization were studied in human and rat liver transplantation. The mechanism of hepatic IR injury in regulating Tregs mobilization and tumor recurrence were explored in CXCL10-/- mice and CXCR3-/- mice model. Results: I. The role of AR in hepatic IR injury AR was over-expressed in liver graft after human and rat liver transplantation and correlated with liver injuries. The knockout of AR attenuated liver damage and inflammatory response both in normal and fatty liver after IR injury. Furthermore, the inhibition of AR suppressed macrophages migration and decreased proinflammatory cytokines/chemokines expressions in isolated macrophages. II. The role of Rap1 in liver IR injury Over-expression of Rap1 was associated with severe liver graft inflammatory response after human and rat liver transplantation, especially in small-for-size liver graft. The knockout of Rap1 reduced liver damage and inflammatory response after mouse hepatic IR injury. Furthermore, the knockout of Rap1 suppressed neutrophils activation and migration, and attenuated neutrophils-induced hepatocytes damage. III. The role of hepatic IR injury in tumor recurrence Patients received the graft with graft weight ratio (GWR) <60% had more circulating Tregs, higher intragraft expressions of CXCL10/CXCR3 and more HCC recurrence after liver transplantation than the recipients with GWR≥60% graft. The knockout of CXCL10/CXCR3 signaling decreased the mobilization and recruitment of Tregs after hepatic IR injury. Moreover, fewer CXCR3+ Tregs were recruited into liver in CXCL10-/- mice. Conclusions: The knockout of either AR or Rap1 attenuated hepatic IR injury through decreasing liver inflammatory response. Enhanced CXCL10/CXCR3 signaling in hepatic IR injury contributed to the mobilization and recruitment of Tregs, which may further promote tumor recurrence after liver transplantation. Understanding the mechanisms of hepatic IR injury and tumor recurrence may provide a novel means to attenuate hepatic IR injury and late phase tumor recurrence after liver transplantation.