Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity

Respiratory Research

Hirohisa Ogawa¹  Hisanori Uehara¹  Hisatsugu Goto²  Yanjuan Chen²  Kazuya Koyama²  Hiroyasu Okazaki²  Yoshinori Aono²  Shuichi Abe²  Seidai Sato²  Yuko Toyoda²  Hiroshi Kawano²  Shinya Hayashi²  Haruka Nishimura²  Yasuhiko Nishioka²  Shintaro Shinohara²  Shun Morizumi² 

[1] Department of Pathology and Laboratory Medicine, Graduate School of Health Biosciences, Tokushima University;Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University;

关键词: Fibrocytes;    Nintedanib;    Pulmonary fibrosis;   

DOI  :  10.1186/s12931-017-0654-2

来源: DOAJ

【 摘 要 】

Abstract Background 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. Methods 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. Results 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. Conclusions 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.

【 授权许可】

Unknown