Fibroblast growth factors (FGFs) influence lung epithelial cells in processes relating to maintenance and repair following injury. Their role in chronic conditions such as asthma is largely unknown, but likely involves fundamental relationships between epithelium and the underlying extracellular matrix (ECM) and fibroblasts. FGFs utilize complex interactions between ECMs (eg, heparan sulfate proteoglycans), soluble cell factors (FGF-binding proteins), and relevant sequential signaling cascades. This relationship affords a crucial role for heparan sulfate proteoglycans, whose sulfated character are differentially expressed in ECMs where they are known to be potent biological modifiers. The goal of this study was to determine whether specific signaling pathways relating to FGF-1 and FGF-2 and expression of selected genes were altered by the model ECM heparin. Phosphorylation (p) of extracellular signal-regulated kinase-1/extracellular signal-regulated-2 was found to be reduced by 500 μg/mL of heparin in type II cells stimulated with 50 to 100 ng/mL of FGF-1 or FGF-2 at 15 min. p-RAF was elevated by low concentrations of heparin with FGF-1 but reduced by heparin with FGF-2. p-c-Myc was reduced by high heparin but elevated by low heparin with FGF-1; 500 μg/mL of heparin down-regulated gene expression of FGF-1, FGF-2, and FGF-7, FGF receptor-2, and FGF binding protein, but not FGFR-1, in type II cells with and without treatment with FGF-1 or FGF-2. Co-culture of type II cells with fibroblasts resulted in reduced expression in the former of FGF-1 and FGF-2, and FGF receptor-2(IIIb), but not FGFR-1 or FGFR-2, and elevation of FGF binding protein. These results demonstrate important regulatory links between FGFs and sulfated ECMs and implicate key interactions between type II cells and fibroblasts in the modulation of airway/alveolar diseases in the lung.