Li Yan, Xu Hailin, Wang Ying, Zhu Yurou, Xu Kun, Yang Zhu, Li Yanbo, Guo Caixia
Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, China.
Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing, 100069, China.
J Nanobiotechnology. 2024 Jun 12;22(1):331. doi: 10.1186/s12951-024-02609-y.
In the context of increasing exposure to silica nanoparticles (SiNPs) and ensuing respiratory health risks, emerging evidence has suggested that SiNPs can cause a series of pathological lung injuries, including fibrotic lesions. However, the underlying mediators in the lung fibrogenesis caused by SiNPs have not yet been elucidated.
The in vivo investigation verified that long-term inhalation exposure to SiNPs induced fibroblast activation and collagen deposition in the rat lungs. In vitro, the uptake of exosomes derived from SiNPs-stimulated lung epithelial cells (BEAS-2B) by fibroblasts (MRC-5) enhanced its proliferation, adhesion, and activation. In particular, the mechanistic investigation revealed SiNPs stimulated an increase of epithelium-secreted exosomal miR-494-3p and thereby disrupted the TGF-β/BMPR2/Smad pathway in fibroblasts via targeting bone morphogenetic protein receptor 2 (BMPR2), ultimately resulting in fibroblast activation and collagen deposition. Conversely, the inhibitor of exosomes, GW4869, can abolish the induction of upregulated miR-494-3p and fibroblast activation in MRC-5 cells by the SiNPs-treated supernatants of BEAS-2B. Besides, inhibiting miR-494-3p or overexpression of BMPR2 could ameliorate fibroblast activation by interfering with the TGF-β/BMPR2/Smad pathway.
Our data suggested pulmonary epithelium-derived exosomes serve an essential role in fibroblast activation and collagen deposition in the lungs upon SiNPs stimuli, in particular, attributing to exosomal miR-494-3p targeting BMPR2 to modulate TGF-β/BMPR2/Smad pathway. Hence, strategies targeting exosomes could be a new avenue in developing therapeutics against lung injury elicited by SiNPs.
在二氧化硅纳米颗粒（SiNPs）暴露增加及随之而来的呼吸健康风险的背景下，新出现的证据表明SiNPs可导致一系列肺部病理损伤，包括纤维化病变。然而，SiNPs引起肺纤维化的潜在介质尚未阐明。
体内研究证实，长期吸入暴露于SiNPs可诱导大鼠肺成纤维细胞活化和胶原沉积。在体外，成纤维细胞（MRC-5）摄取来自SiNPs刺激的肺上皮细胞（BEAS-2B）的外泌体增强了其增殖、黏附和活化。特别是，机制研究表明SiNPs刺激上皮分泌的外泌体miR-494-3p增加，从而通过靶向骨形态发生蛋白受体2（BMPR2）破坏成纤维细胞中的TGF-β/BMPR2/Smad通路，最终导致成纤维细胞活化和胶原沉积。相反，外泌体抑制剂GW4869可消除BEAS-2B经SiNPs处理的上清液对MRC-细胞中miR-494-3p上调的诱导和成纤维细胞活化。此外，抑制miR-494-3p或过表达BMPR2可通过干扰TGF-β/BMPR2/Smad通路改善成纤维细胞活化。
我们的数据表明，肺上皮来源的外泌体在SiNPs刺激后在肺成纤维细胞活化和胶原沉积中起重要作用，特别是外泌体miR-494-3p靶向BMPR2调节TGF-β/BMPR2/Smad通路。因此，针对外泌体的策略可能是开发针对SiNPs引起的肺损伤治疗方法的新途径。
