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

• Published in: Canadian journal of physiology and pharmacology Vol. 88; no. 12; p. 1130
• Main Authors: Pappo, Orit, Ben-Ari, Ziv, Shevtsov, Evgeni, Avlas, Orna, Gassmann, Max, Ravid, Amiram, Cheporko, Yelena, Hochhauser, Edith
• Format: Journal Article
• Language: English
• Published: Canada 01-12-2010
• Subjects: Animals; Apoptosis - drug effects; Caspase 3 - metabolism; DNA, Complementary - genetics; Erythropoietin - administration & dosage; Female; Hematocrit; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Liver - blood supply; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B - metabolism; Phosphorylation; Random Allocation; Recombinant Proteins; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology
• ISSN: 1205-7541
• DOI: 10.1139/Y10-091

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.