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Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice
Author(s) -
Motiño Omar,
Francés Daniel E.,
Casanova Natalia,
FuertesAgudo Marina,
Cucarella Carme,
Flores Juana M.,
VallejoCremades María Teresa,
Olmedilla Luis,
Pérez Peña José,
Bañares Rafael,
Boscá Lisardo,
Casado Marta,
MartínSanz Paloma
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30241
Subject(s) - proinflammatory cytokine , hepatocyte , reperfusion injury , endocrinology , medicine , liver transplantation , oxidative stress , transplantation , cyclooxygenase , inflammation , unfolded protein response , liver injury , ischemia , endoplasmic reticulum , pharmacology , chemistry , enzyme , biochemistry , in vitro
Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase‐2 (COX‐2) is involved in different liver diseases, but the significance of COX‐2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX‐2 induction in hepatocytes against liver IRI. In the present work, hepatocyte‐specific COX‐2 transgenic mice (hCOX‐2‐Tg) and their wild‐type (Wt) littermates were subjected to IRI. hCOX‐2‐Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX‐2‐Tg mice showed a significant attenuation of the IRI‐induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX‐2‐Tg mice against IRI due to a preconditioning‐derived increase in endogenous COX‐2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E 2 (PGE 2 ) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE 2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX‐2 induction and the consequent rise of derived prostaglandins against IRI.