title: The role of excessive versus acute administration of erythropoietin in attenuating hepatic ischemia-reperfusion injury.
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-κB (NF-κB) 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.
authors.affiliation: Department of Histopathology, Rabin Medical Center, Beilinson Hospital, Petah Tiqva, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Ziv
authors.initials: Z
authors.lastname: Ben-Ari
authors.forename: Evgeni
authors.initials: E
authors.lastname: Shevtsov
authors.forename: Orna
authors.initials: O
authors.lastname: Avlas
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Amiram
authors.initials: A
authors.lastname: Ravid
authors.forename: Yelena
authors.initials: Y
authors.lastname: Cheporko
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006400:Hematocrit; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011897:Random Allocation; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D018076:DNA, Complementary; D016328:NF-kappa B; D011994:Recombinant Proteins; D004921:Erythropoietin; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3