The Role of Exercise Training in Preconditioning the Liver Against Ischemia/Reperfusion Injury in an Orthotopic Liver Murine Transplant Model

Abstract

Introduction: Liver transplantation (LT) remains the most effective treatment for end stage liver disease. During transplantation the liver undergoes several major insults including cold storage and subsequent reperfusion, which together reduce immediate function and precipitate innate inflammatory changes known to aggravate adaptive immune rejection. Translational applications to target the host response to ischemia and reperfusion injury (IRI) have been slow to emerge. We have shown that exercise training (ExT) confers protections against IRI in a murine model by altering the liver damaging innate inflammatory events. Methods: 8-week-old C57BL6 mice were exercised (ExT) (60-minutes/d; 4-weeks) or kept sedentary (Sed). After 4-weeks, livers from both ExT and Sed mice were perfused with University of Wisconsin (UW) solution and subjected to 1-hour cold storage (4 °C) prior to orthotopic transplantation into syngeneic C57BL6 mice. 6h following transplantation, liver damage and immune infiltration were assessed. Results: ExT pre-conditioning conferred sustainable graft protection against IRI evident by reduced liver damage, 6-hours following revascularization. Liver from ExT mice showed decreased necrosis compared to Sed and decreased liver infiltration and activation of neutrophils. In addition, ExT increased the infiltration of anti-inflammatory M2-subtype macrophages rather than pro-inflammatory M1 within the graft. Following cold storage, ExT liver grafts showed significantly lower levels of apoptosis and increasesd levels of mitochondrial biogenesis. Conclusion: These findings suggest that livers from ExT mice may be resistant to damage during cold storage and warm I/R and that ExT leads to alteration in inflammatory cells within the liver upon reperfusion.