The Role And Mechanism Of Kupffer Cell Drpl Activating NLRP3 Inflammasome In Fatty Liver Ischemia-reperfusion Injury

Objective:Liver diseases,such as viral hepatitis,cirrhosis,liver cancer and liver failure,have very high morbidity in China.Liver transplantation is the best method to treat end-stage liver disease by various liver damages,acute liver failure and hepatocellular carcinoma.Hepatic ischemia-reperfusion injury,which is easy to result in liver dysfunction and even liver failure,is an unavoidable injury after liver transplantation and partial hepatectomy blocking the hepatic portal.The increasing number of patients who need liver transplantation makes the shortage of donor liver more and more serious.In order to expand the source of donor liver,major transplantation centers gradually accept fatty liver as "marginal donor liver".More and more studies have shown that the donor liver from fatty liver is particularly sensitive to ischemiareperfusion injury,and has very high incidence rate of graft nonfunction after transplantation.However,there are relatively few studies on fatty liver ischemia-reperfusion injury,and there is a lack of effective treatment methods to reduce fatty liver ischemia-reperfusion injury.Traditional Chinese medicine protect liver ischemia-reperfusion injury from multiple levels and various targets,with the characteristics of high safety and less side effects.This study intends to study the role and mechanism of traditional chinese medicine in liver ischemia-reperfusion injury,and to reveal the pathogenesis of fatty liver ischemia-reperfusion injury and to explore the effective means of preventing and treating fatty liver ischemia-reperfusion injury,which could improve the survival rate of liver transplantation patients and reduce perioperative complicationsMethod:In this paper,we studied the effect of Fuyuan Huoxue Decoction on liver ischemiareperfusion injury by the method of network pharmacology,and studied whether Kupffer cells aggravate fatty liver ischemia-reperfusion injury and its possible mechanism in vivo and in vitro experiments.Results:The topological analysis of the "traditional chinese medicine-target-singal pathway-disease" regulatory network shows that there are 2 traditional chinese medicines,33 active components,4 targets and 3 signal pathways,which play a key role in the treatment of liver ischemia-reperfusion injury by Fuyuan Huoxue Decoction.The highest active component of degree in the regulatory network is quercetin and the target is ESR1,The signal pathways with the highest correlation were pl3k Akt signal pathway and Thl and Th2 cell differentiation.In vivo and in vitro experiments show that liver ischemia-reperfusion injury is more serious in fatty liver than in non-steatosis liver.Clearing Kupffer cells in fatty liver can reduce ischemiareperfusion injury.Further mechanism study showed that fatty liver promoted the activation of Kupffer cells in fatty liver,increased the expression of drpl,and then up-regulated the expression of NLRP3.The use of drp1 inhibitor can effectively reduce the expression of NLRP3 and alleviate the ischemia-reperfusion injury in fatty liver.Conclusion:Fuyuan Huoxue Decoction can regulate the balance of immune cells and the production and release of inflammatory mediators through multi-target and multi-channel,so as to play a role in liver ischemia-reperfusion injury;Kupffer cells activated in fatty liver aggravated ischemia-reperfusion injury through drp1-NLRP3 signal pathway.These results of this study provided a new strategy for reducing fatty liver ischemia-reperfusion injury in clinic.