Protective effect of histone deacetylase inhibitor MS-275 on acute liver failure induced by D-galactosamine and lipopolysaccharide in mice / 中华临床感染病杂志

ABSTRACT

Objective To investigate the effect of MS-275, an histone deacetylase ( HDAC ) inhibitor, on acute liver failure ( ALF ) induced by D-galactosamine and lipopolysaccharide in mice. Methods Thirty specific pathogen free (SPF) C57BL/6 male mice were randomly and equally divided into control, ALF model and MS-275 groups. ALF model was induced by D-galactosamine ( D-Gal ) and lipopolysaccharide (LPS), and the mice in MS-275 group received MS-275 (1 mg/kg) at 2 h before the induction of ALF.Serum and liver samples of mice were obtained at 24 h after ALF induction.The serum levels of ALT, AST, TBil and tumor necrosis factor-alpha ( TNF-α) , interferon γ( IFNγ) , interleukin ( IL )-1β, high mobility group box 1 ( HMGB1 ) were tested by biochemical methods or ELISA kit, respectively.The expression of HDAC1, HDAC3, acetylation of histone H3, H4, P65, acetylation and phosphorylation of P65 in liver were detected by Western blotting.The changes of histology in liver was detected by HE staining, and the translocation of P65 in liver was detected by immunohistochemistry. Comparison of variables among the groups was performed using t test.Results MS-275 inhibited the infiltration of inflammatory cells and improved the pathological changes of liver tissue.Compared with ALF group, serum ALT, AST, TBil levels were decreased in MS-275 group ( t =-22.215, -11.914 and-12.160, all P<0.05), but still higher than those in the control group (t=14.852, 11.692 and 8.333, all P<0.05); serum TNF-α, IFNγ, IL-1β, HMGB1 levels were also significantly decreased in MS-275 group (t=-7.926, -3.427, -2.475 and -5.920, all P<0.05), but TNF-αand IFNγwere still higher than those in the control group (t=5.541 and 5.514, all P<0.05).Compared with control group, the expression of class I HDAC in liver tissue was significantly decreased in MS-275 group ( t=-3.676 and-10.576, P<0.05), while the expressions of acetylation of histone H3, H4 and P65 were significantly increased (t=3.976, 5.559 and 4.588, all P<0.05).MS-275 inhibited the translocation of P65 from cytoplasm to the nucleus.Conclusion MS-275 can protect liver from acute failure in mice through enhancing the acetylation levels of non-histones.