title: Acute liver injury attenuation of a novel recombinant sTNFR through blocking hepatic apoptosis.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) α plays a key role in acute liver injury (ALI) induced by injection of d-galactosamine (D-Gal)/lipopolysaccharide (LPS). A novel recombinant trimeric sTNFRII, sTNFRII-gAD, has been tested to be effective in ameliorating ALI, when administered prior to ALI establishment. This study aims to validate the protective effect of sTNFRII-gAD when given after ALI setup and further explore its effect on hepatic apoptosis.
  
  
  METHODS
  The treatments were carried out concomitantly with ALI establishment with clinically approved sTNFRII-Fc (the dimeric sTNFRII) as a positive control. Lethality, liver weight, and serum alanine transaminase were measured, and histological analysis was performed to evaluate liver injury induced by D-Gal/LPS. Additionally, Terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) and Western blot analyses of caspase-3 were used to examine hepatocellular apoptosis.
  
  
  RESULTS
  sTNFRII-gAD given after D-Gal/LPS injection turned out to attenuate animal mortality significantly (p < 0.01), and had better hepatic protection. In terms of apoptosis, both sTNFRII-gAD and sTNFRII-Fc displayed noticeable improvement of apoptosis evidenced by dramatic decline of active caspase-3 compared to the control group.
  
  
  CONCLUSIONS
  The results demonstrated that sTNFRII-gAD therapeutically diminished the lethality induced by D-Gal/LPS, possibly through blocking hepatic apoptosis initiated by TNFα. Of note, sTNFRII-gAD was superior to sTNFRII-Fc in some respects, indicating a promising alternative for the therapeutic strategy against the diseases associated with excessive TNFα.
authors.affiliation: Department of Microbiology & Immunology, School of Medicine, JingGangShan University , Jian , China .
authors.forename: Mansheng
authors.initials: M
authors.lastname: Luo
authors.forename: Ai
authors.initials: A
authors.lastname: Zhao
authors.forename: Jinlong
authors.initials: J
authors.lastname: Li
authors.forename: Yueping
authors.initials: Y
authors.lastname: Chen
authors.forename: Dandan
authors.initials: D
authors.lastname: Tian
authors.forename: Caihong
authors.initials: C
authors.lastname: Wang
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Hu
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053148:Caspase 3 / Q000276:immunology; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Acute liver injury; TNFα; adiponectin; apoptosis; sTNFR