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      Prostaglandin I(2) and E(2) mediate the protective effects of cyclooxygenase-2 in a mouse model of immune-mediated liver injury.

      Hepatology (Baltimore, Md.)

      Animals, Concanavalin A, Cyclooxygenase 2, genetics, physiology, Dinoprostone, analogs & derivatives, Disease Models, Animal, Down-Regulation, drug effects, Drug-Induced Liver Injury, Epoprostenol, pharmacology, Gene Expression Regulation, Gene Expression Regulation, Enzymologic, Inflammation, chemically induced, physiopathology, prevention & control, Interferon-gamma, metabolism, Liver Diseases, Male, Mice, Mice, Knockout, Misoprostol, Mitogens

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          Studies of the molecular and cellular mechanisms of concanavalin A (ConA)-induced liver injury have provided important knowledge on the pathogenesis of many liver diseases involving hepatic inflammation. However, studies identifying hepato-protective factors based on the mechanistic understanding of this model are lacking. Evidence suggests that certain prostaglandin (PG) products of cyclooxygenase (COX)-1 and COX-2 provide important anti-inflammatory and cytoprotective functions in some pathophysiological states. In the present study, we demonstrate a protective role of COX-2 derived PGs in ConA-induced liver injury. COX-2(-/-) mice developed much more severe liver damage upon ConA treatment compared with wild-type and COX-1(-/-) mice. Treatment of COX-2(-/-) mice with misoprostol (a PGE(1/2) analog) or beraprost (a PGI(2) analog) significantly decreased ConA-induced liver injury. Data from both in vivo and in vitro experiments demonstrated that misoprostol and beraprost acted directly on hepatic leukocytes, including natural killer (NK)T and T cells, and down-regulated their production of interferon (IFN)-gamma, which are critical in mediating ConA-induced tissue damage. Collectively, the results provide strong evidence that the protective effects of COX-2 within the liver are mediated through the production of PGE(2) and PGI(2), which exert anti-inflammatory functions. These findings suggest that COX-2-derived PGs may have great therapeutic potentials in treating patients with inflammatory liver diseases.

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