Retinoic acid stimulates immature lung fibroblast growth via a PDGF-mediated autocrine mechanism

All trans-retinoic acid (RA) enhances alveolarization in neonates and reinitiates alveolarization in emphysematous adult rat lungs, suggesting that RA may stimulate cell proliferation by upregulating growth factor ligand and/or receptor expression either indirectly or directly by acting on RA-responsive genes encoding growth factors. We report that RA and 1,25-dihydroxyvitamin D(3) (Vit D), alone and in combination, significantly increase [(3)H]thymidine incorporation in cultured fetal and postnatal rat lung fibroblasts (P < 0.05). The greatest increase (11-fold) was seen in 4-day cells treated with the two agents in combination (P < 0.0001). [(3)H]thymidine incorporation was age dependent. The greatest response to RA occurred in 4-day fibroblasts (P < 0.01), whereas the response to Vit D was greatest in embryonic day 20 fibroblasts (P < 0.001). Neutralizing antibody to platelet-derived growth factor (PDGF)-AB decreased [(3)H]thymidine incorporation in response to RA alone or in combination with Vit D, indicating a role for PDGF. Expression of mRNAs for PDGF-A and PDGF receptor (PDGFR)-alpha and -beta was upregulated at the transcriptional level in an age- and treatment-dependent manner. Thus exogenous RA may influence alveolarization by stimulating fibroblast proliferation through a PDGF-mediated autocrine mechanism, which is enhanced when RA and Vit D are administered in combination.