title: Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4.
abstract: The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol- and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4-mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets.
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, 985910 Nebraska Medical Center, Omaha, NE 68198-5910, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Steve
authors.initials: S
authors.lastname: Nogel
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.forename: Yoko
authors.initials: Y
authors.lastname: Gunji
authors.forename: Maha
authors.initials: M
authors.lastname: Fahrid
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.forename: Kai-Christian
authors.initials: KC
authors.lastname: Muller
authors.forename: Olaf
authors.initials: O
authors.lastname: Holz
authors.forename: Helgo
authors.initials: H
authors.lastname: Magnussen
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005353:Fibronectins / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D015290:Second Messenger Systems
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D005353:Fibronectins; D007527:Isoenzymes; C113936:PTGIR protein, human; D058988:Phosphodiesterase 4 Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D058307:Receptors, Prostaglandin E, EP2 Subtype; C424423:Roflumilast; D005576:Colforsin; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; D016285:Iloprost; D020889:Rolipram; D015232:Dinoprostone; D000420:Albuterol