ID 113984
Title Alternative
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
Author
Okazaki, Hiroyasu Tokushima University
Koyama, Kazuya Tokushima University
Morizumi, Shun Tokushima University
Abe, Shuichi Tokushima University
Chen, Yajuan Tokushima University
Aono, Yoshinori Tokushima University|Higashi Tokushima Medical Center KAKEN Search Researchers
Kagawa, Kozo Tokushima University
Nishimura, Haruka Tokushima University
Kouji, Hiroyuki PRISM BioLab Co., Ltd.|Oita University
Keywords
Wnt/β-catenin/CBP signaling
idiopathic pulmonary fibrosis
Alveolar macrophage
PRI-724
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Experimental Lung Research
ISSN
01902148
15210499
NCID
AA00181680
Publisher
Taylor & Francis
Volume
45
Issue
7
Start Page
188
End Page
199
Published Date
2019-07-12
Remark
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。
論文本文は2020-07-12以降公開予定
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
その他
MEXT report number
甲第3338号
Diploma Number
甲医第1431号
Granted Date
2019-10-24
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences