title: High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity.
abstract: BACKGROUND
  Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose.
  
  
  METHODS
  Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses.
  
  
  RESULTS
  24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.
  
  
  CONCLUSIONS
  HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.
authors.affiliation: Department of Intensive Care Medicine, University of Tampere Medical School, Tampere 33014, Finland. bobyangr@yahoo.com
authors.forename: Runkuan
authors.initials: R
authors.lastname: Yang
authors.forename: Shutian
authors.initials: S
authors.lastname: Zhang
authors.forename: Antonella
authors.initials: A
authors.lastname: Cotoia
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Shengtao
authors.initials: S
authors.lastname: Zhu
authors.forename: Jyrki
authors.initials: J
authors.lastname: Tenhunen
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D007074:Immunoglobulin G / Q000494:pharmacology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D024243:HMGB1 Protein; D007074:Immunoglobulin G; D016328:NF-kappa B; D019938:Cyclin D1; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase