Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, PR China.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, PR China.
Toxicology. 2022 Sep;479:153310. doi: 10.1016/j.tox.2022.153310. Epub 2022 Sep 6.
Silicosis is one of the most serious occupational diseases with the main feature of inflammatory cell infiltration, fibroblasts activation, and large deposition of extracellular matrix in the lung. Increasing evidence indicates that macrophage-derived exosomes may play an important role in the development of silicosis by transferring their loaded microRNAs (miRNAs). Hence we carried out high-throughput sequencing to identify the expression of exosomal miRNA from macrophages exposed to silica or not in the previous study. Then we verified that miR-7219-3p was significantly up-regulated in macrophages and their exosomes after silica-exposure, as well as in the silicotic mice model by qRT-PCR, subsequent experiments confirmed that the increase of miR-7219-3p facilitated fibroblast to myofibroblast trans-differentiation (FMT), as well as cell proliferation and migration. Spouty1 (SPRY1), which served as a negative modulator of the Ras/ERK/MAPK signaling pathway, was verified as the target gene of miR-7219-3p, the knockdown or over-expression of SPRY1 apparently promoted or inhibited FMT via the Ras/ERK/MAPK signaling pathway. Furthermore, the inhibition of exosomal miR-7219-3p partially suppressed FMT and silica-induced pulmonary fibrosis in vitro and in vivo. In brief, our results demonstrated that exosomal miR-7219-3p played an important role in FMT and might be a novel therapeutic target of silicosis.
矽肺是最严重的职业病之一，其主要特征是肺部炎症细胞浸润、成纤维细胞激活和细胞外基质大量沉积。越来越多的证据表明，巨噬细胞来源的外泌体可能通过转移其负载的 microRNAs（miRNAs）在矽肺的发生发展中发挥重要作用。因此，我们在之前的研究中进行了高通量测序，以鉴定暴露于二氧化硅或未暴露于二氧化硅的巨噬细胞中外泌体 miRNA 的表达。然后，我们通过 qRT-PCR 验证了 miR-7219-3p 在二氧化硅暴露后的巨噬细胞及其外泌体中以及矽肺小鼠模型中显著上调，随后的实验证实 miR-7219-3p 的增加促进了成纤维细胞向肌成纤维细胞的转分化（FMT），以及细胞增殖和迁移。Spouty1（SPRY1）被验证为 miR-7219-3p 的靶基因，作为 Ras/ERK/MAPK 信号通路的负调节剂，SPRY1 的敲低或过表达明显通过 Ras/ERK/MAPK 信号通路促进或抑制 FMT。此外，外泌体 miR-7219-3p 的抑制部分抑制了体外和体内的 FMT 和二氧化硅诱导的肺纤维化。总之，我们的结果表明外泌体 miR-7219-3p 在 FMT 中起重要作用，可能是矽肺的一个新的治疗靶点。
