Inhibition of mPGES-1 protects the liver from ischemia/reperfusion injury through prostanoid EP2 receptor

Objectives: Hepatic ischemia/reperfusion (I/R) injury is a major adverse reaction to liver surgery. This study aims to examine the role of endogenous prostaglandin E2 (PGE2) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver injury after hepatic I/R. Methods: Male mPGES-1 deficient (mPGES-1-/-) mice or their wild counterparts (WT) were subjected to 60 minutes of partial hepatic ischemia followed by reperfusion. Results: During hepatic I/R, the hepatic expression of mPGES-1 was enhanced in WT mice. mPGES-1 was expressed in CD68-positive cells (macrophages) and Gr-1-positive cells (neutrophils). Compared with WT mice, mPGES-1-/- mice exhibited attenuated levels of alanine aminotransferase and necrotic area. This was associated with reduced mRNA levels of proinflammatory cytokines. Hepatic neutrophils in mPGES-1-/- mice were decreased, with down-regulated expression of neutrophil-attracting chemokines and their receptors. Hepatic I/R enhanced the hepatic expression of PGE receptor subtype, E prostanoid receptor 2 (EP2), in WT mice, when compared with mPGES-1-/- mice. Selective EP2 antagonist (PF04418948) reduced liver injury and hepatic neutrophils with down-regulated expression of chemokines and their receptors at 24-hour postreperfusion. Conclusions: Inhibition of mPGES-1 and EP2 signaling is a potential therapeutic strategy for attenuation of liver injury after hepatic I/R.