Inhibition of Plasminogen Activator Inhibitor- 1 Attenuates Transforming Growth Factor- β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts
PLoS ONE 11 巻 2 号
e0148969- 頁
2016-02-09 発行
アクセス数 : 570 件
ダウンロード数 : 94 件
今月のアクセス数 : 5 件
今月のダウンロード数 : 0 件
この文献の参照には次のURLをご利用ください : https://ir.lib.hiroshima-u.ac.jp/00048654
ファイル情報(添付) |
PLoSONE_e0148969.pdf
8.11 MB
種類 :
全文
|
タイトル ( eng ) |
Inhibition of Plasminogen Activator Inhibitor- 1 Attenuates Transforming Growth Factor- β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts
|
作成者 |
Takayama Yusuke
|
収録物名 |
PLoS ONE
|
巻 | 11 |
号 | 2 |
開始ページ | e0148969 |
抄録 |
Transforming growth factor-β (TGF-β) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin.We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis.
|
言語 |
英語
|
資源タイプ | 学術雑誌論文 |
出版者 |
Public Library of Science
|
発行日 | 2016-02-09 |
権利情報 |
© 2016 Omori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
|
出版タイプ | Version of Record(出版社版。早期公開を含む) |
アクセス権 | オープンアクセス |
収録物識別子 |
[ISSN] 1932-6203
[DOI] 10.1371/journal.pone.0148969
[DOI] https://doi.org/10.1371/journal.pone.0148969
|