Cyclooxygenase-2 expression in hepatocytes protects against hepatic ischemia/reperfusion injury in mice

Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases but the significance of COX-2 in liver IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of liver IRI. In the present work hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to partial IRI and the results show that hCOX-2-Tg exhibited lower grades of necrosis and inflammation than Wt mice in part by reduced recruitment and infiltration of hepatic macrophages and netrophils with a corresponding decrease in serum levels of pro-inflammatory cytokines. Moreover hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis an increase in autophagic flux and a decrease in endoplasmic reticulum (ER) stress comparing with that observed in Wt mice. Preconditioning of Wt mice resembles the beneficial effects of hCOX-2-Tg mice in IRI due to an increase in endogenous COX-2 expression. Furthermore measurement of PGE2 levels in plasma from patients who underwent orthotopic liver transplantation revealed a significantly negative correlation between PGE2 levels and graft function and time of ischemia. Overall the data support the view of the beneficial effects of hepatic COX-2 dependent prostaglandins after liver IRI.