Erythropoietin increases survival and attenuates fulminant hepatic failure injury induced by d-galactosamine/lipopolysaccharide in mice

Ziv Ben-Ari, Veacheslav Zilbermints, Orit Pappo, Orna Avlas, Eran Sharon, Franklin Greif, Yelena Cheporko, Amiram Ravid, Rivka Shapiro, Edith Hochhauser

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18 Scopus citations

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.

Original languageEnglish
Pages (from-to)18-24
Number of pages7
JournalTransplantation
Volume92
Issue number1
DOIs
StatePublished - 15 Jul 2011
Externally publishedYes

Keywords

  • Erythropoietin
  • Fulminant hepatic failure
  • JNK
  • NF-κB
  • TNF-α

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