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Novel Multi-Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice
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A2664 - Novel Multi-Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice
Author Block: K. Koyama1, K. Kagawa1, H. Nishimura1, H. Kawano1, Y. Toyoda1, H. Goto1, H. Ogawa2, H. Uehara2, Y. Nishioka1; 1Departments of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan, 2Departments of Molecular and Environmental Pathology, Tokushima University, Tokushima, Japan.
Rationale:
After the recent approval of nintedanib, the PDGFR/FGFR/VEGFR inhibitor, the approach to inhibit multiple kinases became to be recognized as one of the promising options in overcoming the poor prognosis of idiopathic pulmonary fibrosis (IPF). TAS-115 is a novel multiple tyrosine kinase inhibitor that targets VEGFR, MET, FMS and PDGFR. The preferable inhibition of FMS and PDGFR by TAS-115 suggests that it might suppress the activity of fibroblasts and fibrocytes, and thus prevent the accumulation of extracellular matrix. In the present study, we evaluated the anti-fibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo.
Methods:
The inhibitory effect of TAS-115 on the phosphorylation of PDGFR or FMS in human lung fibroblast cell line MRC5 or murine bone marrow derived macrophages (BMDMs) was examined by immunoblotting. The proliferation and migration of fibroblasts was investigated by the 3H-thymidine incorporation assay and the trans-well migration assay, respectively. The in vivo anti-fibrotic effect of TAS-115 was assessed by Ashcroft scoring and hydroxyproline assay in the mouse model of bleomycin-induced pulmonary fibrosis.
Results:
TAS-115 inhibited the phosphorylation of PDFR on MRC5 cells, and suppressed the PDGF-induced proliferation and migration of these cells. Moreover, TAS-115 inhibited the phosphorylation of FMS in murine BMDMs, and decreased the production of CCL2, which is the one of the chemoattractants for fibrocytes, under the stimulation of FMS with its ligand MCSF. Importantly, the concentration of TAS-115 to express these inhibitory effects was 10nM, which was lower than that of nintedanib. In the mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 treatment significantly decreased the Aschcroft score and the hydroxyproline content in the lungs, suggesting that TAS-115 attenuated the pulmonary fibrosis in vivo.
Conclusion:
TAS-115 suppressed pulmonary fibrosis by the strong inhibition of PDGFR and FMS. TAS-115 may be a promising anti-fibrotic agent against IPF.
Author Block: K. Koyama1, K. Kagawa1, H. Nishimura1, H. Kawano1, Y. Toyoda1, H. Goto1, H. Ogawa2, H. Uehara2, Y. Nishioka1; 1Departments of Respiratory Medicine and Rheumatology, Tokushima University, Tokushima, Japan, 2Departments of Molecular and Environmental Pathology, Tokushima University, Tokushima, Japan.
Rationale:
After the recent approval of nintedanib, the PDGFR/FGFR/VEGFR inhibitor, the approach to inhibit multiple kinases became to be recognized as one of the promising options in overcoming the poor prognosis of idiopathic pulmonary fibrosis (IPF). TAS-115 is a novel multiple tyrosine kinase inhibitor that targets VEGFR, MET, FMS and PDGFR. The preferable inhibition of FMS and PDGFR by TAS-115 suggests that it might suppress the activity of fibroblasts and fibrocytes, and thus prevent the accumulation of extracellular matrix. In the present study, we evaluated the anti-fibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo.
Methods:
The inhibitory effect of TAS-115 on the phosphorylation of PDGFR or FMS in human lung fibroblast cell line MRC5 or murine bone marrow derived macrophages (BMDMs) was examined by immunoblotting. The proliferation and migration of fibroblasts was investigated by the 3H-thymidine incorporation assay and the trans-well migration assay, respectively. The in vivo anti-fibrotic effect of TAS-115 was assessed by Ashcroft scoring and hydroxyproline assay in the mouse model of bleomycin-induced pulmonary fibrosis.
Results:
TAS-115 inhibited the phosphorylation of PDFR on MRC5 cells, and suppressed the PDGF-induced proliferation and migration of these cells. Moreover, TAS-115 inhibited the phosphorylation of FMS in murine BMDMs, and decreased the production of CCL2, which is the one of the chemoattractants for fibrocytes, under the stimulation of FMS with its ligand MCSF. Importantly, the concentration of TAS-115 to express these inhibitory effects was 10nM, which was lower than that of nintedanib. In the mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 treatment significantly decreased the Aschcroft score and the hydroxyproline content in the lungs, suggesting that TAS-115 attenuated the pulmonary fibrosis in vivo.
Conclusion:
TAS-115 suppressed pulmonary fibrosis by the strong inhibition of PDGFR and FMS. TAS-115 may be a promising anti-fibrotic agent against IPF.
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