Sepsis is an inflammatory reaction disorder state that is induced by infection. The activation and regulation of the immune system play an essential role in the development of sepsis. Our previous studies have shown that ghrelin ameliorates intestinal dysfunction in sepsis. Very little is known about the mechanism of ghrelin and its receptor (GHSR) on the intestinal barrier and the immune function of macrophage regulation. Our research is to investigate the regulatory effect and molecular mechanism of the ghrelin/GHSR axis on intestinal dysfunction and macrophage polarization in septic rats. A rat model of sepsis was established by cecal ligation and puncture (CLP) operation. Then, the sepsis rats were treated with a ghrelin receptor agonist (TZP-101) or ghrelin inhibitor (obestatin). The results suggested that TZP-101 further enhanced ghrelin and GHSR expressions in the colon and spleen of septic rats and obestatin showed the opposite results. Ghrelin/GHSR axis ameliorated colonic structural destruction and intestinal epithelial tight junction injury in septic rats. In addition, the ghrelin/GHSR axis promoted M2-type polarization of macrophages, which was characterized by the decreases of IL-1β, IL-6, and TNF-α, as well as the increase of IL-10. Mechanistically, the ghrelin/GHSR axis promoted E2F2 expression and suppressed the activation of the NF-κB signaling pathway in septic rats. Collectively, targeting ghrelin/GHSR during sepsis may represent a novel therapeutic approach for the treatment of intestinal barrier injury.

中文翻译：

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Ghrelin/GHSR 轴通过灭活 E2F1/NF-κB 信号传导诱导 M2 巨噬细胞并减轻脓毒症大鼠模型中的肠屏障功能障碍

脓毒症是由感染引起的炎症反应紊乱状态。免疫系统的激活和调节在脓毒症的发生中起着至关重要的作用。我们之前的研究表明，生长素释放肽可改善脓毒症患者的肠道功能障碍。关于生长素释放肽及其受体（GHSR）对肠道屏障的作用机制以及巨噬细胞免疫功能的调节知之甚少。我们的研究旨在探讨ghrelin/GHSR轴对脓毒症大鼠肠道功能障碍和巨噬细胞极化的调节作用和分子机制。采用盲肠结扎穿刺（CLP）手术建立脓毒症大鼠模型。然后，用生长素释放肽受体激动剂（TZP-101）或生长素释放肽抑制剂（肥胖素）治疗脓毒症大鼠。结果表明，TZP-101进一步增强脓毒症大鼠结肠和脾脏中ghrelin和GHSR的表达，而obestatin则表现出相反的结果。Ghrelin/GHSR 轴可改善脓毒症大鼠的结肠结构破坏和肠上皮紧密连接损伤。此外，ghrelin/GHSR轴促进巨噬细胞M2型极化，其特征是IL- 1β、IL-6和TNF- α减少，以及IL-10增加。从机制上讲，在脓毒症大鼠中，ghrelin/GHSR 轴促进 E2F2 表达并抑制 NF- κ B 信号通路的激活。总的来说，脓毒症期间的靶向 ghrelin/GHSR 可能代表了治疗肠道屏障损伤的一种新的治疗方法。