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Fibroblast Growth Factor 2 and Transforming Growth Factor 1 Synergism in Human Bronchial Smooth Muscle Cell Proliferation

Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada

Correspondence and requests for reprints should be addressed to Dr. Marek Rola-Pleszczynski, Department of Pediatrics, Immunology Division, Faculty of Medicine, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke, PQ, J1H 5N4 Canada. E-mail: marek.rola-pleszczynski{at}usherbrooke.ca

Bronchial smooth muscle cell (BSMC) hyperplasia is a typical feature of airway remodeling and contributes to airway obstruction and hyperresponsiveness in asthma. Fibroblast growth factor 2 (FGF-2) and transforming growth factor 1 (TGF-1) are sequentially upregulated in asthmatic airways after allergic challenge. Whereas FGF-2 induces BSMC proliferation, the mitogenic effect of TGF-1 remains controversial, and the effect of sequential FGF-2 and TGF-1 co-stimulation on BSMC proliferation is unknown. This study aimed to assess the individual and sequential cooperative effects of FGF-2 and TGF-1 on human BSMC proliferation and define the underlying mechanisms. Mitogenic response was measured using crystal violet staining and [³H]-thymidine incorporation. Steady-state mRNA and protein levels were measured by semiquantitative RT-PCR, Western blot, and ELISA, respectively. TGF-1 (0.1–20 ng/ml) alone had no effect on BSMC proliferation, but increased the proliferative effect of FGF-2 (2 ng/ml) in a concentration-dependent manner (up to 6-fold). Two distinct platelet-derived growth factor receptor (PDGFR) inhibitors, AG1296 and Inhibitor III, as well as a neutralizing Ab against PDGFR, partially blocked the synergism between these two growth factors. In this regard, TGF-1 increased PDGF-A and PDGF-C mRNA expression as well as PDGF-AA protein expression. Moreover, FGF-2 pretreatment increased the mRNA and protein expression of PDGFR and the proliferative effect of exogenous PDGF-AA (140%). Our data suggest that FGF-2 and TGF-1 synergize in BSMC proliferation and that this synergism is partially mediated by a PDGF loop, where FGF-2 and TGF-1 upregulate the receptor (PDGFR) and the ligands (PDGF-AA and PDGF-CC), respectively. This powerful synergistic effect may thus contribute to the hyperplastic phenotype of BSMC in remodeled asthmatic airways.

Key Words: airway remodeling • asthma • hyperplasia • PDGF • smooth muscle

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