诱导多能干细胞来源的条件培养基以及尼达尼布通过抑制内皮-间充质转化改善博来霉素诱导的肺纤维化。
Induced pluripotent stem cell-derived conditioned medium, as well as nintedanib, ameliorates bleomycin-induced pulmonary fibrosis via suppressing endothelial-mesenchymal transition.
作者信息
Yu Wen-Kuang, Yang Yi-Ping, Chen Wei-Chih, Shen Hsiao-Chin, Chiou Shih-Hwa, Ko Yu-Ling, Sun Chuan-Yen, Su Vincent Yi-Fong, Yang Kuang-Yao
机构信息
Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
出版信息
Respir Investig. 2025 Sep;63(5):904-914. doi: 10.1016/j.resinv.2025.07.005. Epub 2025 Jul 18.
BACKGROUND
Pulmonary fibrosis (PF), a debilitating lung disease, is heavily influenced by fibroblasts, which may arise from pulmonary endothelial cells through a process called endothelial-mesenchymal transition (EndoMT). While nintedanib and induced pluripotent stem cell-derived conditioned medium (iPSC-CM) have shown promise in PF treatment, their ability to suppress EndoMT remains uncertain.
METHODS
PF was induced in C57BL/6 mice via intratracheal bleomycin (BLM) instillation. Nintedanib was administered orally, and iPSC-CM was injected through the tail vein. Concurrently, human pulmonary microvascular endothelial cells (HPMECs) were cultured with nintedanib and iPSC-CM, either individually or in combination, and then exposed to BLM to assess their ability to inhibit EndoMT in vitro.
RESULTS
Masson's trichrome staining revealed substantial collagen accumulation in the lungs of BLM-treated mice, which was significantly reduced by nintedanib and iPSC-CM, both individually and in combination, suggesting a reduction in PF. Immunohistochemistry staining and Western blot analysis showed that BLM stimulation increased the expression of collagen-1, α-SMA, and vimentin, while reducing VE-cadherin levels-effects that were reversed by treatment with nintedanib and iPSC-CM, either alone or in combination. Similarly, immunofluorescence staining and Western blotting of BLM-stimulated HPMECs indicated heightened EndoMT, which was effectively suppressed by nintedanib or iPSC-CM. Additionally, in both in vivo and in vitro BLM-induced EndoMT models, focal adhesion kinase (FAK) activity-a key driver of EndoMT-was significantly elevated. Treatment with nintedanib and iPSC-CM, either alone or in combination, markedly reduced FAK activation.
CONCLUSIONS
Nintedanib and iPSC-CM, whether used separately or together, effectively inhibited EndoMT and mitigated BLM-induced PF by suppressing FAK activity.
背景
肺纤维化（PF）是一种使人衰弱的肺部疾病，受成纤维细胞的严重影响，而成纤维细胞可能通过一种称为内皮-间充质转化（EndoMT）的过程由肺内皮细胞产生。虽然尼达尼布和诱导多能干细胞衍生的条件培养基（iPSC-CM）在PF治疗中显示出前景，但其抑制EndoMT的能力仍不确定。
方法
通过气管内滴注博来霉素（BLM）在C57BL/6小鼠中诱导PF。口服给予尼达尼布，并通过尾静脉注射iPSC-CM。同时，将人肺微血管内皮细胞（HPMECs）分别或联合用尼达尼布和iPSC-CM培养，然后暴露于BLM以评估它们在体外抑制EndoMT的能力。
结果
Masson三色染色显示，BLM处理的小鼠肺中大量胶原积累，单独或联合使用尼达尼布和iPSC-CM均使其显著减少，提示PF减轻。免疫组织化学染色和蛋白质印迹分析表明，BLM刺激增加了胶原-1、α-平滑肌肌动蛋白（α-SMA）和波形蛋白的表达，同时降低了血管内皮钙黏蛋白（VE-cadherin）水平，而单独或联合使用尼达尼布和iPSC-CM治疗可逆转这些效应。同样，对BLM刺激的HPMECs进行免疫荧光染色和蛋白质印迹表明EndoMT增强，而尼达尼布或iPSC-CM可有效抑制。此外，在体内和体外BLM诱导的EndoMT模型中，黏着斑激酶（FAK）活性（EndoMT的关键驱动因素）均显著升高。单独或联合使用尼达尼布和iPSC-CM治疗可显著降低FAK激活。
结论
尼达尼布和iPSC-CM单独或联合使用时，均可通过抑制FAK活性有效抑制EndoMT并减轻BLM诱导的PF。
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