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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
Author(s) -
Yin Hao,
Cheng Linling,
Langenbach Robert,
Ju Cynthia
Publication year - 2007
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.21493
Subject(s) - liver injury , concanavalin a , in vivo , cyclooxygenase , pharmacology , prostaglandin e , prostaglandin , immune system , inflammation , prostaglandin e2 , pathogenesis , medicine , immunology , in vitro , chemistry , biology , enzyme , biochemistry , microbiology and biotechnology
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)‐γ, 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. (H EPATOLOGY 2007;45:159–169.)