title: Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.
abstract: BACKGROUND
  Acute-on-chronic liver failure (ACLF) is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc]) prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55) pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF.
  
  
  METHODS
  Chronic liver disease (liver fibrosis/cirrhosis) was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA), and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN)/lipopolysaccharide (LPS) i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations.
  
  
  RESULTS
  Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL)-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA). This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats.
  
  
  CONCLUSIONS
  sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.
authors.affiliation: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Shishan
authors.initials: S
authors.lastname: Bao
authors.forename: Fazal
authors.initials: F
authors.lastname: Tabassam
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Xiang
authors.forename: Gangde
authors.initials: G
authors.lastname: Zhao
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wu
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
mesh_terms: D000818:Animals; D005688:Galactosamine / Q000494:pharmacology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver; D017093:Liver Failure; D017114:Liver Failure, Acute / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D012709:Serum Albumin / Q000494:pharmacology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D007141:Immunoglobulin Fc Fragments; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D005688:Galactosamine