Department of Anesthesiology, Peking University Third Hospital, No. 49, North Garden Street, Haidian District, Beijing, 100191, China.
Department of Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, China.
Inflamm Res. 2022 Aug;71(7-8):911-922. doi: 10.1007/s00011-022-01593-z. Epub 2022 Jun 22.
The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism.
C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines.
The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866.
In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.
本研究旨在探讨促炎脂肪因子 Visfatin 在脓毒症诱导的肠道损伤中的作用，并阐明其潜在机制。
C57BL/6 小鼠接受盲肠结扎穿孔（CLP）手术建立体内脓毒症模型。体外使用 LPS 刺激肠上皮细胞模拟脓毒症诱导的肠道损伤。用 FK866（Visfatin 的抑制剂）联合或不联合 XMU-MP-1（Hippo 信号通路的抑制剂）进行治疗。采用 Western blot 或免疫组化检测 Visfatin、NF-κB 和 Hippo 信号通路相关蛋白的表达水平。通过 TUNEL 染色和 H&E 染色分别检测肠细胞凋亡和肠道损伤。ELISA 用于测定炎症细胞因子的产生。
CLP 小鼠中 Visfatin 的表达增加。FK866 减轻了脓毒症小鼠的肠道病理损伤、炎症细胞因子产生和肠细胞凋亡。同时，FK866 影响 NF-κB 和 Hippo 信号通路。此外，FK866 对炎症反应、凋亡、Hippo 信号和 NF-κB 信号的影响部分被 Hippo 信号通路抑制剂 XMU-MP-1 所消除。体外实验还表明，FK866 对 LPS 诱导的肠细胞炎症反应和凋亡具有保护作用，并调节 NF-κB 和 Hippo 信号通路，而 XMU-MP-1 的加入则削弱了 FK866 的保护作用。
总之，本研究表明抑制 Visfatin 可能通过 Hippo 信号通路减轻脓毒症诱导的肠道损伤，支持进一步研究 Visfatin 作为治疗靶点的可能性。
