| Item type |
文献 / Documents(1) |
| 公開日 |
2019-11-14 |
| アクセス権 |
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アクセス権 |
open access |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_db06 |
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資源タイプ |
doctoral thesis |
| 出版社版DOI |
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関連識別子 |
https://doi.org/10.1080/01902148.2019.1638466 |
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関連名称 |
10.1080/01902148.2019.1638466 |
| 出版タイプ |
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出版タイプ |
NA |
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出版タイプResource |
http://purl.org/coar/version/c_be7fb7dd8ff6fe43 |
| タイトル |
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タイトル |
The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice |
| タイトル別表記 |
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その他のタイトル |
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 |
| 著者 |
岡﨑, 弘泰
佐藤, 正大
小山, 壱也
森住, 俊
アベ, シュウイチ
東, 桃代
Chen, Yajuan
後東, 久嗣
青野, 純典
小川, 博久
香川, 耕造
ニシムラ, ハルカ
河野, 弘
豊田, 優子
上原, 久典
コウジ, ヒロユキ
西岡, 安彦
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| 抄録 |
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内容記述 |
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. |
| キーワード |
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主題 |
Wnt/β-catenin/CBP signaling |
| キーワード |
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主題 |
idiopathic pulmonary fibrosis |
| キーワード |
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主題 |
Alveolar macrophage |
| キーワード |
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主題 |
PRI-724 |
| 書誌情報 |
en : Experimental Lung Research
巻 45,
号 7,
p. 188-199,
発行日 2019-07-12
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
01902148 |
| 収録物ID |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
15210499 |
| 収録物ID |
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収録物識別子タイプ |
NCID |
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収録物識別子 |
AA00181680 |
| 出版者 |
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出版者 |
Taylor & Francis |
| 備考 |
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値 |
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
学位授与者所属 : 徳島大学大学院医科学教育部（医学専攻） |
| EID |
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識別子 |
355461 |
| 言語 |
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言語 |
eng |
| 報告番号 |
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学位授与番号 |
甲第3338号 |
| 学位記番号 |
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値 |
甲医第1431号 |
| 学位授与年月日 |
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学位授与年月日 |
2019-10-24 |
| 学位名 |
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学位名 |
博士（医学） |
| 学位授与機関 |
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学位授与機関名 |
徳島大学 |
k3338_abstract_review.pdf (181 KB)
