The role of excessive versus acute administration of erythropoietin in attenuating hepatic ischemia-reperfusion injury

Orit Pappo, Ziv Ben-Ari*, Evgeni Shevtsov, Orna Avlas, Max Gassmann, Amiram Ravid, Yelena Cheporko, Edith Hochhauser

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Ischemia-reperfusion injury (I/R) is the main cause of primary graft nonfunction. Our aim was to evaluate the effect of excessive versus acute administration of erythropoietin (EPO) in attenuating the hepatic injury induced by I/R in mice. The effect of segmental (70%) hepatic ischemia was evaluated in a transgenic mouse line with constitutive overexpression of human EPO cDNA and in wild-type (WT) mice. Mice were randomly allocated to 5 main experimental groups: (i) WT-sham, (ii) WT ischemia, (iii) WT ischemia + recombinant human erythropoietin (rhEPO), (iv) transgenic-sham, and (v) transgenic ischemia. The EPO-pretreated mice showed a significant reduction in liver enzyme levels and intrahepatic caspase-3 activity and fewer apoptotic hepatocytes (p < 0.05 for all) compared with the WT untreated I/R group. EPO decreased c-Jun N-terminal kinase (JNK) phosphorylation and nuclear factor-kB (NF-kB) expression during I/R. In transgenic I/R livers, baseline histology showed diffused hepatic injury, and no significant beneficial effect was noted between the WT untreated and the transgenic I/R mice. In conclusion, acute pretreatment with EPO in WT mice attenuated in vivo I/R liver injury. However, in excessive EPO overexpression, the initial liver injury abolished the beneficial effect of EPO. These findings have important implications for the potential use of acute EPO in I/R injury during liver transplantation.

Original languageEnglish
Pages (from-to)1130-1137
Number of pages8
JournalCanadian Journal of Physiology and Pharmacology
Volume88
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

Funding

FundersFunder number
Schweizerischer Nationalfonds zur F&#x00F6;rderung der Wissenschaftlichen Forschung125013

    Keywords

    • Apoptosis
    • Caspase 3
    • Erythropoietin
    • In vivo
    • Ischemia-reperfusion
    • Liver
    • Transgenic mice

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