Significance and Therapeutic Potential of Prostaglandin E2 Receptor in Hepatic Ischemia/Reperfusion Injury in Mice *

Abstract

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. (HEPATOLOGY 2005;42:608-617.)

Molecular Patterns of Subclinical and Clinical Rejection of Kidney Allograft: Quantity Matters

“…EP4 agonist was more effective than the EP2 agonist to inhibit acute allograft rejection, suggesting more important role of EP4. Some exciting data have emerged concerning the EP4 selective agonist as a novel agent to protect both posttransplantation inflammatory and alloimmune responses [42,[46][47][48]. However, in our study we were not able to assess the importance of EP4 receptor in progression of renal dysfunction in kidney allografts with findings of subclinical or clinical inflammation as the PTGER4 gene was not included in the evaluated gene set.…”

E-type prostanoid receptor 4 (EP4) in disease and therapy

“…These protective effects were hypothetically explained by increased liver perfusion, anti-platelet effect, inhibition of cytokine release and direct cytoprotective function of PGE 2 (Masaki et al, 1992). Out of the four EP receptors only EP4 receptors were found to be upregulated on hepatocytes in an ischemic mouse model (Kuzumoto et al, 2005). Activation of EP4 receptors by the EP4-selective agonist ONO AE1-329 provided strongest protection against hepatic injury as compared to other selective EP receptor agonists.…”

“…Activation of EP4 receptors by the EP4-selective agonist ONO AE1-329 provided strongest protection against hepatic injury as compared to other selective EP receptor agonists. In detail, the EP4 agonist reduced the serum levels of hepatic injury markers and inhibited the release of proinflammatory cytokines such as TNF-α and IFN-γ, and the chemokines MCP-1 and IP-10, and also decreased the expression of E-selectin and ICAM-1 adhesion molecules in the ischemic liver (Kuzumoto et al, 2005). Importantly, neutrophil infiltration into the liver was also found to be attenuated after EP4 receptor stimulation.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Results from studies in mouse models of steatosis confirmed that COX-2 inhibition protected against the development of steatohepatitis , whether these effects were related to KC-derived PGE 2 , however, is not conclusive and may relate to COX-2 inhibition in other tissues. In this context, it is of considerable importance that PGE 2 was found to elicit positive effects on hepatocytes and sinusoidal cells in models of reperfusion/ischemia injury of the liver, where hepatic microcirculation was improved and liver injury was ameliorated by stimulation of prostaglandin E2 receptor EP4 (Arai et al, 1999;Kuzumoto et al, 2005). Others reported that PGE 2 exerted antiapoptotic and proproliferative effects via activation of EP4 in hepatocytes in vitro and of EP3 in vitro as well as in vivo (Arai et al, 1999;Kataoka et al, 2005;Casado et al, 2007;Meisdalen et al, 2007).…”