Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context
Background: Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represen...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305942 |
| _version_ | 1819108116476723200 |
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| author | Han-Soo Kim Young-Min Yoon Moon Kee Meang Yae Eun Park Ji Yong Lee Tae Hee Lee Ji Eun Lee Ik-Hwan Kim Byung-Soo Youn |
| author_facet | Han-Soo Kim Young-Min Yoon Moon Kee Meang Yae Eun Park Ji Yong Lee Tae Hee Lee Ji Eun Lee Ik-Hwan Kim Byung-Soo Youn |
| author_sort | Han-Soo Kim |
| collection | DOAJ |
| description | Background: Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represent a huge unmet medical need. Methods: A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-β. Eupatilin was assessed in diseased human lung fibroblasts from IPF patients (DHLFs) as well as in human lung epithelial cells (HLECs). The drug's performance was extensively tested in a bleomycin-induced lung fibrosis model (BLM). Global gene expression studies and proteome analysis were performed. Findings: Eupatilin attenuated disease severity of BLM in both preventative and therapeutic studies. The drug inhibited the in vitro transdifferantiation of DHLFs to myofibroblasts upon stimulation with TGF-β. No such induction of the in vitro transdifferantiation was observed in TGF-β treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-β complex, specifically by eliminating expression of the latent TGF-β binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-β. Eupatilin attenuated phosphorylation of Smad3 by TGF-β. Eupatilin induced myofibroblasts to dedifferentiate into intermediate HCS-like cells. Interpretation: Eupatilin may act directly on pathogenic myofibroblasts, disarming them, whereas the anti-fibrotic effect of pirfenidone may be indirect. Eupatilin could increase the efficacy of IPF treatment to curative levels. Keywords: Chromone scaffold, Epithelial–mesenchymal transition, Stem cells, Idiopathic pulmonary fibrosis, Myofibroblasts, Dedifferentiation |
| first_indexed | 2024-12-22T03:04:49Z |
| format | Article |
| id | doaj.art-e63ee86ad3e847cd87b9f8acc15e949c |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T03:04:49Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-e63ee86ad3e847cd87b9f8acc15e949c2022-12-21T18:41:05ZengElsevierEBioMedicine2352-39642019-01-0139484496Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in contextHan-Soo Kim0Young-Min Yoon1Moon Kee Meang2Yae Eun Park3Ji Yong Lee4Tae Hee Lee5Ji Eun Lee6Ik-Hwan Kim7Byung-Soo Youn8Department of Biomedical Sciences, Catholic Kwandong University College of Medicine, Gangneung-si, Gangwon-do 25601, Republic of Korea; Basic Research Division, Biomedical Institute of Mycological Resource, College of Medicine,Catholic Kwandong University, Gangneung-si, Gangwon-do, 25601, Republic of KoreaOsteoNeuroGenInc, Seoul 08501, Republic of KoreaOsteoNeuroGenInc, Seoul 08501, Republic of Korea; Department of Biotechnology, Korea University, Seoul 02841, Republic of KoreaCenter for Theragnosis, Biomedical Research Institute, Korean Institute of Science and Technology, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Anatomy, Yonsei University Wonju College of Medicine, Wonju-si, Gangwon-do 26426, Republic of KoreaSchool of Oriental Medicine, Formulae Pharmacology Department, Gachon University, Seongnam-si 13120, Republic of KoreaCenter for Theragnosis, Biomedical Research Institute, Korean Institute of Science and Technology, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Biotechnology, Korea University, Seoul 02841, Republic of KoreaOsteoNeuroGenInc, Seoul 08501, Republic of Korea; Corresponding author at: OsteoNeuroGen, Inc. Ace High-end Tower 9th 233, Gasandigital-1-ro, Geumcheon-gu, Seoul 08501, Republic of Korea.Background: Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represent a huge unmet medical need. Methods: A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-β. Eupatilin was assessed in diseased human lung fibroblasts from IPF patients (DHLFs) as well as in human lung epithelial cells (HLECs). The drug's performance was extensively tested in a bleomycin-induced lung fibrosis model (BLM). Global gene expression studies and proteome analysis were performed. Findings: Eupatilin attenuated disease severity of BLM in both preventative and therapeutic studies. The drug inhibited the in vitro transdifferantiation of DHLFs to myofibroblasts upon stimulation with TGF-β. No such induction of the in vitro transdifferantiation was observed in TGF-β treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-β complex, specifically by eliminating expression of the latent TGF-β binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-β. Eupatilin attenuated phosphorylation of Smad3 by TGF-β. Eupatilin induced myofibroblasts to dedifferentiate into intermediate HCS-like cells. Interpretation: Eupatilin may act directly on pathogenic myofibroblasts, disarming them, whereas the anti-fibrotic effect of pirfenidone may be indirect. Eupatilin could increase the efficacy of IPF treatment to curative levels. Keywords: Chromone scaffold, Epithelial–mesenchymal transition, Stem cells, Idiopathic pulmonary fibrosis, Myofibroblasts, Dedifferentiationhttp://www.sciencedirect.com/science/article/pii/S2352396418305942 |
| spellingShingle | Han-Soo Kim Young-Min Yoon Moon Kee Meang Yae Eun Park Ji Yong Lee Tae Hee Lee Ji Eun Lee Ik-Hwan Kim Byung-Soo Youn Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context EBioMedicine |
| title | Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context |
| title_full | Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context |
| title_fullStr | Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context |
| title_full_unstemmed | Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context |
| title_short | Reversion of in vivo fibrogenesis by novel chromone scaffoldsReseach in context |
| title_sort | reversion of in vivo fibrogenesis by novel chromone scaffoldsreseach in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418305942 |
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