ANTISENSE OLIGODEOXYNUCLEOTIDES TARGETING PDGF-B MESSENGER-RNA INHIBIT CELL-PROLIFERATION DURING EMBRYONIC RAT LUNG DEVELOPMENT

There is increasing evidence to suggest that platelet-derived growth f actor (PDGF) or PDGF-like molecules play a role in fetal lung morphoge nesis. Our previous studies demonstrated the presence of PDGF-AA and P DGF-BB homodimers in embryonic and fetal rat lung. To explore further the role for PDGF-BB in embryonic lung development, we conducted inter vention studies using PDGF-B chain-specific antisense oligodeoxynucleo tides in a simple embryonic rat lung explant system. Unmodified antise nse PDGF-B oligodeoxynucleotides inhibited, in a concentration-depende nt manner, DNA synthesis of embryonic lung. A maximal inhibition of 50 % was observed. The inhibitory effect of antisense PDGF-B oligodeoxynu cleotides on DNA synthesis was reversed by the addition of exogenous P DGF-BB but not PDGF-AA. Antisense treatment decreased PDGF-BB but not PDGF-AA protein content, as assessed by immunoblot analyses. Incubatio n of lung explants with PDGF-BB neutralizing antibodies also resulted in an inhibition of DNA synthesis. Morphometric analyses of antisense- treated cultures showed a significant reduction in lung size when comp ared to control cultures. The epithelial component of the embryonic lu ngs was specifically reduced, both in mass and DNA labelling index, by antisense treatment. The number of terminal buds of the lung explants was not significantly affected by antisense PDGF-B treatment, Scrambl ed PDGF-B oligodeoxynucleotides had no effect. These data suggest that PDGF-BB is involved in regulating growth, but not the degree of branc hing, of embryonic rat lung.