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

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Brea, R
  • Casanova, N
  • Alvarez-Lucena, C
  • Fuertes-Agudo, M
  • Luque-Tevar, M
  • Cucarella, C
  • Capitani, MC
  • Marinochi, MV
  • Fusini, ME
  • Fraile, J
  • Ronco, MT
  • Boscá, L
  • González-Rodríguez, A
  • García-Monzón, C
  • Martín-Sanz, P
  • Casado, M
  • Francés, DE

Grupos

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 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.

Datos de la publicación

ISSN/ISSNe:
1478-3223, 1478-3231

LIVER INTERNATIONAL  WILEY

Tipo:
Article
Páginas:
2409-2423
PubMed:
38847511
Factor de Impacto:
2,064 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 2

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Keywords

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

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