Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhongshan 2nd Road, Guangzhou 510089, China.
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhongshan 2nd Road, Guangzhou 510089, China.
Int J Med Sci. 2020 Sep 28;17(17):2751-2762. doi: 10.7150/ijms.46302. eCollection 2020.
To date, the effect of vasopressin on organ damages after acute mesenteric ischemia (MI) remains poorly understood. To investigate the effect of terlipressin, a selective vasopressin V1 receptor agonist, versus norepinephrine on the intestinal and renal injuries after acute MI, and to explore the underlying mechanism of terlipressin. Acute MI model was produced by clamping the superior mesenteric artery for 1 hour. Immediately after unclamping, terlipressin or norepinephrine was intravenously administered for 2 hours. Meanwhile, , RAW264.7 cells were treated with lipopolysaccharide or lipopolysaccharide+terlipressin. In addition, wortmannin was used to determine the role of phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway in the potential impacts of terlipressin. MI led to severe hypotension, caused notable intestinal and renal impairments and resulted in high mortality, which were markedly improved by terlipressin or norepinephrine. Terlipressin increased mean arterial pressure, decreased intestinal epithelial cell apoptosis, inhibited the generation of M1 macrophage in intestinal and renal tissues, and hindered the release of inflammatory cytokines after MI. Moreover, in cultured macrophages, terlipressin reduced the mRNA level of specific M1 markers and the release of inflammatory cytokines caused by lipopolysaccharide challenge. Wortmannin decreased the expression of PI3K and Akt induced by terlipressin in cells and in tissues, and abolished the above protective effects conferred by terlipressin. Terlipressin or norepinephrine could effectively improve organ damages and mortality after acute MI. Terlipressin elevates blood pressure and inhibits intestinal epithelial apoptosis and macrophage M1 polarization via the PI3K/Akt pathway.
迄今为止，血管加压素对急性肠系膜缺血（MI）后器官损伤的影响仍知之甚少。本研究旨在探讨选择性血管加压素 V1 受体激动剂特利加压素与去甲肾上腺素对急性 MI 后肠肾损伤的影响，并探讨特利加压素的作用机制。通过夹闭肠系膜上动脉 1 小时来建立急性 MI 模型。在松开夹闭后，立即静脉注射特利加压素或去甲肾上腺素 2 小时。同时，用脂多糖或脂多糖+特利加压素处理 RAW264.7 细胞。此外，还用渥曼青霉素来确定磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）通路在特利加压素潜在影响中的作用。MI 导致严重低血压，引起明显的肠肾损伤，导致高死亡率，特利加压素或去甲肾上腺素可明显改善这些症状。特利加压素增加平均动脉压，减少肠上皮细胞凋亡，抑制肠肾组织中 M1 巨噬细胞的生成，并抑制 MI 后炎症细胞因子的释放。此外，在培养的巨噬细胞中，特利加压素降低了脂多糖刺激引起的特定 M1 标志物的 mRNA 水平和炎症细胞因子的释放。渥曼青霉素降低了特利加压素在细胞和组织中诱导的 PI3K 和 Akt 的表达，并消除了特利加压素赋予的上述保护作用。特利加压素或去甲肾上腺素可有效改善急性 MI 后的器官损伤和死亡率。特利加压素通过 PI3K/Akt 通路升高血压，抑制肠上皮细胞凋亡和巨噬细胞 M1 极化。
