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ID 118786
タイトル別表記
リンパ球特異的タンパク質チロシンキナーゼ特異的阻害剤A-770041は、制御性T細胞におけるTGF-β産生の抑制を介して肺線維症の進行を抑制する。
Lck inhibition attenuate lung fibrosis by suppressing Treg activity
著者
香川, 耕造 徳島大学大学院医学研究科(医学専攻) 徳島大学 教育研究者総覧
Imakura, Takeshi Tokushima University
Murakami, Kojin Tokushima University
山下, 雄也 Tokushima University
キーワード
Idiopathic pulmonary fibrosis
Lymphocyte-specific protein tyrosine kinase
TGF-β
Regulatory T-cells
資料タイプ
学位論文
抄録
Background
Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of Tcells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-β1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs).
Methods
Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-β in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay.
Results
A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-β in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-β1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-β in the supernatant.
Conclusions
These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.
掲載誌名
PLOS ONE
ISSN
19326203
出版者
PLOS
17
10
開始ページ
e0275987
発行日
2022-10-27
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Kozo Kagawa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。
権利情報
This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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3764号
学位記番号
甲医第1589号
学位授与年月日
2023-11-24
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院