Silicosis is a disease characterized by lung inflammation and fibrosis caused by long-term inhalation of free silicon dioxide (SiO). 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 SiO 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 SiO-induced silicosis injury.

中文翻译：

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miR-455–3p 通过调节 VEGF-C/VEGFR3 调节矽肺的淋巴管生成


矽肺是因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。近年研究发现，矽肺的发生、发展过程中出现大量淋巴管增生。 miRNA 在淋巴管生成中发挥重要作用。然而，miRNA对矽肺淋巴管生成的调控和机制仍不清楚。本研究观察了矽肺大鼠的淋巴管生成情况，筛选了VEGF-C靶向的miRNA，并在体外研究了miRNA对人淋巴内皮细胞（HLEC）管状结构形成的影响。结果表明，SiO促进胶原Ⅰ和α-SMA的表达，TNF-α、IL-6和VEGF-C先升高后降低，促进淋巴管形成。生物信息学方法筛选miR-455–3p与VEGF-C的靶向结合，双荧光素酶报告基因证实VEGF-C为miR-455–3p的靶基因，且miR-455–3p在肺组织中下调矽肺大鼠。转染 miR-455–3p 抑制剂可下调 HLEC 中 miR-455–3p 的表达水平，上调 VEGF-C 和 VEGFR-3 的表达水平，增强迁移能力并增加管形成。 miR-455–3p Mimics 的转染显示出相反的趋势。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SiO诱导的矽肺损伤提供新的治疗策略。