Beneficial effects of hepatic cyclooxygenase‐2 expression against cholestatic injury after common bile duct ligation in mice

Abstract

Background and Aims: Cyclooxygenase-2 (COX-2) is involved in different liver dis-eases, but little is known about the significance of COX-2 in cholestatic injury. Thisstudy was designed to elucidate the role of COX-2 expression in hepatocytes duringthe pathogenesis of obstructive cholestasis.Methods: We used genetically modified mice constitutively expressing human COX-2in hepatocytes. Transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates wereeither subjected to a mid-abdominal laparotomy or common bile duct ligation (BDL)for 2 or 5 days. Then, we explored the mechanisms underlying the role of COX-2 andits derived prostaglandins in liver function, and the synthesis and excretion of bileacids (BA) in response to cholestatic liver injury.Results: After BDL, hCOX-2-Tg mice showed lower grades of hepatic necrosis and in -flammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associ-ated with lower mRNA levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tgmice displayed a differential metabolic pattern of BA synthesis that led to an improvedclearance after BDL-induced accumulation. In addition, an enhanced response to theBDL-induced oxidative stress and hepatic apoptosis was observed. In vitro experi-ments using hepatic cells that stably express hCOX-2 confirmed the cytoprotectiverole of prostaglandin E2 against BA toxicity.Conclusions: Taken together, our data indicate that constitutive expression of COX-2in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammationand cell damage and by modulating BA metabolism, pointing to a role for COX-2 as adefensive response against cholestasis-derived BA accumulation and injury.