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.
Liebeskind
A
A
Department of Pediatrics, University of Kentucky Medical School, Lexington, Kentucky 40536, USA.
Srinivasan
S
S
Kaetzel
D
D
Bruce
M
M
D000375:Aging / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D016922:Cellular Senescence; D004338:Drug Combinations; D005333:Fetus / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D013936:Thymidine / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation; D014807:Vitamin D / Q000494:pharmacology
D004338:Drug Combinations; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D014807:Vitamin D; D014212:Tretinoin; D017479:Receptors, Platelet-Derived Growth Factor; D013936:Thymidine