Department of Anesthesiology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, 321000 Jinhua, Zhejiang, China.
Discov Med. 2024 Aug;36(187):1600-1609. doi: 10.24976/Discov.Med.202436187.146.
Macrophages are activated in ventilator-induced lung injury (VILI), accompanied by macrophage pyroptosis. Remimazolam (Re) plays a role in inhibiting macrophage activation. In this study, we aimed to investigate the mechanism of Re in VILI.
A VILI model (20 mL/kg mechanical ventilation) was created using C57BL/6 mice. Alveolar macrophages were isolated from bronchoalveolar lavage fluid (BALF) and received mechanical stretching to simulate the mechanical ventilation . VILI model mice were treated with Re (16 mg/kg) to assess the alveolar structure, wet/dry (W/D) weight ratio, endothelial barrier antigen (EBA) permeability index, BALF protein content, inflammatory factors, macrophage pyroptosis, pyroptosis-related factors, and translocator protein (TSPO) level using a series of biological experiments. Whether Re alleviated macrophage pyroptosis by regulating TSPO was determined by rescue experiments.
Re alleviated VILI, as evidenced by improvement of abnormal morphology of lung tissues during VILI and decreases in the lung W/D weight ratio, lung EBA permeability index, and BALF protein content. Re attenuated pulmonary inflammation and macrophage pyroptosis during VILI via down-regulation of inflammatory factors (myeloperoxidase, malondialchehyche, 8-hydroxy-2 deoxyguanosine, interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2, interleukin-1β, and interleukin-18), and pyroptosis factors (cleaved gasdermin D (GSDMD)/GSDMD value, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and caspase-1). Re activated TSPO in macrophages. TSPO overexpression rescued the cell stretch-inhibited macrophage viability and cell stretch-induced macrophage pyroptosis.
Re alleviates VILI by activating TSPO to inhibit macrophage pyroptosis.
巨噬细胞在呼吸机诱导的肺损伤（VILI）中被激活，伴随着巨噬细胞焦亡。雷米唑仑（Re）在抑制巨噬细胞激活方面发挥作用。在这项研究中，我们旨在研究 Re 在 VILI 中的作用机制。
使用 C57BL/6 小鼠建立 VILI 模型（20 mL/kg 机械通气）。从支气管肺泡灌洗液（BALF）中分离肺泡巨噬细胞，并进行机械拉伸以模拟机械通气。用 Re（16 mg/kg）处理 VILI 模型小鼠，以通过一系列生物学实验评估肺泡结构、湿/干（W/D）重量比、内皮屏障抗原（EBA）通透性指数、BALF 蛋白含量、炎症因子、巨噬细胞焦亡、焦亡相关因子和转位蛋白（TSPO）水平。通过挽救实验确定 Re 是否通过调节 TSPO 来减轻巨噬细胞焦亡。
Re 缓解了 VILI，表现在 VILI 期间肺组织的异常形态得到改善，肺 W/D 重量比、肺 EBA 通透性指数和 BALF 蛋白含量降低。Re 通过下调炎症因子（髓过氧化物酶、丙二醛、8-羟基-2 脱氧鸟苷、白细胞介素-6、肿瘤坏死因子-α、巨噬细胞炎症蛋白-2、白细胞介素-1β和白细胞介素-18）和焦亡因子（裂解的 GSDMD/GSDMD 值、NOD 样受体热蛋白结构域相关蛋白 3（NLRP3）和半胱天冬酶-1）来减轻 VILI 期间的肺部炎症和巨噬细胞焦亡。Re 在巨噬细胞中激活了 TSPO。TSPO 过表达挽救了细胞拉伸抑制的巨噬细胞活力和细胞拉伸诱导的巨噬细胞焦亡。
Re 通过激活 TSPO 来抑制巨噬细胞焦亡来缓解 VILI。
