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Antifibrotic Effects of Focal Adhesion Kinase Inhibitor in Bleomycin-induced induced Pulmonary Fibrosis in Mice

Kinoshita, Katsuhiro and Aono, Yoshinori and Azuma, Momoyo and Kishi, Jun and Takezaki, Akio and Kishi, Masami and Makino, Hideki and Okazaki, Hiroyasu and Uehara, Hisanori and Izumi, Keisuke and Sone, Saburo and Nishioka, Yasuhiko (2013) Antifibrotic Effects of Focal Adhesion Kinase Inhibitor in Bleomycin-induced induced Pulmonary Fibrosis in Mice. American Journal of Respiratory Cell and Molecular Biology. ISSN 1044-1549

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which involved in various biological functions including cell survival, proliferation, migration and adhesion. FAK is also known to be an essential factor for transforming growth factor-β (TGF-β) to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors including platelet-derived growth factor and insulin-like growth factor-I in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by TGF-β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice, even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis, and it can become a promising target for therapeutic approaches to pulmonary fibrosis.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7807

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