Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2

Jun Ikari, Joel M. Michalski, Shunichiro Iwasawa, Yoko Gunji, Steve Nogel, Joo Hun Park, Amy J. Nelson, Maha Farid, Xingqi Wang, Nancy Schulte, Hesham Basma, Myron L. Toews, Carol Feghali-Bostwick, Hermann Tenor, Xiangde Liu, Stephen I. Rennard

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Lung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2) stimulates VEGF production from lung fibroblasts via the E-prostanoid (EP)-2 receptor. The EP2 signaling pathway uses cyclic adenosine monophosphate (cAMP) as a secondmessenger, andcAMPis degraded by phosphodiesterases (PDEs). This study investigates whether phosphodiesterase inhibition modulates the human lung fibroblast VEGF production induced by PGE2. Human fetal lung fibroblasts were cultured with PGE2 and PDE inhibitors. The PDE4 inhibitors roflumilast, roflumilast N-oxide, androlipramwith PGE2 increasedVEGF release,asquantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF releasewith either an EP2 or an EP4 agonist. Roflumilast augmentedthe cytosolic cAMP levels induced by PGE2 and VEGF release with other agents that use the cAMP signaling pathway. Roflumilast-augmented VEGF release was completely inhibited by a protein kinase A (PKA) inhibitor. Roflumilast with PGE2 increased VEGF mRNA levels, and the blockade of mRNA synthesis inhibited the augmented VEGF release. The stimulatory effect of roflumilast on VEGF releasewas replicated using primary healthy and COPD lung fibroblasts. These findings demonstrate that PDE4 inhibition can modulate human lung fibroblast VEGF release by PGE2 acting through the EP2 and EP4 receptor-cAMP/PKA signaling pathway. Through this action, PDE4 inhibitors such as roflumilast could contribute to the survival of lung endothelial cells.

Original languageEnglish (US)
Pages (from-to)571-581
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
StatePublished - Oct 2013


  • COPD lung fibroblasts
  • Human lung fibroblasts
  • Phosphodiesterase 4
  • Prostaglandin E
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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