Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Physiology, School of Medicine, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Rd, Nanjing, Jiangsu, 210009, China.
Key Laboratory of Environmental Medicine Engineering, School of Public Health, Ministry of Education, Southeast University, Nanjing, Jiangsu, 210009, China.
Part Fibre Toxicol. 2023 Jul 19;20(1):29. doi: 10.1186/s12989-023-00543-9.
Chronic exposure to silica can lead to silicosis, one of the most serious occupational lung diseases worldwide, for which there is a lack of effective therapeutic drugs and tools. Epithelial mesenchymal transition plays an important role in several diseases; however, data on the specific mechanisms in silicosis models are scarce. We elucidated the pathogenesis of pulmonary fibrosis via single-cell transcriptome sequencing and constructed an experimental silicosis mouse model to explore the specific molecular mechanisms affecting epithelial mesenchymal transition at the single-cell level. Notably, as silicosis progressed, glycoprotein non-metastatic melanoma protein B (GPNMB) exerted a sustained amplification effect on alveolar type II epithelial cells, inducing epithelial-to-mesenchymal transition by accelerating cell proliferation and migration and increasing mesenchymal markers, ultimately leading to persistent pulmonary pathological changes. GPNMB participates in the epithelial-mesenchymal transition in distant lung epithelial cells by releasing extracellular vesicles to accelerate silicosis. These vesicles are involved in abnormal changes in the composition of the extracellular matrix and collagen structure. Our results suggest that GPNMB is a potential target for fibrosis prevention.
慢性暴露于二氧化硅可导致矽肺，这是全球最严重的职业性肺部疾病之一，目前缺乏有效的治疗药物和手段。上皮-间充质转化在几种疾病中发挥着重要作用；然而，关于矽肺模型中具体机制的数据却十分匮乏。我们通过单细胞转录组测序阐明了肺纤维化的发病机制，并构建了实验性矽肺小鼠模型，以在单细胞水平上探索影响上皮-间充质转化的具体分子机制。值得注意的是，随着矽肺的进展，糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）对肺泡 II 型上皮细胞持续发挥放大作用，通过加速细胞增殖和迁移，增加间充质标志物，诱导上皮-间充质转化，进而导致持续的肺部病理改变。GPNMB 通过释放细胞外囊泡来加速矽肺，从而参与远处肺上皮细胞的上皮-间充质转化。这些囊泡参与细胞外基质组成和胶原结构的异常变化。我们的研究结果表明，GPNMB 是预防纤维化的一个潜在靶点。
