Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China.
J Hazard Mater. 2024 Jan 5;461:132733. doi: 10.1016/j.jhazmat.2023.132733. Epub 2023 Oct 6.
Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial cells during silicosis progression remain unexplored. To fill this knowledge gap, a mouse model of silicosis was established. Single cell sequencing, spatial transcriptome sequencing, western blotting, immunofluorescence staining, tube-forming and wound healing assays were used to explore the effects of silicon dioxide on macrophage-endothelial interactions. To investigate the mechanism of macrophage-mediated fibrosis, MMP12 was specifically inactivated using siRNA and pharmacological approaches, and macrophages were depleted using disodium chlorophosphite liposomes. Compared to the normal saline group, the silica dust group showed altered macrophage-endothelial interactions. Matrix metalloproteinase family member MMP12 was identified as a key mediator of the altered function of macrophage-endothelial interactions after silica exposure, which was accompanied by pro-inflammatory macrophage activation and fibrotic progression. By using ablation strategies, macrophage-derived MMP12 was shown to mediate endothelial cell dysfunction by accumulating on the extracellular matrix. During the inflammatory phase of silicosis, MMP12 secreted by pro-inflammatory macrophages caused decreased endothelial cell viability, reduced migration, decreased trans-endothelial resistance and increased permeability; while during the fibrotic phase, macrophage-derived MMP12 sustained endothelial cell injury through accumulation on the extracellular matrix.
巨噬细胞对于维持内皮细胞功能至关重要。然而，在矽肺进展过程中，巨噬细胞和内皮细胞之间相互作用的潜在影响和机制仍未被探索。为了填补这一知识空白，建立了矽肺的小鼠模型。通过单细胞测序、空间转录组测序、Western blot、免疫荧光染色、管形成和划痕愈合实验，探讨了二氧化硅对巨噬细胞-内皮细胞相互作用的影响。为了研究巨噬细胞介导纤维化的机制，使用 siRNA 和药理学方法特异性失活 MMP12，并用二氯膦酸钠脂质体耗竭巨噬细胞。与生理盐水组相比，二氧化硅粉尘组表现出改变的巨噬细胞-内皮相互作用。基质金属蛋白酶家族成员 MMP12 被鉴定为二氧化硅暴露后改变巨噬细胞-内皮相互作用功能的关键介质，同时伴有促炎巨噬细胞激活和纤维化进展。通过使用消融策略，证明巨噬细胞来源的 MMP12 通过在细胞外基质上积累来介导内皮细胞功能障碍。在矽肺的炎症期，促炎巨噬细胞分泌的 MMP12 导致内皮细胞活力降低、迁移减少、跨内皮电阻降低和通透性增加；而在纤维化期，巨噬细胞来源的 MMP12 通过在细胞外基质上积累来维持内皮细胞损伤。
