Original Paper

Apoptosis

, Volume 18, Issue 5, pp 547-555

Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury

  • Z. Ben-AriAffiliated withLiver Disease Center, Sheba Medical CenterLiver Research LaboratorySackler School of Medicine, Tel Aviv University Email author 
  • , Y. IssanAffiliated withResearch Laboratory, Felsenstein Medical Research Center
  • , Y. KatzAffiliated withDepartment of Surgery A, Rabin Medical Center, Beilinson Hospital
  • , M. SultanAffiliated withLiver Research Laboratory
  • , M. SafranAffiliated withLiver Research Laboratory
  • , Laniado-Schwartzman MichalAffiliated withDepartments of Pharmacology, New York Medical College
  • , G. Abraham NaderAffiliated withDepartments of Pharmacology, Joan C. Edwards School of Medicine, Marshall University
  • , R. KornowskiAffiliated withResearch Laboratory, Felsenstein Medical Research Center
  • , F. GriefAffiliated withDepartment of Surgery A, Rabin Medical Center, Beilinson Hospital
    • , O. PappoAffiliated withDepartment of Histopathology, Sheba Medical Center
    • , E. HochhauserAffiliated withSackler School of Medicine, Tel Aviv University

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Abstract

Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)–dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB’s regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation.

Keywords

Heme oxygenase-1 Cobalt-protoporphyrin Nuclear factor-kappaB (NF-κB) Ischemia reperfusion injury Liver