Department of Emergency, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China; Department of Emergency Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China.
Lung Transplantation Center, Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China; Department of Cardiothoracic Surgery, The Second Affiliated Hospital Nanchang University, Nanchang, Jiangxi, China.
Int Immunopharmacol. 2024 Apr 20;131:111794. doi: 10.1016/j.intimp.2024.111794. Epub 2024 Mar 7.
Exploring the protective effect of ARC@DPBNP on lipopolysaccharides (LPS)-induced ALI and its underlying mechanism.
ALI model was established by intransally administrating LPS (4 mg/kg) into C57BL/6 mice. The suppression effects of ALI was first compared between ARC (intragastric administrated, with doses ranging from 10 to 80 mg/kg) and ARC@BPBNPs (intratracheally administrated, with doses ranging from 1 to 4 mg/kg). Changes in lung histology post intratracheal intervention of 3 mg/kg ARC@DPBNPs were detected. The expression of pyrotosis pathway-related proteins in lungs as well as in RAW264.7 cells was detected by western blotting. The ASC expression in lung macrophages was examined using immune-fluorescent staining. The polarization of RAW264.7 cells and lung macrophages were detected by flow cytometry. The network pharmacology was constructed by Cytoscape, and the molecular docking was perfomed by AutoDock Vina.
Docking predicted the high affinity of ARC to MAPK1 (ERK2). HE staining showed that ARC@DPBNPs attenuated LPS-induced ALI at a remarkably lower dose than ARC. The improved histopathological changes, lung W/D weight ratio, and decreased of inflammatory factor levels in lung collectively demonstrated the alleviation effects of ARC@DPBNPs. Compared with the LPS group, ARC@DPBNPs down-regulated the ERK pathway, resulted in a suppression of the macrophage pyroptosis and M1 polarization. This suppression effects could be removed by the ERK activator Ro 67-7476.
ARC@DPBNPs attenuated ALI by suppressing LPS-induced macrophage pyroptosis and polarization, probably through down-regulation of the ERK pathway.
探讨 ARC@DPBNP 对脂多糖（LPS）诱导的急性肺损伤（ALI）的保护作用及其机制。
通过气管内给予 LPS（4mg/kg）建立 C57BL/6 小鼠 ALI 模型。首先比较了 ARC（灌胃给予，剂量范围为 10-80mg/kg）和 ARC@BPBNPs（气管内给予，剂量范围为 1-4mg/kg）对 ALI 的抑制作用。检测了 3mg/kg ARC@DPBNPs 气管内干预后肺组织学变化。通过 Western blot 检测肺组织和 RAW264.7 细胞中细胞焦亡途径相关蛋白的表达。采用免疫荧光染色检测肺巨噬细胞中 ASC 的表达。采用流式细胞术检测 RAW264.7 细胞和肺巨噬细胞的极化。通过 Cytoscape 构建网络药理学，通过 AutoDock Vina 进行分子对接。
docking 预测 ARC 与 MAPK1（ERK2）具有高亲和力。HE 染色显示，ARC@DPBNPs 以明显低于 ARC 的剂量减轻 LPS 诱导的 ALI。改善的组织病理学变化、肺湿/干重比和肺中炎症因子水平的降低共同证明了 ARC@DPBNPs 的缓解作用。与 LPS 组相比，ARC@DPBNPs 下调了 ERK 通路，抑制了巨噬细胞细胞焦亡和 M1 极化。这种抑制作用可以被 ERK 激活剂 Ro 67-7476 去除。
ARC@DPBNPs 通过抑制 LPS 诱导的巨噬细胞细胞焦亡和极化来减轻 ALI，可能通过下调 ERK 通路。
