The Mechanism Of Prostaglandin E2 Activating EP4 To Alleviate APAP Induced Acute Liver Failure In Mice

Background:Acute liver failure is the clinical manifestation of severe sudden liver injury,which can be caused by many reasons.Excessive intake of acetaminophen(APAP)is one of the most common reasons.APAP can directly damage hepatocytes by depleting glutathione in cells,leading to hepatocyte death.Necrotic hepatocytes release a large number of damage related molecular patterns,activate a series of immune cells mainly composed of liver macrophages,and regulate the whole pathological process.PGE2,as one of the most abundant prostaglandins,has the widest distribution and many biological activities.In the process of inflammation,PGE2 can often play the role of promoting or inhibiting inflammation at the same time.The final effect depends on cell type,local PGE2 concentration,receptor type and tissue microenvironment.In the early study,PGE2 showed significant remission in the acute liver failure model induced by galactosamine/lipopolysaccharide,APAP and carbon tetrachloride.However,the mechanism of PGE2 to alleviate APAP induced acute liver failure is still unclear.Objective: To clarify the effect of dmPGE2 on APAP induced ALF in mice,explore the role of PGE2 in regulating the function of liver macrophages in APAP induced ALF,and construct PGE2 alleviating APAP induced hepatocyte injury model.To explore the mechanism of PGE2 alleviating the damage of APAP induced hepatocytes.Method:(1)The model of ALF mice induced by APAP was established.The level of serum transaminase and serum cytokines are detected.(2)PGE2 and EP4 antagonists were used to treat the induced monocyte lines U937 and THP-1 to detect the transcription level of TNF-?.(3)Human hepatocyte line L02 was used to construct APAP injured hepatocyte model,and the cell activity was detected after treatment with different doses of PGE2.The expression of EP receptor EP1,EP2,EP3 and EP4 in each cell line was detected,and the main effective EP receptor type was verified by EP receptor antagonist or EP receptor overexpression model.(4)The effect of PGE2 was blocked by autophagy inhibitors in the cell model,and the effect of PGE2 on inflammation was verified in animal experiments.Result:(1)Dm PGE2 can significantly reduce serum transaminase,TNF-? and IL-10 levels of ALF mice induced by APAP.(2)PGE2 can activate EP4 receptor on macrophage and inhibit the production of TNF-?.(3)PGE2 can directly alleviate the damage of APAP to L02 hepatocyte line,which can be blocked by EP4 antagonist.Overexpression of EP4 receptor in Hep G2 cell line can observe the alleviative effect of PGE2 on APAP injury.(4)Autophagy inhibitors can block PGE2 from alleviating the damage of L02 hepatocyte line induced by APAP and dmPGE2 from alleviating the ALF of mice induced by APAP.Conclusion:dmPGE2 can alleviate the ALF induced by APAP in mice.PGE2 can activate EP4 receptor of macrophage to inhibit the secretion of TNF-?.PGE2 can also activate EP4 receptor of hepatocyte to promote autophagy and enhance the tolerance of hepatocyte to APAP.