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Background
Platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) 1/2, and vascular endothelial growth factor (VEGF) have been implicated in the pathogenesis of pulmonary fibrosis [1-5]. Nintedanib is a tyrosine kinase inhibitor that is specific also for PDGFR? and ?, FGFR1, 2, and 3, and VEGFR1, 2, and 3 [6-8]. In two phase III clinical trials (INPULSIS 1 and 2), treatment with nintedanib for one year led to reductions in the annual rate of decline in forced vital capacity versus placebo in patients with idiopathic pulmonary fibrosis (IPF) [9]. However, the mechanisms by which nintedanib regulates pulmonary fibrosis is not fully explored. Several studies have reported the anti-fibrotic effects of BIBF 1000 [10], and nintedanib (BIBF1120) [7, 11]. However, the roles of main targets, PDGFR, FGFR and VEGFR of nintedanib have not yet been analyzed in detail.
Fibrocytes are monocyte-derived cells that are a subpopulation of mesenchymal progenitor cells [12]. Fibrocytes appear to be derived from the differentiation of CD14-positive peripheral blood mononuclear cells, and express markers of hematopoietic cells, leukocytes, and fibroblast products [12, 13]. Marked increases in circulating fibrocyte numbers and a positive correlation between the abundance of fibroblastic foci and the number of lung fibrocytes have been reported in patients with IPF [14, 15]. Moeller et al. also showed that the percentage of CD45/collagen-1-positive fibrocytes was increased in the peripheral blood of patients with IPF, and proposed that the quantification of circulating fibrocytes may allow for the prediction of early mortality in these patients [16]. These findings strongly suggest that fibrocytes are involved in the pathogenesis of pulmonary fibrosis. Furthermore, we previously indicated that the PDGF signaling pathway, which is a potential target for nintedanib, plays a critical role in fibrocyte migration into fibrotic lungs and contributes to fibrogenesis [17]. We also demonstrated that fibrocytes play a role in the pathogenesis of pulmonary fibrosis by producing various growth factors [18] (Abe S, et al. manuscript in preparation). However, the effects of nintedanib on fibrocytes remain unclear.
Therefore, we herein focus on fibrocytes and discuss several rationales for the anti-fibrotic properties of nintedanib. We assess the effects of nintedanib on the proliferation of fibroblasts induced by fibrocytes, the differentiation of fibrocytes from monocytes, and the migration of fibrocytes. We show that nintedanib reduces...