Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis

Abstract

BackgroundRecent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling is detrimental. Exogenous ligands Fibroblast Growth Factor (FGF) 7 and 10 improve murine lung repair and increase survival after injury via tyrosine kinase FGF receptor 2b-signaling. Therefore, the level and location of FGF/FGFR expression as well as the exogenous effect of the most highly expressed FGFR2b ligand, FGF1, was analyzed on human lung fibroblasts.MethodsFGF ligand and receptor expression was evaluated in donor and IPF whole lung homogenates using western blotting and qPCR. Immunohistochemistry for FGF1 and FGFR1/2/3/4 were performed on human lung tissue. Lastly, the effects of FGF1, a potent, multi-FGFR ligand, were studied on primary cultures of IPF and non-IPF donor fibroblasts. Western blots for pro-fibrotic markers, proliferation, FACS for apoptosis, transwell assays and MetaMorph analyses on cell cultures were performed.ResultsWhole lung homogenate analyses revealed decreased FGFR b-isoform expression, and an increase in FGFR c-isoform expression. Of the FGFR2b-ligands, FGF1 was the most significantly increased in IPF patients; downstream targets of FGF-signaling, p-ERK1/2 and p-AKT were also increased. Immunohistochemistry revealed FGF1 co-localization within basal cell sheets, myofibroblast foci, and Surfactant protein-C positive alveolar epithelial type-II cells as well as co-localization with FGFR1, FGFR2, FGFR3, FGFR4 and myofibroblasts expressing the migratory marker Fascin. Both alone and in the presence of heparin, FGF1 led to increased MAPK-signaling in primary lung fibroblasts. While smooth muscle actin was unchanged, heparin + FGF1 decreased collagen production in IPF fibroblasts. In addition, FGF1 + heparin increased apoptosis and cell migration. The FGFR inhibitor (PD173074) attenuated these effects.ConclusionsStrong expression of FGF1/FGFRs in pathogenic regions of IPF suggest that aberrant FGF1-FGFR signaling is increased in IPF patients and may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0242-2) contains supplementary material, which is available to authorized users.

Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis

“…Interestingly, in this study, FGFR1/2IIIb receptor levels were decreased, while FGFR1/2/3IIIc levels were increased in IPF lungs, indicating that FGF‐1/FGFR c‐isoform signalling is predominant in IPF . Furthermore, IPF lung fibroblasts treated with FGF‐1 plus heparin displayed decreased collagen production with increased apoptosis and cell migration but showed no change in proliferation or α‐smooth muscle actin (α‐SMA) expression . Previous studies, including our own, show strong evidence suggesting that FGF‐1 has an anti‐fibrotic role.…”

“…A recent study showed the increased expression of FGF‐1 in the lungs of IPF patients compared with non‐fibrotic lung. Interestingly, in this study, FGFR1/2IIIb receptor levels were decreased, while FGFR1/2/3IIIc levels were increased in IPF lungs, indicating that FGF‐1/FGFR c‐isoform signalling is predominant in IPF . Furthermore, IPF lung fibroblasts treated with FGF‐1 plus heparin displayed decreased collagen production with increased apoptosis and cell migration but showed no change in proliferation or α‐smooth muscle actin (α‐SMA) expression .…”

Vocal cord inflammatory myofibroblastic tumor with mucoid deposits harboring TIMP3–ALK fusion: A potential diagnostic pitfall

“…Among these markers, the tumor cells were positive only for fascin. Fascin is not a specific marker of stellate cells because it is highly expressed in neurons and dendritic cells and has been shown in myofibroblasts . Therefore, there is a possibility that the presented tumor was an ALK ‐rearranged stellate cell tumor; however, we could not confirm this hypothesis.…”

Study on the Association between the Fibroblast Growth Factor Receptor 4 Expression and High-Risk Human Papillomavirus Infection in Cervical Cancer and Precancerous Lesions

“…However, this disease development process was regulated by multiple genes and factors after high-risk HPV infection. As a member of the fibroblast growth factor receptor (FGFR) family, FGFR4 was a primary factor in the repairing and proliferation of fibroblasts, endothelial cells, and smooth muscle cells [6,7], so it could be speculated that FGFR4 may participate in the process of cervical cancer after HPV infection. Many researches showed that FGFR4 was overexpressed in multiple human tumor tissues, and especially was closely related with the incidence and development of nasopharynx cancer, colorectal cancer, and other mucosal malignant tumors [8,9].…”