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

• Published in: Liver international Vol. 44; no. 9; pp. 2409 - 2423
• Main Authors: Brea, Rocío, Casanova, Natalia, Alvarez‐Lucena, Carlota, Fuertes‐Agudo, Marina, Luque‐Tevar, María, Cucarella, Carme, Capitani, María C., Marinochi, María V., Fusini, Matías E., Lahoz, Agustín, Nogueroles, Marina López, Fraile, Juan, Ronco, María T, Boscá, Lisardo, González‐Rodríguez, Águeda, García‐Monzón, Carmelo, Martín‐Sanz, Paloma, Casado, Marta, Francés, Daniel E.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2024
• Subjects: Animals; Apoptosis; BDL; Bile acids; Bile Acids and Salts - metabolism; Bile ducts; Cholestasis; Cholestasis - metabolism; Common Bile Duct - surgery; COX‐2; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Damage accumulation; Defensive behavior; Disease Models, Animal; Gallbladder diseases; Genetic modification; Hepatocytes; Hepatocytes - metabolism; Humans; Inflammation; Injuries; Leukocytes (neutrophilic); Ligation; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Male; Mice; Mice, Transgenic; mRNA; Necrosis; Oxidative Stress; Pathogenesis; PGE2; Prostaglandin E2; Prostaglandin endoperoxide synthase; Prostaglandins; Synthesis; Toxicity; Transgenic mice; PGE2; BDL; bile acids; cholestasis; liver; COX‐2
• ISSN: 1478-3223; 1478-3231; 1478-3231
• DOI: 10.1111/liv.16004

Background and Aims Cyclooxygenase‐2 (COX‐2) is involved in different liver diseases, but little is known about the significance of COX‐2 in cholestatic injury. This study was designed to elucidate the role of COX‐2 expression in hepatocytes during the pathogenesis of obstructive cholestasis. Methods We used genetically modified mice constitutively expressing human COX‐2 in hepatocytes. Transgenic mice (hCOX‐2‐Tg) and their wild‐type (Wt) littermates were either 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 and its derived prostaglandins in liver function, and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury. Results After BDL, hCOX‐2‐Tg mice showed lower grades of hepatic necrosis and inflammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associated with lower mRNA levels of pro‐inflammatory cytokines. Furthermore, hCOX‐2‐Tg mice displayed a differential metabolic pattern of BA synthesis that led to an improved clearance after BDL‐induced accumulation. In addition, an enhanced response to the BDL‐induced oxidative stress and hepatic apoptosis was observed. In vitro experiments using hepatic cells that stably express hCOX‐2 confirmed the cytoprotective role of prostaglandin E2 against BA toxicity. Conclusions Taken together, our data indicate that constitutive expression of COX‐2 in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammation and cell damage and by modulating BA metabolism, pointing to a role for COX‐2 as a defensive response against cholestasis‐derived BA accumulation and injury.