Exercise training decreases hepatic injury via changes in immune response to liver ischemia/reperfusion in mice.

BACKGROUND & AIMS Liver ischemia-reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth consistent with the notion that the liver IRI can serve as a pre-metastatic niche. Exercise training (ExT) confers a sustainable protection reducing IRI in some animal models and has been associated with improved survival in cancer patients; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. APPROACH & RESULTS Mice were randomized into exercise (ExT) and sedentary groups prior to liver IRI and tumor injection. Computerized dynamic network analysis (DyNA) of 20 inflammatory mediators was utilized to dissect the sequence of post-I/R mediator interactions that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NETs formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present three weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. CONCLUSIONS ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver pre-metastatic niches induced by liver IRI through the use of exercise training as a non-pharmacologic therapy prior to curative surgical approaches.