Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive pulmonary scarring, decline in lung function, and often results in death within 3-5 five years after diagnosis. Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of IPF; however, the mechanism through which FGF signaling contributes to pulmonary fibrosis remains unclear. We hypothesized that FGF receptor (FGFR) signaling in fibroblasts is required for the fibrotic response to bleomycin. To test this, mice with mesenchyme-specific tamoxifen-inducible inactivation of FGF receptors 1, 2, and 3 (α mice) were lineage labeled and administered intratracheal bleomycin. Lungs were collected for histologic analysis, whole lung RNA and protein, and dissociated for flow cytometry and FACS. Bleomycin-treated α mice have decreased pulmonary fibrosis, collagen production, and fewer α-smooth muscle actin-positive (αSMA+) myofibroblasts compared with controls. Freshly isolated α mesenchymal cells from bleomycin-treated mice have decreased collagen expression compared with wild type mesenchymal cells. Furthermore, lineage labeled FGFR-deficient fibroblasts have decreased enrichment in fibrotic areas and decreased proliferation. These data identify a cell autonomous requirement for mesenchymal FGFR signaling in the development of pulmonary fibrosis, and for the enrichment of the αpositive (α+) mesenchymal lineage in fibrotic tissue following bleomycin exposure. We conclude that mesenchymal FGF signaling is required for the development of pulmonary fibrosis, and that therapeutic strategies aimed directly at mesenchymal FGF signaling could be beneficial in the treatment of IPF.

A new FGFR inhibitor disrupts the TGF‐β1‐induced fibrotic process

“…[25][26][27] FGFs are associated with the pathogenesis of PF, and FGF2-neutralizing antibodies successfully inhibit the TGF-β1-mediated fibrotic process. 20 It has been also reported that FGF-2 and FGFR1IIIc are involved in EMT and advanced cancer progression, which may be regulated by TGF-β1 autonomously secreted from cancer cells. 25,28 Moreover,…”

“…In agreement with these observations, administration of TGF‐β1 to CCD18‐Lu fibroblasts increased the phosphorylation of FGFR3 and FGFR1, accompanied by induction of ECM proteins in this study. Although all FGFR1‐4 were expressed in freshly isolated lung mesenchyme, only FGFR1 was expressed when isolated fibroblasts are cultured . In addition, low expression levels of FGFR3 and FGFR4 in cultured lung fibroblasts was also reported .…”

“…were expressed in freshly isolated lung mesenchyme, only FGFR1 was expressed when isolated fibroblasts are cultured. 20 In addition, low expression levels of FGFR3 and FGFR4 in cultured lung fibroblasts was also reported. 34 Therefore, we cautiously propose that although the inhibitory activity of IM-1918 on FGFR3 was about two-fold higher than on FGFR1, FGFR1 expression in lung fibroblasts was much higher than that of FGFR3, allowing clear exhibi- Recently, an important study showed that the relative amounts of FGF-2 and TGF-β determine the invasive potential by FGFR substrate (FRS2) regulation in medulloblastoma.…”

The effects of atorvastatin on the kidney injury in mice with pulmonary fibrosis

“…Intratracheal BLM instillation caused the generation of oxidative stress as well as the injuries of alveolar epithelial and mesenchymal cells within the lung of murines. And then, oxidative stress mediated inflammatory reactions and the releasing of interleukin‐1, macrophage inflammatory protein‐1, fibroblast growth factor (FGF), platelet‐derived growth factor (PDGF), connective tissue growth factor (CTGF) and transforming growth factor‐beta (TGF‐β) from pulmonary epithelial and mesenchymal cells, and alveolar macrophages . These cytokines and growth factors generated PF, by the regulation of the fibroblast/myofibroblast proliferation, the myofibroblast differentiation, the production and releasing of ECM components from fibroblast/myofibroblast and their accumulation in ECM…”

“…And then, oxidative stress mediated inflammatory reactions and the releasing of interleukin-1, macrophage inflammatory protein-1, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF) and transforming growth factor-beta (TGF-b) from pulmonary epithelial and mesenchymal cells, and alveolar macrophages. [13][14][15][16] These cytokines and growth factors generated PF, by the regulation of the fibroblast/myofibroblast proliferation, the myofibroblast differentiation, the production and releasing of ECM components from fibroblast/myofibroblast and their accumulation in ECM. [17] There are mutual relationships between the lungs and the kidneys in both health and disease.…”