Abstract
We have developed a strong inhibitor (S252W mutant soluble ectodomain of fibroblast growth factor recptor-2 IIIc, msFGFR2) that binds FGFs strongly and blocks the activation of FGFRs. In vitro, msFGFR2 could inhibit the promoting effect of transforming growth factor (TGF)-β1 on the proliferation of primary lung fibroblasts. In vivo, msFGFR2 alleviated lung fibrosis through inhibiting the expression of α-smooth muscle actin (SMA) and collagen deposit. In Western blotting of the right lung tissues and immunohistochemical assay, we found the level of p-FGFRs, p-mitogen activated protein kinase (MAPK) and p-Smad3 in the mice of bleomycin (BLM) group treated with msFGFR2 was down dramatically compared with the mice of BLM group, which suggested the activations of FGF and TGF-β signals were blocked meanwhile. In summary, msFGFR2 attenuated BLM-induced fibrosis and is an attractive therapeutic candidate for human pulmonary fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Bleomycin
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Blotting, Western
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Cell Proliferation / drug effects
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Collagen / metabolism
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Fibroblast Growth Factors / metabolism*
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Fibroblasts / cytology
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Fibroblasts / drug effects*
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Fibroblasts / metabolism
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Lung / drug effects*
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Lung / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism
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Peptide Fragments / pharmacology
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Peptide Fragments / therapeutic use*
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / prevention & control*
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Receptor, Fibroblast Growth Factor, Type 2 / pharmacology
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Receptor, Fibroblast Growth Factor, Type 2 / therapeutic use*
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Receptors, Fibroblast Growth Factor / metabolism*
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Recombinant Proteins / pharmacology
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Recombinant Proteins / therapeutic use*
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Smad3 Protein / metabolism
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Transforming Growth Factor beta1 / metabolism*
Substances
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Actins
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Peptide Fragments
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Receptors, Fibroblast Growth Factor
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Recombinant Proteins
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta1
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msFGFR2 protein
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Bleomycin
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Fibroblast Growth Factors
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Collagen
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Receptor, Fibroblast Growth Factor, Type 2
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Mitogen-Activated Protein Kinases