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

Am J Physiol Lung Cell Mol Physiol. 2000 Jul;279(1):L81-90. doi: 10.1152/ajplung.2000.279.1.L81.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / metabolism
  • Animals
  • Autocrine Communication / physiology*
  • Cell Division / drug effects
  • Cellular Senescence
  • Drug Combinations
  • Fetus / metabolism
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / physiology
  • Ligands
  • Lung / cytology
  • Lung / drug effects*
  • Lung / embryology
  • Platelet-Derived Growth Factor / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Thymidine / metabolism
  • Tretinoin / pharmacology*
  • Up-Regulation
  • Vitamin D / pharmacology


  • Drug Combinations
  • Ligands
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Vitamin D
  • Tretinoin
  • Receptors, Platelet-Derived Growth Factor
  • Thymidine