Daphnetin Alleviates Bleomycin-Induced Pulmonary Fibrosis through Inhibition of Epithelial-to-Mesenchymal Transition and IL-17A
Author:
Park Soo-Jin1ORCID, Ryu Hyung Won1ORCID, Kim Ji-Hyeong12ORCID, Hahn Hwa-Jeong1, Jang Hyun-Jae1ORCID, Ko Sung-Kyun23ORCID, Oh Sei-Ryang12ORCID, Lee Hyun-Jun12ORCID
Affiliation:
1. Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju-si 28116, Republic of Korea 2. Department of Biomolecular Science, University of Science & Technology (UST), Daejeon 34113, Republic of Korea 3. Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju-si 28116, Republic of Korea
Abstract
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.
Funder
KRIBB Research Initiative Program National Research Foundation of Korea
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