Chen Zhen, Yun Xiang, Tian Jiaqi, Li Fei, Zhang Zitong, Meng Jiahua, Li Ning, Bian Hongying, Duan Shuyin, Zhang Lin
Clinical Medical Research Center for Women and Children Diseases, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, China.
Jinan (Preparatory) Key Laboratory of Women's Diseases and Fertility Preservation, Jinan, 250001, China.
Adv Healthc Mater. 2025 Feb;14(4):e2403227. doi: 10.1002/adhm.202403227. Epub 2024 Oct 9.
Silicosis is a severe lung disease characterized by diffuse pulmonary fibrosis, for which there is currently no effective treatment. Pirfenidone (PFD) shows great antifibrotic potential but is clinically hindered by low bioavailability and gastrointestinal side effects. To address these limitations, this study develops a PFD delivery system (PFD-Exo) using J774A.1 macrophage-derived exosomes. Firstly, PFD is loaded via sonication, then PFD-Exo is characterized using Raman spectral imaging and UV absorption spectroscopy. Finally, in vitro and in vivo silicosis models are established to evaluate its antifibrotic effects. Results show that PFD-Exo outperforms free PFD in inhibiting TGF-β1-induced transdifferentiation of primary lung fibroblasts in vitro. In a mouse model of silicosis, PFD-Exo is found to be accumulated in the lungs following intratracheal administration and significantly ameliorates pulmonary inflammation and fibrosis while minimizing gastrointestinal side effects. Mechanistic studies reveal that PFD-Exo modulates the TGF-β signaling pathway by downregulating SMAD3 and upregulating SMAD7 and NOGGIN. In conclusion, this study provides the first evidence of macrophage-derived exosomes as an effective PFD delivery system for silicosis treatment and offers a promising strategy for other refractory pulmonary diseases.
矽肺是一种以弥漫性肺纤维化为特征的严重肺部疾病，目前尚无有效的治疗方法。吡非尼酮（PFD）具有巨大的抗纤维化潜力，但在临床上受到低生物利用度和胃肠道副作用的阻碍。为了解决这些局限性，本研究利用J774A.1巨噬细胞衍生的外泌体开发了一种PFD递送系统（PFD-Exo）。首先，通过超声处理加载PFD，然后使用拉曼光谱成像和紫外吸收光谱对PFD-Exo进行表征。最后，建立体外和体内矽肺模型以评估其抗纤维化作用。结果表明，在体外抑制转化生长因子-β1（TGF-β1）诱导的原代肺成纤维细胞转分化方面，PFD-Exo优于游离PFD。在矽肺小鼠模型中，发现气管内给药后PFD-Exo在肺中积累，并显著改善肺部炎症和纤维化，同时将胃肠道副作用降至最低。机制研究表明，PFD-Exo通过下调SMAD3和上调SMAD7及NOGGIN来调节TGF-β信号通路。总之，本研究首次证明巨噬细胞衍生的外泌体可作为治疗矽肺的有效PFD递送系统，并为其他难治性肺部疾病提供了一种有前景的策略。
