| Background: Hepatic ischemia/reperfusion(I/R)injury is a major complication caused by a variety of clinical settings,such as partial hepatectomy,liver transplantation,severe trauma,hemorrhagic shock,and vascular surgery,which result in postoperative liver dysfunction.Up to now,the effective therapeutic methods for liver ischemia-reperfusion injury are very limited,so it is very urgent to explore new therapeutic strategies.Maresin1 is a pro-resolving lipid mediator that has been shown to have potent anti-oxidative stress,anti-inflammatory,and pro-resolving properties.In addition,a large number of studies have shown that Maresin1 can reduce the organ damage caused by ischemia-reperfusion,but the potential mechanism is still unclear.Meanwhile,whether Ma R1 can alleviate ischemia/reperfusion-induced liver injury in mice remains to be further investigated.Objective: This experiment aims to reveal the mechanism by which Ma R1 exerts its protective effect in liver ischemia-reperfusion,and provide a new option for the treatment of hepatic ischemia-reperfusion injury.Methods: In vivo,all wild-type(WT)mice were subjected to partial(70%)hepatic warm ischemia injury for 1 hour followed by 6 hours of reperfusion.First,the serum of the sham group and the surgery group was collected to assess the expression level of Ma R1 in circulation.To explore the role of Maresin1 in liver ischemia-reperfusion injury,mice in the experimental group were treated with different doses of Maresin1(5ng-20ng/mouse)at the initiation of reperfusion through tail vein administration;After surgery,the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum were analyzed,and the tissue damage was evaluated by H & E staining.At the same time,liver tissues were collected to determine the activity of antioxidant enzymes and the levels of lipid peroxidation products.To investigate the role of the Lipoxin A4 receptor(ALXR)and Akt pathways in Maresin1-mediated hepatoprotective effects,ALXR antagonist(boc2)and Akt inhibitor(LY294002)were injected into mice by intraperitoneal or subcutaneous administration,respectively.At the end of reperfusion,mice were sacrificed to collect liver tissue and blood samples.Serum and liver samples from each group were then analyzed for serum transaminase levels,histopathological changes,inflammatory cytokine release,and oxidative stress to assess liver damage.In vitro,we isolated primary hepatocytes and non-parenchymal cells and then divided these cells into the normoxia group and hypoxia-reoxygenation(H/R)group.Each group was treated with different concentrations of Ma R1(0-100 n M).After reoxygenation,the cell proteins of the indicated groups were collected for Western blotting examination,and the supernatant was collected to analyze the level of lactate dehydrogenase(LDH).Results: 1)Compared with the sham-operated group,the level of Ma R1 in the circulation was significantly up-regulated in mice after hepatic ischemia-reperfusion injury;2)Ma R1 could alleviate hepatic ischemia-reperfusion injury in a dose-dependent manner,as demonstrated by reducing serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels,diminishing tissue necrotic area,inhibiting the inflammatory response,suppressing oxidative stress and decreasing the hepatocytes apoptosis;3)Mechanically,the beneficial effect of Ma R1 is dependent on the ALXR receptor and the protective effect of Ma R1 can be completely blocked by pretreatment with ALXR antagonist Boc2 before surgery;4)Ma R1 can induce the activation of Akt,and this activation is dependent on ALXR;Akt inhibitors can also completely reverse the Ma R1-mediated hepatoprotective effect.Conclusion: These results confirm that Maresin1 can attenuate liver injury during ischemia-reperfusion,and this protective effect is dependent on the ALXR/Akt signaling pathway. |
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