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Reversion of in vivo fibrogenesis by novel chromone scaffolds

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...

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Autores principales: Kim, Han-Soo, Yoon, Young-Min, Meang, Moon Kee, Park, Yae Eun, Lee, Ji Yong, Lee, Tae Hee, Lee, Ji Eun, Kim, Ik-Hwan, Youn, Byung-Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355727/
https://www.ncbi.nlm.nih.gov/pubmed/30611717
http://dx.doi.org/10.1016/j.ebiom.2018.12.017
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author Kim, Han-Soo
Yoon, Young-Min
Meang, Moon Kee
Park, Yae Eun
Lee, Ji Yong
Lee, Tae Hee
Lee, Ji Eun
Kim, Ik-Hwan
Youn, Byung-Soo
author_facet Kim, Han-Soo
Yoon, Young-Min
Meang, Moon Kee
Park, Yae Eun
Lee, Ji Yong
Lee, Tae Hee
Lee, Ji Eun
Kim, Ik-Hwan
Youn, Byung-Soo
author_sort Kim, Han-Soo
collection PubMed
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.
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spelling pubmed-63557272019-02-08 Reversion of in vivo fibrogenesis by novel chromone scaffolds Kim, Han-Soo Yoon, Young-Min Meang, Moon Kee Park, Yae Eun Lee, Ji Yong Lee, Tae Hee Lee, Ji Eun Kim, Ik-Hwan Youn, Byung-Soo EBioMedicine Research paper 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. Elsevier 2019-01-02 /pmc/articles/PMC6355727/ /pubmed/30611717 http://dx.doi.org/10.1016/j.ebiom.2018.12.017 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Kim, Han-Soo
Yoon, Young-Min
Meang, Moon Kee
Park, Yae Eun
Lee, Ji Yong
Lee, Tae Hee
Lee, Ji Eun
Kim, Ik-Hwan
Youn, Byung-Soo
Reversion of in vivo fibrogenesis by novel chromone scaffolds
title Reversion of in vivo fibrogenesis by novel chromone scaffolds
title_full Reversion of in vivo fibrogenesis by novel chromone scaffolds
title_fullStr Reversion of in vivo fibrogenesis by novel chromone scaffolds
title_full_unstemmed Reversion of in vivo fibrogenesis by novel chromone scaffolds
title_short Reversion of in vivo fibrogenesis by novel chromone scaffolds
title_sort reversion of in vivo fibrogenesis by novel chromone scaffolds
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355727/
https://www.ncbi.nlm.nih.gov/pubmed/30611717
http://dx.doi.org/10.1016/j.ebiom.2018.12.017
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