Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

Molecular Medicine

Wenbo Li¹  Da Tang²  Guang Fu²  Ping Sun³  Meihong Deng⁴  Patricia A. Loughran⁵  Melanie J. Scott⁶  Timothy R. Billiar⁶ 

[1] Department of Burn and Plastic Surgery, The Second Xiangya Hospital, Central South University, 410000, Changsha, People’s Republic of China;Department of General Surgery, The Third Xiangya Hospital, Central South University, 410000, Changsha, People’s Republic of China;Department of Hepatobiliary Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China;Department of Surgery, Ohio State University Medical School, Columbus, OH, USA;Department of Surgery, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Department of Surgery, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Pittsburgh Trauma Research Center, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Pittsburgh Liver Research Center, University of Pittsburgh, 15213, Pittsburgh, PA, USA;

关键词: Lipid mediators;    Hepatic ischemia/reperfusion;    Hepatocytes;    Inflammation;    Oxidative stress;    Apoptosis;   

DOI  :  10.1186/s10020-021-00280-9

来源: Springer

【 摘 要 】

BackgroundHepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown.MethodsWT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury.ResultsMaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt.ConclusionsMaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.

【 授权许可】

CC BY