The protective effect of dexmedetomidine on the liver injury in sepsis through inhibition of necroptosis

Abstract Background Sepsis-induced liver injury leads to extensive necroptosis in hepatocytes, which is the main factor of liver dysfunction. This study aims to investigate the protective effect of dexmedetomidine (DEX) on septic liver and to explore whether its molecular mechanism is related to the modulation of necroptosis. Methods The model of septic liver injury was induced by cecal ligation and puncture (CLP) in rats. DEX and necrostatin-1(Nec-1), a specific antagonist of necroptosis, were administered 1 h before CLP. The levels of arterial blood gas (ABG), serum AST and ALT were measured at 6, 12 and 24 h after CLP. The survival rate was observed 24 h after CLP. Liver pathological changes and apoptosis, the contents of IL-6 and TNF-α in liver tissue homogenates, the ROS content in liver tissue, and the expression levels of RIP1, RIP3, MLKL and HMGB1 were detected. Results At 6, 12, and 24 h after CLP, the levels of ALT and AST levels increased, and liver enzyme levels gradually increased with the progression of sepsis. In ABG analysis, P a O 2 gradually decreased and lactic acid concentration gradually increased during these three time periods. The morphological impairment of liver tissues, increased apoptosis, elevated inflammatory factors (IL-6 and TNF-α), increased ROS level and necroptosis components (RIP1, RIP3, MLKL and HMGB1) were all observed in sepsis rats. However, these injuries can be ameliorated by pretreatment with DEX. Meanwhile, Nec-1 pretreatment also reduced the expression of RIP1, RIP3, MLKL, HMGB1, and ROS level. Conclusion Our study suggests that DEX alleviates septic liver injury, and the mechanism is associated with the inhibition of necroptosis.