Guo Lingli, Han Lu, Zhang Jing, Shen Mengyao, Li Jiacheng, Zhang Kuijie, Chen Ruru, Liu Heliang
College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China; Hebei Key Laboratory of Organ Fibrosis, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
Hebei Key Laboratory of Organ Fibrosis, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
Chem Biol Interact. 2025 Feb 25;408:111385. doi: 10.1016/j.cbi.2025.111385. Epub 2025 Jan 10.
Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of silicosis. High mobility group box 1 (HMGB1) has been found to induce EMT in fibrotic diseases. Previous studies have revealed a critical role of HMGB1 in silicosis, whereas the detail mechanisms still obscure. Here, we observed that HMGB1 protein was increased in the serum of silicosis patients and in the lung tissues of silicotic mice. The levels of HMGB1, receptor for advanced glycation end products (RAGE) and β-catenin protein were increased in the alveolar EMT cell model established by the treatment of transforming growth factor β1 (TGF-β1) and conditioned mediums derived from silica-stimulated macrophages. The activation of HMGB1, RAGE, β-catenin, EMT process, as well as cell migration triggered by TGF-β1 in RLE-6TN cells could be enhanced by treatment with recombinant HMGB1 protein (rHMGB1) and decreased by HMGB1 chemical inhibitor glycyrrhizin or RAGE inhibitor FPS-ZM1. And RAGE suppression could alleviate HMGB1-mediated the aggravation of β-catenin signaling, cell migration and EMT process induced by TGF-β1. Furthermore, both HMGB1 inhibition and RAGE knockout effectively alleviated the lung function impairment, EMT process, pulmonary inflammation and fibrosis in silicotic mice. These findings suggested that HMGB1 might promote EMT through RAGE/β-catenin axis in silicosis. And HMGB1 might constitute a therapeutic target for ameliorating the fibrosis of silicosis.
上皮-间质转化（EMT）与矽肺的发病机制有关。已发现高迁移率族蛋白B1（HMGB1）在纤维化疾病中可诱导EMT。先前的研究揭示了HMGB1在矽肺中的关键作用，但其具体机制仍不清楚。在此，我们观察到矽肺患者血清和矽肺小鼠肺组织中HMGB1蛋白增加。在通过转化生长因子β1（TGF-β1）和二氧化硅刺激的巨噬细胞来源的条件培养基建立的肺泡EMT细胞模型中，HMGB1、晚期糖基化终产物受体（RAGE）和β-连环蛋白的蛋白水平升高。用重组HMGB1蛋白（rHMGB1）处理可增强RLE-6TN细胞中HMGB1、RAGE、β-连环蛋白的激活、EMT过程以及TGF-β1触发的细胞迁移，而HMGB1化学抑制剂甘草甜素或RAGE抑制剂FPS-ZM1可降低上述作用。并且抑制RAGE可减轻HMGB1介导的TGF-β1诱导的β-连环蛋白信号转导增强、细胞迁移和EMT过程。此外，抑制HMGB1和敲除RAGE均能有效减轻矽肺小鼠的肺功能损害、EMT过程、肺部炎症和纤维化。这些发现提示，在矽肺中HMGB1可能通过RAGE/β-连环蛋白轴促进EMT。并且HMGB1可能构成改善矽肺纤维化的治疗靶点。
