title: The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/D-galactosamine in mice.
abstract: BACKGROUND
  Acute liver failure (ALF) is a severe and life-threatening clinical syndrome resulting in a high mortality and extremely poor prognosis. Recently, a water-soluble CO-releasing molecule (CORM-3) has been shown to have anti-inflammatory effect. The present study was to investigate the effect of CORM-3 on ALF and elucidate its underlying mechanism.
  
  
  METHODS
  ALF was induced by a combination of LPS/D-GalN in mice which were treated with CORM-3 or inactive CORM-3 (iCORM-3). The efficacy of CORM-3 was evaluated based on survival, liver histopathology, serum aminotransferase activities (ALT and AST) and total bilirubin (TBiL). Serum levels of inflammatory cytokines (TNF-alpha, IL-6, IL-1beta and IL-10) and liver immunohistochemistry of NF-kappaB-p65 were determined; the expression of inflammatory mediators such as iNOS, COX-2 and TLR4 was measured using Western blotting.
  
  
  RESULTS
  The pretreatment with CORM-3 significantly improved the liver histology and the survival rate of mice compared with the controls; CORM-3 also decreased the levels of ALT, AST and TBiL. Furthermore, CORM-3 significantly inhibited the increased concentration of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and increased the anti-inflammatory cytokine (IL-10) productions in ALF mice. Moreover, CORM-3 significantly reduced the increased expression of iNOS and TLR4 in liver tissues and inhibited the nuclear expression of NF-kappaB-p65. CORM-3 had no effect on the increased expression of COX-2 in the ALF mice. An iCORM-3 failed to prevent acute liver damage induced by LPS/D-GalN.
  
  
  CONCLUSIONS
  These findings provided evidence that CORM-3 may offer a novel alternative approach for the management of ALF through anti-inflammatory functions.
authors.affiliation: Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China. bingrongliu@qq.com.
authors.forename: Bing-Zhu
authors.initials: BZ
authors.lastname: Yan
authors.forename: Bao-Shan
authors.initials: BS
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Zhang
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Pei
authors.forename: An-Chao
authors.initials: AC
authors.lastname: Zhu
authors.forename: Xiao-Ren
authors.initials: XR
authors.lastname: Wang
authors.forename: Bing-Rong
authors.initials: BR
authors.lastname: Liu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D005688:Galactosamine; D018836:Inflammation Mediators / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009942:Organometallic Compounds; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C440499:lipopolysaccharide, Escherichia coli O111 B4; C476530:tricarbonylchloro(glycinato)ruthenium(II); D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin