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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
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
青野, 純典 Tokushima University|Higashi Tokushima Medical Center KAKEN研究者をさがす
Nishimura, Haruka Tokushima University
Kouji, Hiroyuki PRISM BioLab Co., Ltd.|Oita University
キーワード
Wnt/β-catenin/CBP signaling
idiopathic pulmonary fibrosis
Alveolar macrophage
PRI-724
資料タイプ
学位論文
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
ISSN
01902148
15210499
cat書誌ID
AA00181680
出版者
Taylor & Francis
45
7
開始ページ
188
終了ページ
199
発行日
2019-07-12
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
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3338号
学位記番号
甲医第1431号
学位授与年月日
2019-10-24
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系