• Han-Soo Kim, Young-Min Yoon, Moon Kee Meang, Yae Eun Park, Ji Yong Lee, Tae Hee Lee, Ji Eun Lee, Ik-Hwan Kim, and Byung-Soo Youn.
• Department 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 Korea.
• EBioMedicine. 2019 Jan 1; 39: 484-496.

BackgroundMyofibroblasts 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.MethodsA 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.FindingsEupatilin 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.InterpretationEupatilin 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.Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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