Dataset Information

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-?. 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-?. No such induction of the in vitro transdifferantiation was observed in TGF-? treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-? complex, specifically by eliminating expression of the latent TGF-? binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-?. Eupatilin attenuated phosphorylation of Smad3 by TGF-?. 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.

SUBMITTER: Kim HS

PROVIDER: S-EPMC6355727 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reversion of in vivo fibrogenesis by novel chromone scaffolds.

Kim Han-Soo HS Yoon Young-Min YM Meang Moon Kee MK Park Yae Eun YE Lee Ji Yong JY Lee Tae Hee TH Lee Ji Eun JE Kim Ik-Hwan IH Youn Byung-Soo BS

EBioMedicine 20190102

<h4>Background</h4>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.<h4>Methods</h4>A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-β. Eupatilin w ...[more]

PMID: 30611717

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Dataset Information

Reversion of in vivo fibrogenesis by novel chromone scaffolds.

Background

Methods

Findings

Interpretation

Publications

Reversion of in vivo fibrogenesis by novel chromone scaffolds.

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