酪氨酸激酶抑制剂TAS-115可减轻博来霉素诱导的小鼠肺纤维化。,American Journal of Respiratory Cell and Molecular Biology

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酪氨酸激酶抑制剂TAS-115可减轻博来霉素诱导的小鼠肺纤维化。
American Journal of Respiratory Cell and Molecular Biology ( IF 5.9 ) Pub Date : 2019-04-01 , DOI: 10.1165/rcmb.2018-0098oc
Kazuya Koyama _{1,

2} , Hisatsugu Goto ₁ , Shun Morizumi ₁ , Kozo Kagawa ₁ , Haruka Nishimura ₁ , Seidai Sato ₁ , Hiroshi Kawano ₁ , Yuko Toyoda ₁ , Hirohisa Ogawa ₃ , Sakae Homma ₂ , Yasuhiko Nishioka ₁

Affiliation

包括血小板衍生的生长因子在内的生长因子的信号通路可以被认为是克服特发性肺纤维化预后不良的具体靶标。最近批准的多种激酶抑制剂Nintedanib对特发性肺纤维化患者显示出有希望的抗纤维化作用。但是，其功效仍然有限，并且在某些情况下，由于诸如胃肠道疾病的毒性，必须中止治疗。因此，仍然需要毒性更低的更有效的药物。TAS-115是一种新型的多酪氨酸激酶抑制剂，除其他分子外，它还优选靶向血小板衍生的生长因子受体（PDGFR），血管内皮生长因子受体和c-FMS。在这个研究中，我们评估了TAS-115在体外和体内对肺纤维化的抗纤维化作用。TAS-115抑制人肺成纤维细胞系MRC-5细胞上PDGFR的磷酸化，并抑制其血小板衍生的生长因子诱导的增殖和迁移。此外，TAS-115在巨噬细胞集落的刺激下，抑制了小鼠骨髓来源的巨噬细胞中c-FMS的磷酸化，巨噬细胞集落刺激因子的受体，并降低了CCL2的产生，CCL2是另一种诱导肺纤维化的关键分子。 -刺激因子。重要的是，TAS-115对PDGFR和c-FMS的抑制作用比nintedanib高3到10倍。在博来霉素诱导的肺纤维化的小鼠模型中，TAS-115显着抑制博来霉素处理过的肺中肺纤维化的发展和胶原蛋白的沉积。这些数据表明，TAS-115对PDGFR和c-FMS的强烈抑制可能是克服肺纤维化难治性发病机制的一种有前途的策略。

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The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice.

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.

更新日期：2019-11-01

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