Abstract：
Silicosis is a disease characterized by lung inflammation and fibrosis caused by long-term inhalation of free silicon dioxide (SiO2). Recent studies have found that a large number of lymphatic hyperplasia occurs during the occurrence and development of silicosis. miRNAs play an important role in lymphangiogenesis. However, the regulation and mechanism of miRNAs on lymphangiogenesis in silicosis remain unclear. In this study, lymphangiogenesis was observed in silicosis rats, and VEGF-C-targeted miRNAs were screened, and the effect of miRNAs on the formation of human lymphatic endothelial cells (HLECs) tubular structure was investigated in vitro. The results showed that SiO2 promoted the expressions of Collagen Ι and α-SMA, TNF-α, IL-6 and VEGF-C increased first and then decreased, and promoted the formation of lymphatic vessels. Bioinformatics methods screened miR-455-3p for targeted binding to VEGF-C, and dual luciferase reporter genes confirmed VEGF-C as the target gene of miR-455-3p, and miR-455-3p was down-regulated in the lung tissue of silicosis rats. Transfection of miR-455-3p Inhibitors down-regulated the expression level of miR-455-3p and up-regulated the expression levels of VEGF-C and VEGFR-3 in HLECs, enhanced migration ability and increased tube formation. Transfection of miR-455-3p Mimics showed an opposite trend. These results suggest that miR-455-3p further regulates the tubular structure formation of HLECs by regulating VEGF-C/VEGFR3. Therefore, targeting miR-455-3p may provide a new therapeutic strategy for SiO2-induced silicosis injury.
摘要：
矽肺是一种由长期吸入游离二氧化硅（SiO2）引起的以肺部炎症和纤维化为特征的疾病。近年来研究发现,在矽肺的发生和发展过程中,会出现大量的淋巴管增生。miRNA在淋巴管生成中起重要作用。然而,miRNAs对矽肺淋巴管生成的调控机制尚不清楚。在这项研究中,在矽肺大鼠中观察到淋巴管生成，和VEGF-C靶向的miRNA进行筛选，并在体外研究了miRNAs对人淋巴管内皮细胞（HLECs）管状结构形成的影响。结果表明,SiO2可促进胶原蛋白I和α-SMA的表达,TNF-α,IL-6和VEGF-C先升高后降低,促进淋巴管的形成。生物信息学方法筛选miR-455-3p靶向结合VEGF-C,双荧光素酶报告基因证实VEGF-C为miR-455-3p的靶基因,miR-455-3p在矽肺大鼠肺组织中表达下调。转染miR-455-3p抑制剂下调miR-455-3p的表达水平，上调VEGF-C和VEGFR-3的表达水平，增强的迁移能力和增加的管形成。转染miR-455-3p模拟物显示相反的趋势。这些结果表明,miR-455-3p通过调节VEGF-C/VEGFR3进一步调节HLEC的管状结构形成。因此,靶向miR-455-3p可能为SiO2诱导的矽肺损伤提供新的治疗策略.
