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.

This work was supported by the following projects: Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (PID2022-143192OB-I00; PID2020- 113238RB-I00), Research Grant PICT 2018-01446 and 2021-0152 from Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT), iCOOP from CSIC (COOPB23081), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CB06/04/1069), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CB/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686, and Fondo Europeo de Desarrollo Regional. C.L. and M.L-T. are both recipients of FPI fellowships from MINECO: PRE2021-097824 and PRE2020-094885, respectively. D.F. received a fellowship Ministerio de Educación de ArgentinaFundación Carolina.

15 páginas, 8 figuras

Peer reviewed