STAT3 Inhibitors Alleviates Acute Hepatic Damage Induced By Lipopolysaccharide/D-Galactosamine In Mice

Objective:Acute hepatic damage is a life-threatening syndrome accompanied by high morbidity around the world,which is induced by viruses,bacteria,drugs,toxins,and alcohol.A growing body of evidence shows that inhibition of STAT3 plays an anti-inflammatory role in inflammation-related experimental models.For this study,we aimed to elucidate the mechanism and related mechanism of STAT3 and its inhibitors in the LPS/D-Gal N induced mouse acute hepatic damage model.Methods:The mice in the LPS/D-Gal N group were injected intraperitoneally with LPS(10 μg/kg)combined with D-Gal N(700 mg/kg)to induce acute liver injury.To investigate whether STAT3 is involved in the development of acute hepatic injury,we used two kinds of STAT3 inhibitors:S3I-201 and Stattic,STAT3 inhibitor was injected intraperitoneally 0.5h before LPS / D-Gal N injection.The levels of plasma transaminase,liver histomorphology,interleukin-6(IL-6),and tumor necrosis factor(TNF-α)in mice pretreated with STAT3 inhibitors were analyzed after 6 hours LPS/D-Gal N injection.Previous studies suggest that a large number of hepatocytes apoptosis in LPS/D-Gal N induced acute liver injury.To further reveal whether STAT3 inhibitors regulates the development of acute liver injury by regulating hepatocyte apoptosis,we measured the activities of caspase-3,caspase-8,and caspase-9 in liver tissue of mice pretreated with STAT3 inhibitors.Meanwhile,we analyzed the expression of cleaved caspase-3 and cleaved PARP by Western Blot,and the apoptosis of hepatocytes by TUNEL staining.To further explore whether the STAT3 inhibitor has clinical significance in acute liver injury treatment,S31-201 was injected intraperitoneally 1.5h after LPS / D-Gal N injection.And transaminase,IL-6,and TNF-α were detected.Results:(1)Pretreatment with STAT3 inhibitor inhibited the elevation of transaminase induced by LPS / D-Gal N,alleviated the histological abnormalities of liver,inhibited the production of inflammatory cytokines IL-6 and TNF-α,blocked the activation of caspase cascade,and reduced the number of TUNEL positive cells.Western blot results showed that LPS /D-Gal N inhibited the production of IL-6 and TNF-α The up-regulation of caspase-3 and PARP was inhibited by STAT3 pretreatment.(2)Posttreatmentwith S31-201 reduced the LPS / D-Gal N induced decrease of transaminase and hepatocyte apoptosis.Conclusion: This study suggests that STAT3 is activatedin LPS /D-Gal N-induced acute liver injury,STAT3 inhibitors may have potential application value in the treatment of inflammatory liver disease.