Dasatinib suppresses TGFβ-induced epithelial mesenchymal transition and inhibits pulmonary fibrosis

[Background] Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells may contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been reported that imatinib attenuated bleomycin (BLM)-induced fibrosis in mice. Dasatinib (DAS) is tyrosine kinase inhibitor against platelet derived growth factor receptor as well as imatinib. However, there have been no studies on the effects of DAS on pulmonary fibrosis. [Aim] Our aim is to investigate the effect of DAS on TGFβ-induced EMT in human alveolar epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. [Materials and Methods] A549 cells were stimulated with TGFβ and treated with or without DAS. We analyzed epithelial and mesenchymal markers by quantitative real time PCR and western blot and cell motility by wound healing assay. We developed a mouse model for pulmonary fibrosis by intravenous injection of BLM. Either DAS or vehicle was administered by oral gavage, and mice were sacrificed on day 22. We evaluated pathological findings and measured the collagen contents in the lungs of the mice. [Results] In vitro , TGFβ-induced expression of mesenchymal proteins and transcriptional factors were significantly suppressed by the treatment with DAS. Furthermore, DAS markedly inhibited TGFβ-induced cell motility. In vivo, treatment with DAS significantly attenuated BLM-induced lung fibrosis and collagen contents in the lungs. [Conclusion] These findings suggest that DAS inhibits pulmonary fibrosis by suppressing TGFβ-induced EMT. DAS may be a promising and novel anti-fibrotic agent for the prevention of IPF.