Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
National Hospital Organization Higashi Tokushima Medical Center, Tokushima, Japan.
Respir Res. 2017 Sep 15;18(1):172. doi: 10.1186/s12931-017-0654-2.
Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear.
Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin.
Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects.
These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.
尼达尼布是一种针对血小板衍生生长因子受体（PDGFR）、成纤维细胞生长因子受体（FGFR）和血管内皮生长因子受体（VEGFR）的酪氨酸激酶抑制剂，最近已被批准用于特发性肺纤维化。纤维细胞是骨髓来源的祖细胞，可产生生长因子并促进肺部纤维化。然而，尼达尼布对纤维细胞功能的影响尚不清楚。
从健康志愿者的外周血中分离人单核细胞。使用 ELISA 和 Western blot 分析纤维细胞中生长因子及其受体的表达。从增殖的角度研究尼达尼布对纤维细胞刺激肺成纤维细胞能力的影响。还评估了尼达尼布对纤维细胞分化和迁移的直接作用。我们研究了尼达尼布是否影响博来霉素处理的小鼠肺部纤维细胞的积累。
人纤维细胞产生 PDGF、FGF2 和 VEGF-A。尼达尼布和每个生长因子受体的特异性抑制剂显著抑制了纤维细胞上清液刺激的肺成纤维细胞的增殖。尼达尼布抑制了体外生长因子诱导的纤维细胞迁移和分化。尼达尼布给药减少了博来霉素诱导的肺纤维化模型中的纤维细胞数量，这与抗纤维化作用有关。
这些结果支持纤维细胞作为生长因子的产生者和应答者的作用，并表明尼达尼布的抗纤维化作用至少部分是通过抑制纤维细胞功能介导的。
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