Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory
interstitial lung disease. Although there is no cure for IPF, the development of drugs with improved efficacy in the treatment of IPF is required.
Daphnetin, a natural
coumarin derivative, has immunosuppressive, anti-inflammatory, and
antioxidant activities. However, its antifibrotic effects have not yet been elucidated. In this study, we investigated the antifibrotic effects of
daphnetin on
pulmonary fibrosis and the associated molecular mechanism. We examined the effects of
daphnetin on splenocytes cultured in Th17 conditions, lung epithelial cells, and a mouse model of
bleomycin (BLM)-induced
pulmonary fibrosis. We identified that
daphnetin inhibited
IL-17A production in developing Th17 cells. We also found that
daphnetin suppressed epithelial-to-mesenchymal transition (EMT) in TGF-β-treated BEAS2B cells through the regulation of AKT phosphorylation. In BLM-treated mice, the
oral administration of
daphnetin attenuated lung histopathology and improved lung mechanical functions. Our findings clearly demonstrated that
daphnetin inhibited
IL-17A and EMT both in vitro and in vivo, thereby protecting against BLM-induced
pulmonary fibrosis. Taken together, these results suggest that
daphnetin has potent
therapeutic effects on lung
fibrosis by modulating both Th17 differentiation and the TGF-β signaling pathway, and we thus expect
daphnetin to be a drug candidate for the treatment of IPF.