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

Authors
Ikari, J; Michalski, JM; Iwasawa, S; Gunji, Y; Nogel, S; Park, JH; Nelson, AJ; Farid, M; Wang, X; Schulte, N; Basma, H; Toews, ML; Feghali-Bostwick, C; Tenor, H; Liu, X; Rennard, SI
Citation
American journal of respiratory cell and molecular biology, 49(4):571-581, 2013
Journal Title
American journal of respiratory cell and molecular biology
ISSN
1044-15491535-4989
Abstract
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 second messenger, and cAMP is 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, and rolipram with PGE2 increased VEGF release, as quantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF release with either an EP2 or an EP4 agonist. Roflumilast augmented the 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 release was 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.
MeSH terms
Aminopyridines/pharmacologyBenzamides/pharmacologyCells, CulturedCyclic AMP/genetics/metabolismCyclic AMP-Dependent Protein Kinases/genetics/metabolismCyclic Nucleotide Phosphodiesterases, Type 4/*metabolismCyclopropanes/pharmacologyDinoprostone/*pharmacologyFibroblasts/drug effects/metabolismHumansLung/cytology/*drug effects/*metabolismPhosphodiesterase 4 Inhibitors/*pharmacologyPulmonary Disease, Chronic Obstructive/metabolismRNA, Messenger/geneticsReceptors, Prostaglandin E, EP2 Subtype/genetics/metabolismSignal Transduction/drug effectsVascular Endothelial Growth Factor A/genetics/*metabolism
DOI
10.1165/rcmb.2013-0004OC
PMID
23656623
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pulmonary & Critical Care Medicine
AJOU Authors
박, 주헌
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