Li Chen, Feng Xiaorong, Li Songhang, He Xing, Luo Zeli, Cheng Xia, Yao Jie, Xiao Jie, Wang Xiaofei, Wen Dingke, Liu Duanya, Li Yanfei, Zhou Hong, Ma Lu, Lin Tongyu, Cai Xiaoxiao, Lin Yunfeng, Guo Lu, Yang Mu
Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Mol Ther. 2024 Mar 6;32(3):766-782. doi: 10.1016/j.ymthe.2024.01.022. Epub 2024 Jan 24.
Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.
特发性肺纤维化（IPF）是一种慢性致死性疾病，目前尚无证实有效的预防疾病进展的方法。尽管巨噬细胞介导的肺泡炎在疾病发展过程中参与了肌成纤维细胞转化，但由于缺乏合适的动物模型，持续巨噬细胞极化的模式仍未得到充分研究。在此，通过在第7天整合气管内给予2.5 U/kg博来霉素和10 Gy胸部照射，我们构建了一种具有持续肺泡炎介导纤维化的小鼠模型，该模型模拟了我们所研究的IPF患者的大多数临床特征。结合患者和小鼠IPF模型的scRNA-seq数据，揭示了CCL2/CCR2轴在驱动M1巨噬细胞极化中的决定性作用，并进一步证实M1巨噬细胞在促进肺泡炎以导致肌成纤维细胞活化方面发挥作用。合成了与四重ccr2-siRNA结合的多个粘性末端四面体框架核酸（FNA-siCCR2）以靶向M1巨噬细胞。FNA-siCCR2成功阻断了IPF小鼠模型肺实质中巨噬细胞的积聚，从而防止肌成纤维细胞活化并导致疾病缓解。总体而言，我们的研究为开发一种新型IPF小鼠模型奠定了基础，揭示了M1巨噬细胞作为潜在治疗靶点，并通过使用FNA-siCCR2建立了新的治疗策略，这与IPF领域的临床情况和转化研究高度相关。
