Abstract
The soluble ectodomain of fibroblast growth factor receptor-IIIc (sFGFR2c) is able to bind to fibroblast growth factor (FGF) ligands and block the activation of the FGF-signaling pathway. In this study, sFGFR2c inhibited lung fibrosis dramatically in vitro and in vivo. The upregulation of α-smooth muscle actin (α-SMA) in fibroblasts by transforming growth factor-β1 (TGF-β1) is an important step in the process of lung fibrosis, in which FGF-2, released by TGF-β1, is involved. sFGFR2c inhibited α-SMA induction by TGF-β1 via both the extracellular signal-regulated kinase 1/2 (ERK1/2) and Smad3 pathways in primary mouse lung fibroblasts and the proliferation of mouse lung fibroblasts. In a mouse model of bleomycin (BLM)-induced lung fibrosis, mice were treated with sFGFR2c from d 3 or d 10 to 31 after BLM administration. Then we used hematoxylin and eosin staining, Masson staining and immunohistochemical staining to evaluate the inhibitory effects of sFGFR2c on lung fibrosis. The treatment with sFGFR2c resulted in significant attenuation of the lung fibrosis score and collagen deposition. The expression levels of α-SMA, p-FGFRs, p-ERK1/2 and p-Smad3 in the lungs of sFGFR2c-treated mice were markedly lower. sFGFR2c may have potential for the treatment of lung fibrosis as an FGF-2 antagonist.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and lethal lung disorder of unknown etiology
Binding of sFGFR2c to fibroblast growth factor (FGF)-2 as Detected by SPR
The binding of sFGFR2c to fibroblast growth factor-2 (FGF-2) was measured by SPR (Figure 1A)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and lethal lung disorder of unknown etiology. IPF involves extracellular matrix (ECM) remodeling and deposition, collagen accumulation and fibroblast destruction [1]. Myofibroblasts are generally considered to be key effector cells in the development of fibrosis [2,3], the hallmark of which is the expression of α-smooth muscle actin (α-SMA). The polypeptide mediators and growth factors believed to be pivotal for fibrosis include transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor, connective tissue growth factor (CTGF), insulin-like growth factor, epi-. In addition to α-SMA, TGF-β induces key markers and effectors of myofibroblast differentiation, including CTGF (CCN2). CTGF is a common target for both TGF-β and ET-1 [12] and is an important mediator of ECM deposition [13]
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