title: Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice.
abstract: Prostaglandin E2 (PGE2) 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 PGE2 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 PGE2-EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury.
authors.affiliation: Department of Surgery, Nara Medical University, Nara, Japan.
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Kuzumoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Naoya
authors.initials: N
authors.lastname: Ikeda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizuno
authors.forename: Satoru
authors.initials: S
authors.lastname: Akashi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsurui
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kashizuka
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kubo
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kanehiro
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D008102:Liver Circulation; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D018078:Receptors, Prostaglandin E; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase