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

Autores de IIS La Fe

• 

  Agustín Gerardo Lahoz Rodríguez

  Autor

Participantes ajenos a IIS La Fe

• Brea, Rocio
• Casanova, Natalia
• Alvarez-Lucena, Carlota
• Fuertes-Agudo, Marina
• Luque-Tevar, Maria
• Cucarella, Carme
• Capitani, Maria C
• Marinochi, Maria V
• Fusini, Matias E
• Nogueroles, Marina Lopez
• Fraile, Juan
• Ronco, Maria T
• Bosca, Lisardo
• Gonzalez-Rodriguez, Agueda
• Garcia-Monzon, Carmelo
• Martin-Sanz, Paloma
• Casado, Marta
• Frances, Daniel E

Grupos

• Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Abstract

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 5days. 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. Invitro 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.

Keywords

• BDL; bile acids; cholestasis; COX-2; liver; PGE(2)