EFFECTS OF PLATELET-DERIVED GROWTH-FACTOR ISOFORMS ON HUMAN LUNG FIBROBLAST PROLIFERATION AND PROCOLLAGEN GENE-EXPRESSION

Platelet-derived growth factor (PDGF), a potent mitogen for fibroblast s, is a potentially important cytokine in the pathogenesis of fibropro liferative disorders of lung. Different isoforms of PDGF include a het erodimer composed of A and B chains and homodimers composed of A or B chains. The biological significance of the different isoforms is unkno wn, but they have been shown to differ in their mitogenic potency in s ome systems. Their effects on other fibroblast functions have not been fully examined We undertook this study to determine the effect of PDG F isoforms on human lung fibroblast proliferation and procollagen synt hesis. Cultured lung fibroblasts (IMR-90, WI-38, GeNa) were incubated in the presence of varying concentrations of highly purified PDGF-AB o btained from platelets or recombinant PDGF-AA or -BB homodimers. Incor poration of [H-3]thymidine was determined as a measure of mitogenic ac tivity. Fetal lung fibroblasts (IMR-90, WI-38) and an adult fibroblast strain (GeNA) responded similarly to the different isoforms, with max imum mitogenic activity observed at 5-10 ng/mL Cell cycle analysis usi ng three additional normal adult lung fibroblast strains indicated tha t all PDGF isoforms stimulated similar proportions of cells to cycle o ver a 7-day period Fibroblast procollagen synthesis, measured after pu lse labeling with [H-3]proline, was not increased even at concentratio ns of the PDGF isoforms that were maximally mitogenic. Moreover, stead y-state levels of alpha1(I) and alpha1(III) procollagen mRNA levels, d etermined by northern analysis and dot blot hybridization, were not ch anged after exposure to any of the PDGF isoforms. While all PDGF isofo rms are potent mitogens for fetal and adult lung fibroblasts, it was c oncluded that they do not directly stimulate procollagen gene expressi on or procollagen synthesis in vitro. The results suggest that PDGF is oforms are potentially important mitogens for lung fibroblasts, but ot her factors are likely to be involved in the stimulation of fibroblast procollagen synthesis that is observed in fibroproliferative disorder s of lung.