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

all trans-retinoic acid (RA) enhances alveolarization in neonates and reini tiates 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-respon sive genes encoding growth factors. We report that RA and 1,25-dihydroxyvit amin D-3 (Vit D), alone and in combination, significantly increase [H-3] th ymidine 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). [H-3] thymidine incorpora tion was age dependent. The greatest response to RA occurred in 4-day fibro blasts (P < 0.01), whereas the response to Vit D was greatest in embryonic day 20 fibroblasts (P< 0.001). Neutralizing antibody to platelet-derived gr owth factor (PDGF)-AB decreased [H-3] thymidine incorporation in response t o RA alone or in combination with Vit D, indicating a role for PDGF. Expres sion of mRNAs for PDGF-A and PDGF receptor (PDGFR)-alpha and -beta was upre gulated at the transcriptional level in an age- and treatment-dependent man ner. Thus exogenous RA may influence alveolarization by stimulating fibrobl ast proliferation through a PDGF-mediated autocrine mechanism, which is enh anced when RA and Vit D are administered in combination.