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The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice.
Koyama, Kazuya; Goto, Hisatsugu; Morizumi, Shun; Kagawa, Kozo; Nishimura, Haruka; Sato, Seidai; Kawano, Hiroshi; Toyoda, Yuko; Ogawa, Hirohisa; Homma, Sakae; Nishioka, Yasuhiko.
Afiliação
  • Koyama K; 1 Department of Respiratory Medicine and Rheumatology and.
  • Goto H; 2 Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.
  • Morizumi S; 1 Department of Respiratory Medicine and Rheumatology and.
  • Kagawa K; 1 Department of Respiratory Medicine and Rheumatology and.
  • Nishimura H; 1 Department of Respiratory Medicine and Rheumatology and.
  • Sato S; 1 Department of Respiratory Medicine and Rheumatology and.
  • Kawano H; 1 Department of Respiratory Medicine and Rheumatology and.
  • Toyoda Y; 1 Department of Respiratory Medicine and Rheumatology and.
  • Ogawa H; 1 Department of Respiratory Medicine and Rheumatology and.
  • Homma S; 3 Department of Molecular and Environmental Pathology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; and.
  • Nishioka Y; 2 Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.
Am J Respir Cell Mol Biol ; 60(4): 478-487, 2019 04.
Article em En | MEDLINE | ID: mdl-30540913
The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Pulmonar / Quinolinas / Tioureia / Receptores do Fator de Crescimento Derivado de Plaquetas / Receptor de Fator Estimulador de Colônias de Macrófagos / Inibidores de Proteínas Quinases Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Am J Respir Cell Mol Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibrose Pulmonar / Quinolinas / Tioureia / Receptores do Fator de Crescimento Derivado de Plaquetas / Receptor de Fator Estimulador de Colônias de Macrófagos / Inibidores de Proteínas Quinases Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Am J Respir Cell Mol Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos