Role of endogenous PGE2 in liver repair after hepatic ischemia/reperfusion

Yoshiya Ito, Nobuyuki Nishizawa, Koji Eshima, Hirotoki Ohkubo, Tomoyoshi Inoue, Hideki Amano, Masataka Majima
2018 Proceedings for Annual Meeting of The Japanese Pharmacological Society  
Hepatic ischemia/reperfusion (I/R) injury is a major adverse reaction to liver surgery. Impaired liver repair following hepatic I/R affects the outcome of the patients. This study aims to examine the role of endogenous PGE2 produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver repair following hepatic I/R. Methods: mPGES-1 deficient (mPGES-1-/-) mice or their wild counterparts (WT) were subjected to partial hepatic ischemia followed by
more » ... ion. ALT, necrotic area, cytokines, and cellular growth factors were determined and compared. The hepatic macrophages were assessed by immunofluorescence and flow cytometry analysis. Results: Compared with WT mice, mPGES-1-/-mice exhibited reductions in ALT, necrotic area, and enhancement of growth factors (HGF and EGF) at 48 h and 96 h post-reperfusion (repair phase). mPGES-1-/-mice also showed increases in hepatic macrophage accumulation into the injured region, with down-regulated expression of genes related to proinflammatory macrophage phenotype and up-regulated genes related to restorative macrophage phenotype. Flow cytometry analysis revealed reduction in Ly6Chigh macrophages together with pro-inflammatory mediators, and increasing Ly6Clow macrophages with anti-inflammatory mediators in mPGES-1-/-mice. In vitro, mPGES-1 was expressed in cultured bone marrow (BM)-derived macrophages polarized toward the pro-inflammatory, but not the restorative profile. Adoptive transfer of BM-derived mPGES-1-deficient macrophages into WT mice promoted liver repair. Mice treated with the mPGES-1 inhibitor Compound III displayed acceleration of liver repair. Conclusions: These results suggest that mPGES-1 in pro-inflammatory macrophages impairs liver repair after hepatic I/R injury. Targeting mPGES-1 in liver repair following hepatic I/R could be of therapeutic benefit.
doi:10.1254/jpssuppl.wcp2018.0_po2-6-6 fatcat:ke55tkyxeneb5e44bkb7hbopb4