The Role And Machinism Of Acidic Microenvironment In Regulating The Severity Of Hepatic Ischemia/Reperfusion Injury By Modulating The Differentiation And Function Of Hepatic Immune Cells

Hepatic ischemia-reperfusion injury(HIRI)was an important cause of liver injury post surgical operations such as hepatectomy and liver transplantation.Abnormal immune function played a central role in the occurrence and development of HIRI,but mechanisms of its occurrence were still unclear.Macrophages(m(?))in the liver could be differentiated into M1 and M2 cells,which presented strong immunomodulatory ability and were considered to be core immune cells in the process of HIRI.Recently data proved that severe acidic microenvironment had been formed by local hypoxia and anaerobic glycolysis during HIRI,while whether or not the differentiation and function of macrophage could be regulated by acid had not been studied.This study aimed to explore the role of acidic microenvironment in the pathogenesis of HIRI and the underline mechanism of acid in regulating the macrophages in liver.The study found that in the mouse ischemia-reperfusion model,intrahepatic microenvironment was transformed into an acidic environment,which was aggravated with the time of ischemia and accompanied by aggravation of liver damage;the use of Na HCO3 to reduce the acidic microenvironment could protect ischemia-reperfusion injury,besides,the removal of macrophages could abolish the protective effect of Na HCO3;further observation revealed that the acidic microenvironment could induce the transformation of macrophages into M1 cells in the liver,while Na HCO3 treatment could reverse and induce the differentiation of M2 cells;in vitro experiments had shown that the acidic culture environment can also induce M0 to differentiate into M1 cells,and reducing the acid could promote the conversion of M0 to M2 cells;mechanism experiments show that the regulation of the acidic microenvironment on macrophages depends on PPAR-? related mechanisms.The use of PPAR-? agonist can reduce the regulatory effect of acidic microenvironment on macrophages.Our research confirmed the role of acidic microenvironment in regulating liver macrophage differentiation and function and PPAR-? related mechanisms during liver ischemia-reperfusion pathology.Preventing the formation of acidic microenvironment would become a promising treatment strategy post liver resection and liver transplantation to reduce liver ischemia-reperfusion injury.