Our Strategy to Overcome Hepatic Ischemia Reperfusion Injury -From Bench to Bedside-

Abstract

Background: In the field of liver surgery, especially transplantation, ischemia reperfusion injury (IRI) causes approximately 10% of early graft failure and leads to a higher incidence of acute and chronic rejection. It is an urgent issue to overcome IRI from the viewpoint of organ preservation. This study aims to reveal the molecular mechanism and develop the effective protective way to prevent the liver IRI for a safer liver surgery. Methods :We applied the established partial warm hepatic IRI model in mice and investigated changes of immune responses due to IR, and compared the efficacy of various biological molecules (neutrophil elastase inhibitor, recombinant Galectin-9, recombinant thrombomodulin and so on), antioxidant agents (vitamins C and E) and maneuvers (preoperative short-term fasting). The liver damage was assessed by serum alanine aminotransferase (sALT) level, histological observations, change in expression profile of various cytokines and analysis of intracellular molecules. Results: The most effective way to improve IRI was the preoperative short-term (12 hours) fasting. It exhibited a remarkable therapeutic effect compared with any other drug or diet we have so far examined. The up-regulation of Forkhead Box O1 (FOXO-1) induced by the raised acetylated histone and β-hydroxybutyric acid was a crucial factor for the short-term fasting to ameliorate the liver injury due to IR. Conclusion: Preoperative short-term dietary restriction might play an important role to overcome liver IRI and have a therapeutic potential for clinical setting.