任天堂
MAPK/ERK通路
细胞外基质
癌症研究
成纤维细胞
纤维化
焦点粘着
信号转导
肺纤维化
细胞生物学
医学
体外
化学
生物
特发性肺纤维化
肺
病理
内科学
生物化学
作者
Wenting Yang,Pei Lin,Yiju Cheng,Xiao Wu,Bin Tang,Honglan Zhu,Menglin Zhang,Yuquan Zhang
标识
DOI:10.1016/j.intimp.2022.109409
摘要
Nintedanib is an effective treatment for pulmonary fibrosis (PF), but the exact mechanism by which this agent works to delay the progression of PF remains unclear. In this study, we explored whether nintedanib alleviates PF at least partially by inhibiting the focal adhesion kinase (FAK)/ERK/S100A4 signalling pathway. Bleomycin (BLM) was used to induce PF in a mouse model, and human fetal lung fibroblast 1 (HFL-1) cells were exposed to transforming growth factor-β 1 (TGF-β1) to create an in vitro model of PF. In both models, nintedanib was administered either alone or in conjunction with a FAK vector. In mouse lung tissues, histopathology, inflammatory factor levels, and collagen content were assessed; in HFL-1 cells, HFL-1 activity was assessed, along with collagen I, collagen III, and α-SMA levels. Both mouse tissue and HFL-1 cells were examined for levels of indices associated with extracellular matrix and the FAK/ERK/S100A4 signalling pathway. In mice exposed to BLM, lung inflammation and extracellular matrix deposition were significantly increased. These factors were alleviated by nintedanib treatment but were aggravated by overexpression of FAK. In HFL-1 cells, nintedanib inhibited HFL-1 activity and collagen I, collagen III, and α-SMA levels, whereas overexpression of FAK produced the opposite effect. In both tissues and cells, the FAK/ERK/S100A4 signalling pathway was activated, but nintedanib was able to suppress this pathway. These results suggest that nintedanib alleviates PF by inhibiting the FAK/ERK/S100A4 signalling pathway both in vivo and in vitro.
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