ID | 113984 |
タイトル別表記 | ブレオマイシン肺線維症マウスに対するWnt/βカテニン/CBPシグナル新規阻害薬PRI-724の抗線維化効果
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著者 |
岡﨑, 弘泰
徳島大学大学院医科学教育部(医学専攻)
森住, 俊
Tokushima University
Abe, Shuichi
Tokushima University
Chen, Yajuan
Tokushima University
Nishimura, Haruka
Tokushima University
Kouji, Hiroyuki
PRISM BioLab Co., Ltd.|Oita University
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キーワード | Wnt/β-catenin/CBP signaling
idiopathic pulmonary fibrosis
Alveolar macrophage
PRI-724
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資料タイプ |
学位論文
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抄録 | Purpose/Aim of the Study: Wnt/β-catenin signaling was reported to be activated in pulmonary fibrosis, and was focused on as a target for antifibrotic therapy. However, the mechanism how the inhibition of Wnt/β-catenin signaling ameliorate pulmonary fibrosis has not been fully elucidated. The purpose of this study is to explore the target cells of Wnt/β-catenin inhibition in pulmonary fibrosis and to examine the antifibrotic effect of the novel inhibitor PRI-724 specifically disrupting the interaction of β-catenin and CBP.
Materials and Methods: The effect of C-82, an active metabolite of PRI-724, on the expression of TGF-β1 and α-smooth muscle actin (SMA) was examined on fibroblasts and macrophages. We also examined the effects of PRI-724 in mouse model of bleomycin-induced pulmonary fibrosis. Results: The activation and increased accumulation of β-catenin in the canonical pathway were detected in lung fibroblasts as well as macrophages stimulated by Wnt3a using Western blotting. Treatment with C-82 reduced CBP protein and increased p300 protein binding to β-catenin in the nucleus of lung fibroblasts. In addition, C-82 inhibited the expression of SMA in lung fibroblasts treated with TGF-β, indicating the inhibition of myofibroblast differentiation. In the fibrotic lungs induced by bleomycin, β-catenin was stained strongly in macrophages, but the staining of β-catenin in alveolar epithelial cells and fibroblasts was weak. The administration of PRI-724 ameliorated pulmonary fibrosis induced by bleomycin in mice when administered with a late, but not an early, treatment schedule. Analysis of bronchoalveolar fluid (BALF) showed a decreased number of alveolar macrophages. In addition, the level of TGF-β1 in BALF was decreased in mice treated with PRI-724. C-82 also inhibited the production of TGF-β1 by alveolar macrophages. Conclusions: These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs. |
掲載誌名 |
Experimental Lung Research
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ISSN | 01902148
15210499
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cat書誌ID | AA00181680
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出版者 | Taylor & Francis
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巻 | 45
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号 | 7
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開始ページ | 188
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終了ページ | 199
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発行日 | 2019-07-12
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備考 | 内容要旨・審査要旨・論文本文の公開
本論文は,著者Hiroyasu Okazakiの学位論文として提出され,学位審査・授与の対象となっている。 This is an Accepted Manuscript of an article published by Taylor & Francis in Experimental Lung Research on 12/07/2019, available online: http://www.tandfonline.com/10.1080/01902148.2019.1638466 |
EDB ID | |
出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
博士論文全文を含む
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文科省報告番号 | 甲第3338号
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学位記番号 | 甲医第1431号
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学位授与年月日 | 2019-10-24
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学位名 |
博士(医学)
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学位授与機関 |
徳島大学
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部局 |
病院
医学系
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