Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

• Published in: American journal of respiratory cell and molecular biology Vol. 56; no. 4; pp. 532 - 538
• Main Authors: Patel, Brijeshkumar S, Rahman, Md Mostafizur, Baehring, Gina, Xenaki, Dikaia, Tang, Francesca Su-May, Oliver, Brian G, Ammit, Alaina J
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.04.2017
• Subjects: Aminopyridines - pharmacology; Anti-Inflammatory Agents - pharmacology; Benzamides - pharmacology; Chronic obstructive pulmonary disease; Cyclic AMP - biosynthesis; Cyclopropanes - pharmacology; Cytokines; Dexamethasone - pharmacology; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Enzymes; Formoterol Fumarate - pharmacology; Hospitals; Humans; Interleukin-8 - metabolism; Kinases; Lung - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Smooth muscle; Statistical analysis; Studies; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Up-Regulation - drug effects; mitogen-activated protein kinase phosphatase 1; β2-agonists; corticosteroids; IL-8; roflumilast N-oxide
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2016-0191OC

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 β -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 β -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 β -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.