Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice

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 PGE2 receptor in I/R injury. Although all four receptors were expressed in the naive liver, EN expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EN agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EN 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 EN agonist treatment. Finally, to confirm the therapeutic efficacy of the EN 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 EN agonist survived. In conclusion, the PGE(2)-EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EN agonist effectively protects against ischemic injury.