Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms...

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Bibliographic Details
Published in:Bioscience reports 2018-12, Vol.38 (6)
Main Authors: Chen, Kui-Jun, Li, Qing, Weng, Chang-Mei, Duan, Zhao-Xia, Zhang, Dong-Dong, Chen, Zhi-Qiang, Chen, Jing, Wang, Jian-Min
Format: Article
Language:English
Subjects:
Alternative Splicing - drug effects
Alveolar Epithelial Cells - drug effects
Alveolar Epithelial Cells - pathology
Animals
Bleomycin - administration & dosage
Cell Proliferation - drug effects
Disease Models, Animal
Epithelial-Mesenchymal Transition - genetics
Fibroblasts - drug effects
Gene Expression Regulation - drug effects
Humans
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - pathology
Lung - pathology
Mice, Transgenic
Protein Isoforms - genetics
Receptor, Fibroblast Growth Factor, Type 2 - genetics
RNA-Binding Proteins - genetics
Signal Transduction - drug effects
Smad Proteins - genetics
Transforming Growth Factor beta - genetics
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Summary:Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.
ISSN:0144-8463
1573-4935
DOI:10.1042/BSR20180445