Zhong Zuoquan, Gao Yefei, He Chunxiao, Li Weijie, Sang Le, Huang Yunlei, Chen Xing, Xie Mengyao, Zhang Chu, Yu Yuefang, Zhu Ting, Sun Jian
Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China.
Shaoxing People's Hospital, Shaoxing, China.
Cell Signal. 2025 Apr;128:111635. doi: 10.1016/j.cellsig.2025.111635. Epub 2025 Jan 30.
Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease with high mortality rate. Although Nintedanib (Nin) is an effective treatment for IPF, its precise mechanism of action remains unclear. In this study, we performed an integrated analysis of single-cell sequencing and RNA-seq data from lung tissues of both fibrotic and Nin-treated fibrotic mice to uncover new therapeutic mechanisms of Nin in IPF. Our results revealed an increase in interstitial macrophages following bleomycin (BLM) treatment. We used Monocle2, Cellchat, and in vivo experiments to demonstrate that Nin can inhibit Clec7a in interstitial macrophages, thereby suppressing the SPP1-mediated profibrotic pathway. Additionally, we utilized Scenic to predict transcription factors and identified NFκB as a major transcription factor in interstitial macrophages. In the in vitro experiments, we found that inhibiting Clec7a improved the secretion of SPP1 by M2 macrophages through the NFκB pathway. In subsequent in vivo experiments, we found that inhibiting of Clec7a improves pulmonary fibrosis through the NFκB/SPP1 pathway, and Nin alleviated BLM-induced pulmonary fibrosis by inhibiting Clec7a in interstitial macrophages. In summary, our study indicates that interstitial macrophages are upregulated in pulmonary fibrosis, and Nin reduces fibrosis by inhibiting Clec7a in interstitial macrophages, which in turn diminishes the NFκB /SPP1 pathway. These findings provided a new perspective on the mechanism of action of Nin in treating pulmonary fibrosis.
特发性肺纤维化（IPF）是一种死亡率很高的终末期肺部疾病。尽管尼达尼布（Nin）是治疗IPF的有效药物，但其确切作用机制仍不清楚。在本研究中，我们对纤维化小鼠和尼达尼布治疗的纤维化小鼠肺组织的单细胞测序和RNA测序数据进行了综合分析，以揭示尼达尼布在IPF中的新治疗机制。我们的结果显示，博来霉素（BLM）治疗后间质巨噬细胞增加。我们使用Monocle2、Cellchat和体内实验证明，尼达尼布可以抑制间质巨噬细胞中的Clec7a，从而抑制SPP1介导的促纤维化途径。此外，我们利用Scenic预测转录因子，并确定NFκB是间质巨噬细胞中的主要转录因子。在体外实验中我们发现，抑制Clec7a可通过NFκB途径改善M2巨噬细胞分泌SPP1。在随后的体内实验中，我们发现抑制Clec7a可通过NFκB/SPP1途径改善肺纤维化，而尼达尼布通过抑制间质巨噬细胞中的Clec7a减轻BLM诱导的肺纤维化。总之，我们的研究表明，肺纤维化中间质巨噬细胞上调，尼达尼布通过抑制间质巨噬细胞中的Clec7a减少纤维化，进而减弱NFκB /SPP1途径。这些发现为尼达尼布治疗肺纤维化的作用机制提供了新的视角。
