The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice

• Material Type: 博士論文
• ISSN: 0190-2148
• Title: The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice
• Volume: 45 7
• Author/Editor: Okazaki, Hiroyasu; Sato, Seidai; Koyama, Kazuya; Morizumi, Shun; Abe, Shuichi; Azuma, Momoyo; Chen, Yajuan; Goto, Hisatsugu; Aono, Yoshinori; Ogawa, Hirohisa; Kagawa, Kozo; Nishimura, Haruka; Kawano, Hiroshi; Toyoda, Yuko; Uehara, Hisanori; Kouji, Hiroyuki; Nishioka, Yasuhiko
• Author Heading: Okazaki, Hiroyasu; Sato, Seidai; Koyama, Kazuya; Morizumi, Shun; Abe, Shuichi; Azuma, Momoyo; Chen, Yajuan; Goto, Hisatsugu; Aono, Yoshinori; Ogawa, Hirohisa; Kagawa, Kozo; Nishimura, Haruka; Kawano, Hiroshi; Toyoda, Yuko; Uehara, Hisanori; Kouji, Hiroyuki; Nishioka, Yasuhiko
• Publication, Distribution, etc.: Taylor & Francis
• Publication Date: 2019-07-12
• Publication Date (W3CDTF): 2019-07-12
• Alternative Title: 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
• Periodical title: Experimental Lung Research
• Degree grantor/type: 徳島大学
• Date Granted: 2019-10-24
• Date Granted (W3CDTF): 2019-10-24
• Dissertation Number: 甲第3338号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第3338号
• Text Language Code: eng
• Subject Heading: Wnt/β-catenin/CBP signaling; idiopathic pulmonary fibrosis; Alveolar macrophage; PRI-724
• Target Audience: 一般
• Note (General): 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.
• DOI: info:doi/10.1080/01902148.2019.1638466; https://doi.org/info:doi/10.1080/01902148.2019.1638466
• Persistent ID (NDL): info:ndljp/pid/11525839; https://dl.ndl.go.jp/pid/11525839
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2020-08-11T22:41:34+09:00
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
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• Periodical Title (URI): http://repo.lib.tokushima-u.ac.jp/113984
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp