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ID 48654
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著者
Omori, Keitaro 大学院医歯薬保健学研究院(医) 広大研究者総覧
Hattori, Noboru 大学院医歯薬保健学研究院(医) 広大研究者総覧
Senoo, Tadashi 大学院医歯薬保健学研究院(医)
Takayama, Yusuke 大学院医歯薬保健学研究院
Masuda, Takeshi 大学院医歯薬保健学研究院(医) 広大研究者総覧
Nakashima, Taku 大学院医歯薬保健学研究院(医) 広大研究者総覧
Iwamoto, Hiroshi 大学院医歯薬保健学研究院(医) 広大研究者総覧
Fujitaka, Kazunori 大学院医歯薬保健学研究院(医) 広大研究者総覧
Hamada, Hironobu 大学院医歯薬保健学研究科(保) 広大研究者総覧
Kohno, Nobuoki 大学院医歯薬保健学研究院(医)
抄録(英)
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.
掲載誌名
PLoS ONE
11巻
2号
開始ページ
e0148969
出版年月日
2016-02-09
出版者
Public Library of Science
ISSN
1932-6203
出版者DOI
言語
英語
NII資源タイプ
学術雑誌論文
広大資料タイプ
学術雑誌論文
DCMIタイプ
text
フォーマット
application/pdf
著者版フラグ
publisher
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.
関連情報URL
部局名
医歯薬保健学研究科