203 Background: Ischemia/Reperfusion (I/R) injury is a major factor in poor liver function following transplantation (OLT). Abrogation of the I/R syndrome would have a favorable impact on the outcome of liver transplantation. This study was designed to determine whether overexpression of hemeoxygenase-1 (HO-1), an inducible heat shock protein (hsp) 32, that protects against or limits the severity of oxidative injury, reduces I/R injury in well-defined rat models of an ex-vivo isolated perfusion and OLT. Methods: In the first series, Sprague-Dawley (SD) rats were treated with: i/ Cobalt protoporphyrin (CoPP; 5mg/kg ip), an HO-1 inducer or ii) Zinc protoporphyrin (ZnPP; 5mg/kg ip), an HO-1 inhibitor (n=4 rats/group). Livers were harvested 24h later, stored for 6h at 4°C in UW solution, and then perfused for 2h on an isolated perfusion rat liver apparatus. Liver portal vein blood flow and bile production were assessed serially, and liver samples were collected for histological evaluation at the conclusion of experiment. In the second series, SD rats (n=6/group) were pretreated with either CoPP or ZnPP (5mg/kg ip). 24h later livers were harvested, stored for 24h at 4°C in UW solution, and then transplanted to syngeneic (SD) hosts. Animal survival was assessed at day 21. In parallel, hepatocyte injury was evaluated by histology and serum sGOT levels, and HO-1 expression was analyzed by Western blots. Results: In the first series, livers harvested from CoPP-treated rats showed significantly (*p<0.05) improved portal venous blood flow (Fig. 1) and increased bile production (Fig. 2), as compared to ZnPP-treated control animals. These data correlated with histological Banff criteria, where hepatocyte injury/lobular disarray were graded 0-1 (CoPP) vs. 2-3 (ZnPP). In the second series, 4 out of 6 rats survived 21 days after transplantation of livers from CoPP-pretreated donors (vs. 2/6 in ZnPP) (Fig. 3). By day 21, I/R-induced hepatocyte injury, as measured by sGOT release, was reduced in CoPP group (192±40 vs. 502±3 IU/L in ZnPP). consistent with CoPP-mediated preservation of histological detail (Suzuki score: 0-1 vs. 1-3 in ZnPP). Moreover, unlike in ZnPP group, improved liver function after CoPP pretreatment was accompanied by overexpression of HO-1 gene, as shown by Western blots.Fig. 1: Portal Blood FlowFig. 2: Bile ProductionFig. 3: OLT SurvivalConclusion: CoPP-induced HO-1 overexpression protects against I/R injury of rat livers in ex-vivo models of cold ischemia followed by reperfusion or OLT. Pretreatment with CoPP, but not with ZnPP, an HO-1 inhibitor, ameliorated I/R-induced hepatocyte injury and improved liver function. This study documents the potential utility of HO-1-inducing agents in preventing I/R injury in clinical setting.