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Transplantation. 2011 Jul 15;92(1):18-24. doi: 10.1097/TP.0b013e31821cdea5.

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

Author information

1
Liver Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.

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.

PMID:
21516061
DOI:
10.1097/TP.0b013e31821cdea5
[Indexed for MEDLINE]

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