Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

We examined the effects of upregulation of heme oxygenase-l (HO-1) in steat otic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Z ucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adeno viral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, incre ased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP) , upregulation of HO-1 by Western blots correlated with amelioration of his tologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the b eneficial effects of Ad-HO-1 gene transfer, documenting the direct involvem ent of HO-1 in protection against I/R injury. Following cold ischemia/isotr ansplantation, HO-1 overexpression extended animal survival from 40% in unt reated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect cor related with preserved hepatic architecture, improved liver function, and d epressed infiltration by T cells and macrophages. Hence, CoPP- or gene ther apy-induced HO-1 prevented I/R injury in steatotic rat livers. These findin gs provide the rationale for refined new treatments that should increase th e supply of usable donor livers and ultimately improve the overall success of liver transplantation.