Bronchial smooth muscle cell (BSMC) hyperplasia is a typical feature of airway remodelling and contributes to airway obstruction and hyperresponsiveness in asthma. Fibroblast growth factor 2 (FGF2) and transforming growth factor 1 (TGF1) are sequentially up-regulated in asthmatic airways after allergic challenge. Whereas FGF2 induces BSMC proliferation, the mitogenic effect of TGF1 remains controversial and the effect of sequential FGF2 and TGF1 co-stimulation on BSMC proliferation is unknown. This study aims to assess the individual and sequential cooperative effects of FGF2 and TGF1 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 semi-quantitative RT-PCR, Western blot and ELISA, respectively. TGF1 (0.1-20 ng/ml) alone had no effect on BSMC proliferation, but increased the proliferative effect of FGF2 (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, TGF1 increased PDGF-A and PDGF-C mRNA expression as well as PDGF-AA protein expression. Moreover, FGF2 pre-treatment increased the mRNA and protein expression of PDGFR and the proliferative effect of exogenous PDGF-AA (140%). Our data suggest that FGF2 and TGF1 synergize in BSMC proliferation and this synergism is partially mediated by a PDGF loop, where FGF2 and TGF1 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 remodelled asthmatic airways.