title: Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells.
abstract: Roflumilast is an orally active phosphodiesterase 4 inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has a demonstrated antiinflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1,000 nM) alone had no effect on AMP production from ASM cells, and significant potentiation of the long-acting β2-agonist formoterol-induced cAMP could only be achieved at the highest concentration of RNO tested (1,000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterol-induced expression of antiinflammatory mitogen-activated protein kinase phosphatase 1. Consequently, tumor necrosis factor-induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, because there was the potential for phosphodiesterase 4 inhibitors and long-acting β2-agonists to interact with corticosteroids to achieve superior antiinflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the antiinflammatory effect of dexamethasone by measuring the impact on IL-8 secretion. Although RNO alone did not significantly enhance the cytokine repression achieved with steroids, RNO in combination with formoterol significantly enhanced the antiinflammatory effect of dexamethasone in ASM cells. This was linked to increased mitogen-activated protein kinase phosphatase 1 expression in ASM cells, suggesting that a molecular mechanism is responsible for augmented antiinflammatory actions of combination therapeutic approaches that include RNO.
authors.affiliation: 1 Faculty of Pharmacy and.
authors.forename: Brijeshkumar S
authors.initials: BS
authors.lastname: Patel
authors.affiliation: 1 Faculty of Pharmacy and.
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: 2 Woolcock Emphysema Centre and.
authors.forename: Gina
authors.initials: G
authors.lastname: Baehring
authors.affiliation: 3 Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; and.
authors.forename: Dikaia
authors.initials: D
authors.lastname: Xenaki
authors.affiliation: 2 Woolcock Emphysema Centre and.
authors.forename: Francesca Su-May
authors.initials: FS
authors.lastname: Tang
authors.affiliation: 2 Woolcock Emphysema Centre and.|3 Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; and.|4 Centre for Health Technologies and Molecular Biosciences, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Oliver
authors.affiliation: 2 Woolcock Emphysema Centre and.|4 Centre for Health Technologies and Molecular Biosciences, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D003521:Cyclopropanes / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D000068759:Formoterol Fumarate / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D003521:Cyclopropanes; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D000242:Cyclic AMP; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517734:roflumilast N-oxide; D000068759:Formoterol Fumarate
keywords: IL-8; corticosteroids; mitogen-activated protein kinase phosphatase 1; roflumilast N-oxide; β2-agonists