Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China.
Department of Occupational Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, China.
J Cell Mol Med. 2021 May;25(9):4466-4477. doi: 10.1111/jcmm.16524. Epub 2021 Apr 8.
Macrophages play a key role in silicosis, and exosomes are potent mediators of intercellular communication. This suggests that macrophage-derived exosomes have a potential contribution to the pathogenesis of silicosis. To investigate whether macrophage-derived exosomes promote or inhibit lung fibrosis, in vitro, silica-exposed macrophage-derived exosomes (SiO -Exos) were collected and cocultured with fibroblasts. The expression of collagen I and α-SMA was evaluated. Furthermore, the endoplasmic reticulum (ER) stress markers BIP, XBP1s and P-eIF2α were assessed after treatment with or without the ER stress inhibitor 4-PBA. In vivo, mice were pre-treated with the exosome secretion inhibitor GW4869 prior to silica exposure. After sacrifice, lung tissues were histologically examined, and the expression of proinflammatory cytokines (TNF-α, IL-1β and IL-6) in bronchoalveolar lavage fluid (BALF) was measured. The results showed that the expression of collagen I and α-SMA was up-regulated after treatment with SiO -Exos, accompanied by increased expression of BIP, XBP1s and P-eIF2α. Pre-treatment with 4-PBA reversed this effect. More importantly, an in vivo study demonstrated that pre-treatment with GW4869 decreased lung fibrosis and the expression of TNF-α, IL-1β and IL-6 in BALF. These results suggested that SiO -Exos are profibrogenic and that the facilitating effect is dependent on ER stress.
巨噬细胞在矽肺中发挥关键作用，外泌体是细胞间通讯的有效介质。这表明巨噬细胞来源的外泌体可能对矽肺的发病机制有潜在贡献。为了研究巨噬细胞来源的外泌体是否促进或抑制肺纤维化，在体外，收集了暴露于二氧化硅的巨噬细胞来源的外泌体（SiO -Exos）并与成纤维细胞共培养。评估了胶原 I 和 α-SMA 的表达。此外，在用或不用内质网（ER）应激抑制剂 4-PBA 处理后，评估了 ER 应激标志物 BIP、XBP1s 和 P-eIF2α。在体内，在用二氧化硅暴露前，用外泌体分泌抑制剂 GW4869 预处理小鼠。牺牲后，对肺组织进行组织学检查，并测量支气管肺泡灌洗液（BALF）中促炎细胞因子（TNF-α、IL-1β 和 IL-6）的表达。结果表明，SiO -Exos 处理后胶原 I 和 α-SMA 的表达上调，同时 BIP、XBP1s 和 P-eIF2α 的表达增加。用 4-PBA 预处理可逆转此作用。更重要的是，体内研究表明，GW4869 的预处理可减少肺纤维化和 BALF 中 TNF-α、IL-1β 和 IL-6 的表达。这些结果表明 SiO -Exos 具有促纤维化作用，促进作用依赖于内质网应激。
