*Purpose: Orthotopic liver transplantation (LTx) serves as the gold standard of care in patients with end-stage liver disease. However, a major obstacle to the immediate post-transplant success of LTx is hepatic ischemia/reperfusion injury (IRI), a consequence of inflammatory response driven by the innate immune system. To reduce the severity of the inflammatory response we have recently shown that exercise training (ExT) confers sustainable protection against warm liver IRI. The protective role of exercise in liver transplant remains partially understood, thus, we aim to determine whether ExT can ameliorate the cold and warm IRI and improve outcomes after transplant surgery.

*Methods: Eight-week-old C57BL/6 mice were randomized into ExT or sedentary groups. The ExT group was subjected to 5x/week of 1-hour treadmill-running at a pace of 12-meters/minute for four weeks followed by 2-days of rest for four weeks before 1-hour cold storage and liver transplant into congenic sedentary mice.

*Results: Orthotopic liver transplants from ExT mice showed significantly better outcomes after transplantation compared to grafts from sedentary mice. This was evident by reduced serum ALT/AST/LDH levels at 6-hours following revascularization (ExT vs Sedentary p<0.05). Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in the transplanted livers from ExT mice implying a protective effect associated with decreased intragraft inflammatory cytokine (IL-6, TNFα, IL-1A and IL-1β) and chemokine (CXCL1/2/10 and MCP1) cascades. Decreased neutrophil infiltration, decreased neutrophil extracellular trap (NETs) formation, and increased M2 phenotypic recipient macrophages were also observed in the grafts from ExT trained mice. Further support for this observation was garnered through in vitro studies wherein co-culture of healthy neutrophils and macrophages incubated with liver flushed from pre-transplant sedentary graft induced NETs and polarized macrophages to be M1 phenotype whereas a reversed effect was seen using hepatic flush from ExT grafts. In addition, hepatocytes in the ExT grafts, during cold storage, showed decreased HMGB1 translocation and release as well as augmented hepatocyte mitochondrial biogenesis pathways, thus protecting the graft from apoptosis.

*Conclusions: Exercise training of potential liver donors mitigates the initial host inflammatory response after orthotopic transplantation with concurrent protection of liver graft from cold and warm IRI. Ext of living potential donors may represents a potential therapeutic intervention to improve transplant outcomes.

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