BACKGROUND & AIMS Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. 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 and repair following hepatic I/R. METHODS mPGES-1 deficient (Ptges-/-) mice or their wild-type (WT) counterparts were subjected to partial hepatic ischemia followed by reperfusion. The role of E prostanoid receptor 4 (EP4) was then studied using a genetic knockout model and a selective antagonist. RESULTS Compared with WT mice, Ptges-/- mice exhibited reductions in alanine aminotransferase (ALT), necrotic area, neutrophil infiltration, chemokines, and proinflammatory cytokine levels. Ptges-/- mice also showed promoted liver repair and increased Ly6Clow macrophages (Ly6Clow/CD11bhigh/F4/80high-cells) with expression of anti-inflammatory and reparative genes, while WT mice exhibited delayed liver repair and increased Ly6Chigh macrophages (Ly6Chigh/CD11bhigh/F4/80low-cells) with expression of proinflammatory genes. Bone marrow (BM)-derived mPGES-1-deficient macrophages facilitated liver repair with increases in Ly6Clow macrophages. In vitro, mPGES-1 was expressed in macrophages polarized toward the proinflammatory profile. Mice treated with the mPGES-1 inhibitor Compound III displayed increased liver protection and repair. Hepatic I/R enhanced the hepatic expression of PGE receptor subtype, EP4, in WT mice, which was reduced in Ptges-/- mice. A selective EP4 antagonist and genetic deletion of Ptger4, which codes for EP4, accelerated liver repair. The proinflammatory gene expression was upregulated by stimulation of EP4 agonist in WT macrophages but not in EP4-deficient macrophages. CONCLUSIONS These results indicate that mPGES-1 regulates macrophage polarization as well as liver protection and repair through EP4 signaling during hepatic I/R. Inhibition of mPGES-1 could have therapeutic potential by promoting liver repair after acute liver injury. LAY SUMMARY Hepatic ischemia/reperfusion injury is a serious complication that occurs in liver surgery. Herein, we demonstrated that inducible prostaglandin E2 synthase (mPGES-1), an enzyme involved in synthesizing prostaglandin E2, worsens the injury and delays liver repair through accumulation of proinflammatory macrophages. Inhibition of mPGES-1 offers a potential therapy for both liver protection and repair in hepatic ischemia/reperfusion injury.

中文翻译：

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抑制微粒体前列腺素E合酶-1促进小鼠肝损伤后的肝脏修复

背景和目的 肝缺血/再灌注 (I/R) 损伤后的肝脏修复对生存至关重要。本研究旨在检查诱导型微粒体 PGE 合酶-1 (mPGES-1) 产生的内源性前列腺素 E2 (PGE2)，PGE2 生成的终末酶，在肝 I/R 后的肝损伤和修复中的作用。方法 mPGES-1 缺陷 (Ptges-/-) 小鼠或其野生型 (WT) 对应物经受部分肝缺血，然后再灌注。然后使用基因敲除模型和选择性拮抗剂研究 E 前列腺素受体 4 (EP4) 的作用。结果 与 WT 小鼠相比，Ptges-/- 小鼠表现出丙氨酸转氨酶 (ALT)、坏死面积、中性粒细胞浸润、趋化因子和促炎细胞因子水平的降低。Ptges-/- 小鼠还表现出促进肝脏修复和增加 Ly6Clow 巨噬细胞 (Ly6Clow/CD11bhigh/F4/80high 细胞)，并表达抗炎和修复基因，而 WT 小鼠表现出肝脏修复延迟和 Ly6Chigh 巨噬细胞 (Ly6Chigh/CD11bhigh) 增加/F4/80low-cells) 表达促炎基因。骨髓 (BM) 衍生的 mPGES-1 缺陷巨噬细胞通过 Ly6Clow 巨噬细胞的增加促进肝脏修复。在体外，mPGES-1 在朝着促炎特征极化的巨噬细胞中表达。用 mPGES-1 抑制剂化合物 III 治疗的小鼠表现出增强的肝脏保护和修复。肝脏 I/R 增强了 PGE 受体亚型 EP4 在 WT 小鼠中的肝脏表达，而在 Ptges-/- 小鼠中则降低了。选择性 EP4 拮抗剂和编码 EP4 的 Ptger4 基因缺失，加速肝脏修复。促炎基因表达通过刺激 WT 巨噬细胞中的 EP4 激动剂而上调，但在缺乏 EP4 的巨噬细胞中则不然。结论 这些结果表明，mPGES-1 在肝脏 I/R 期间通过 EP4 信号传导调节巨噬细胞极化以及肝脏保护和修复。抑制 mPGES-1 可能通过促进急性肝损伤后的肝脏修复而具有治疗潜力。概述 肝缺血/再灌注损伤是肝脏手术中发生的严重并发症。在这里，我们证明了诱导型前列腺素 E2 合酶 (mPGES-1)，一种参与合成前列腺素 E2 的酶，通过促炎巨噬细胞的积累加重损伤并延迟肝脏修复。