title: Erythropoietin increases survival and attenuates fulminant hepatic failure injury induced by D-galactosamine/lipopolysaccharide in mice.
abstract: BACKGROUND
  Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), d-galactosamine (GalN)-induced FHF is a well-established model of liver injury in mice. Erythropoietin has a powerful tissue-protective effect in animal models. The aim of this study was to investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) administration in FHF mice.
  
  
  METHODS
  C57BL/6 (n=42) mice were studied in vivo in a fulminant model induced by GalN/LPS. rhEPO was administered 30 min after the induction of FHF. Serum liver enzymes and hepatic tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were determined. Histologic analysis was performed, and apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor (NF)-κB and c-Jun-N-terminal kinase (JNK) activation were studied using Western blot analysis.
  
  
  RESULTS
  After the induction of FHF, all control mice died within 12 hr of GalN/LPS administration. However, 83% of mice that were administered rhEPO were alive 2 weeks later, and overall survival improved (Kaplan-Meier, P<0.001). The serum liver enzymes, hepatic TNF-α and IL-1β levels, liver histologic injury, and apoptotic hepatocytes were significantly reduced in FHF mice that were administered rhEPO compared with untreated mice. A significant decrease in hepatic NF-κB and JNK activation was noted in FHF rhEPO-treated mice compared with FHF untreated mice.
  
  
  CONCLUSIONS
  The administration of rhEPO brought about increased survival and attenuation of the hepatic injury. This was associated with decreased hepatic NF-κB and JNK activation and thus TNF-α and IL-1β levels. These findings have important implications for the potential use of rhEPO in FHF.
authors.affiliation: Liver Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Ben-Ari
authors.forename: Veacheslav
authors.initials: V
authors.lastname: Zilbermints
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Orna
authors.initials: O
authors.lastname: Avlas
authors.forename: Eran
authors.initials: E
authors.lastname: Sharon
authors.forename: Franklin
authors.initials: F
authors.lastname: Greif
authors.forename: Yelena
authors.initials: Y
authors.lastname: Cheporko
authors.forename: Amiram
authors.initials: A
authors.lastname: Ravid
authors.forename: Rivka
authors.initials: R
authors.lastname: Shapiro
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D005688:Galactosamine / Q000633:toxicity; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases