title: Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2.
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.
authors: 1 Department of Internal Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, and.
authors: Jun
authors: J
authors: Ikari
authors: Joel M
authors: JM
authors: Michalski
authors: Shunichiro
authors: S
authors: Iwasawa
authors: Yoko
authors: Y
authors: Gunji
authors: Steve
authors: S
authors: Nogel
authors: Joo Hun
authors: JH
authors: Park
authors: Amy J
authors: AJ
authors: Nelson
authors: Maha
authors: M
authors: Farid
authors: Xingqi
authors: X
authors: Wang
authors: Nancy
authors: N
authors: Schulte
authors: Hesham
authors: H
authors: Basma
authors: Myron L
authors: ML
authors: Toews
authors: Carol
authors: C
authors: Feghali-Bostwick
authors: Hermann
authors: H
authors: Tenor
authors: Xiangde
authors: X
authors: Liu
authors: Stephen I
authors: SI
authors: Rennard
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C424423:Roflumilast; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015232:Dinoprostone