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Significance and therapeutic potential of prostaglandin E 2 receptor in hepatic ischemia/reperfusion injury in mice
Author(s) -
Kuzumoto Yukiyasu,
Sho Masayuki,
Ikeda Naoya,
Hamada Kaoru,
Mizuno Takashi,
Akashi Satoru,
Tsurui Yoshikazu,
Kashizuka Hisanori,
Nomi Takeo,
Kubo Atsushi,
Kanehiro Hiromichi,
Nakajima Yoshiyuki
Publication year - 2005
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.20827
Subject(s) - reperfusion injury , medicine , pharmacology , ischemia , prostaglandin e2 , prostaglandin , receptor
Prostaglandin E 2 (PGE 2 ) mediates a variety of innate and adaptive immunity through four distinct receptors: EP1‐EP4. It has been suggested that each EP plays a unique and pivotal role in various disease conditions. We investigated the pathophysiological role of EP receptors in hepatic ischemia/reperfusion (I/R) injury. In this study, a 70% hepatic ischemic model was used in male C57BL/6 mice. Selective EP agonists were used to clarify the function of each PGE 2 receptor in I/R injury. Although all four receptors were expressed in the naïve liver, EP4 expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EP4 agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EP4 agonist downregulated the local expressions of several proinflammatory cytokines, chemokines, and adhesion molecules in the early phase of reperfusion. In contrast, it augmented the local expression of an anti‐inflammatory cytokine, interleukin 10. Additionally, the neutrophil accumulation was also inhibited by EP4 agonist treatment. Finally, to confirm the therapeutic efficacy of the EP4 agonist in hepatic I/R injury, the nonischemic shunt liver was removed after 120 minutes of ischemia, resulting in the death of 86% of control mice within 48 hours. In sharp contrast, 80% of mice treated with the EP4 agonist survived. In conclusion , the PGE 2 ‐EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury. (H EPATOLOGY 2005.)