Platelet-derived growth factor (PDGF)-BB-stimulated glycosaminoglycan (GAG) synthesis/secretion in fetal lung fibroblasts is dependent upon sequential activation of the PDGF -receptor, phosphatidylinositol-3 kinase (PI-3K), the serine/threonine kinase Akt-1,2 and the GTPase Rab3D. Since the Akt pathway has been implicated in cell survival mechanisms, we investigated whether the pathway regulating GAG synthesis/secretion was anti-apoptotic. PDGF-BB treatment protected fetal lung fibroblasts against serumstarvation- induced apoptosis while wortmannin, an inhibitor of of PI-3K, abrogated this protective effect. Transfection of constitutively-active Akt into fetal lung fibroblasts also safe-guarded the cells from apoptosis induced by serum starvation. In order to determine whether the anti-apoptotic response was due, at least in part, to GAGs, we treated lung fibroblasts with -D-xyloside as well as with topically-applied GAGs, specifically those produced by fetal lug fibroblasts. -D-xyloside increased GAG synthesis/secretion and diminished apoptosis. Application of sulfated GAGs, chondroitin sulfate and heparan sulfate, but not non-sulfated hyaluronan, also resulted in diminished apoptosis. Moreover, topically-applied sulfated GAGs increased BAD phosphorylation and diminished caspase 3 and 7 cleavage, indicating an anti-apototic response. These data are compatible with the PDGF-BB-GAG signaling pathway regulating programmed fibroblast death in the fetal lung.