Lck inhibition attenuate lung fibrosis by suppressing Treg activity
Kagawa, Kozo Tokushima University
Sato, Seidai Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Koyama, Kazuya Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Imakura, Takeshi Tokushima University
Murakami, Kojin Tokushima University
Yamashita, Yuya Tokushima University
Naito, Nobuhito Tokushima University Tokushima University Educator and Researcher Directory
Ogawa, Hirohisa Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Kawano, Hiroshi Tokushima University Tokushima University Educator and Researcher Directory
Idiopathic pulmonary fibrosis
Lymphocyte-specific protein tyrosine kinase
Thesis or Dissertation
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).
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.
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.
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.
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.
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k3764_abstract.pdf 176 KB
k3764_review.pdf 99.8 KB
k3764_fulltext.pdf 1.55 MB
|MEXT report number
Doctor of Medical Science