RRC ID 55917
Author Kanemaru R, Takahashi F, Kato M, Mitsuishi Y, Tajima K, Ihara H, Hidayat M, Wirawan A, Koinuma Y, Hayakawa D, Yagishita S, Ko R, Sato T, Harada N, Kodama Y, Nurwidya F, Sasaki S, Niwa SI, Takahashi K.
Title Dasatinib Suppresses TGFβ-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis.
Journal Lung
Abstract PURPOSE:Transforming growth factor β (TGFβ)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo.
METHODS:TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM).
RESULTS:A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model.
CONCLUSIONS:These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.
Volume 196(5)
Pages 531-541
Published 2018-10-1
DOI 10.1007/s00408-018-0134-6
PII 10.1007/s00408-018-0134-6
PMID 29926178
MeSH A549 Cells Alveolar Epithelial Cells / drug effects* Alveolar Epithelial Cells / metabolism Alveolar Epithelial Cells / pathology Animals Antigens, CD / metabolism Bleomycin Bronchi / drug effects* Bronchi / metabolism Bronchi / pathology Cadherins / metabolism Cell Movement / drug effects Collagen Type I / metabolism Collagen Type IV / metabolism Dasatinib / pharmacology* Disease Models, Animal Epithelial-Mesenchymal Transition / drug effects* Fibronectins / metabolism Humans Mice, Inbred ICR Phosphorylation Pulmonary Fibrosis / metabolism Pulmonary Fibrosis / pathology Pulmonary Fibrosis / prevention & control* Signal Transduction / drug effects Smad2 Protein / metabolism Smad3 Protein / metabolism Transforming Growth Factor beta1 / pharmacology*
IF 2.231
Times Cited 5
Human and Animal Cells A549(RCB0098)