Reversion of in vivo fibrogenesis by novel chromone scaffolds

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)484-496
Number of pages13
JournalEBioMedicine
Volume39
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Chromones
Scaffolds
Idiopathic Pulmonary Fibrosis
Myofibroblasts
Lung
Fibrosis
Bleomycin
Pharmaceutical Preparations
Epithelial Cells
Military electronic countermeasures
eupatilin
Hepatic Stellate Cells
Depolymerization
Phosphorylation
Proteome
Fibroblasts
Therapeutics
Gene expression
Lung Diseases
Actins

Keywords

  • Chromone scaffold
  • Dedifferentiation
  • Epithelial–mesenchymal transition
  • Idiopathic pulmonary fibrosis
  • Myofibroblasts
  • Stem cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kim, H. S., Yoon, Y. M., Meang, M. K., Park, Y. E., Lee, J. Y., Lee, T. H., ... Youn, B. S. (2019). Reversion of in vivo fibrogenesis by novel chromone scaffolds. EBioMedicine, 39, 484-496. https://doi.org/10.1016/j.ebiom.2018.12.017

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.

In: EBioMedicine, Vol. 39, 01.01.2019, p. 484-496.

Research output: Contribution to journalArticle

Kim, HS, Yoon, YM, Meang, MK, Park, YE, Lee, JY, Lee, TH, Lee, JE, Kim, IH & Youn, BS 2019, 'Reversion of in vivo fibrogenesis by novel chromone scaffolds', EBioMedicine, vol. 39, pp. 484-496. https://doi.org/10.1016/j.ebiom.2018.12.017
Kim HS, Yoon YM, Meang MK, Park YE, Lee JY, Lee TH et al. Reversion of in vivo fibrogenesis by novel chromone scaffolds. EBioMedicine. 2019 Jan 1;39:484-496. https://doi.org/10.1016/j.ebiom.2018.12.017
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. In: EBioMedicine. 2019 ; Vol. 39. pp. 484-496.
@article{3d3e1af1850547bf82b8346054e7528b,
title = "Reversion of in vivo fibrogenesis by novel chromone scaffolds",
abstract = "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, Dedifferentiation, Epithelial–mesenchymal transition, Idiopathic pulmonary fibrosis, Myofibroblasts, Stem cells",
author = "Kim, {Han Soo} and Yoon, {Young Min} and Meang, {Moon Kee} and Park, {Yae Eun} and Lee, {Ji Yong} and Lee, {Tae Hee} and Lee, {Ji Eun} and Kim, {Ik Hwan} and Youn, {Byung Soo}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ebiom.2018.12.017",
language = "English",
volume = "39",
pages = "484--496",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Reversion of in vivo fibrogenesis by novel chromone scaffolds

AU - Kim, Han Soo

AU - Yoon, Young Min

AU - Meang, Moon Kee

AU - Park, Yae Eun

AU - Lee, Ji Yong

AU - Lee, Tae Hee

AU - Lee, Ji Eun

AU - Kim, Ik Hwan

AU - Youn, Byung Soo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Chromone scaffold

KW - Dedifferentiation

KW - Epithelial–mesenchymal transition

KW - Idiopathic pulmonary fibrosis

KW - Myofibroblasts

KW - Stem cells

UR - http://www.scopus.com/inward/record.url?scp=85059308569&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059308569&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2018.12.017

DO - 10.1016/j.ebiom.2018.12.017

M3 - Article

C2 - 30611717

AN - SCOPUS:85059308569

VL - 39

SP - 484

EP - 496

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -