RT Journal Article
SR Electronic
T1 Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe COPD
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.083493
DO 10.1124/mol.112.083493
A1 Thuncia Moodley
A1 Sylvia Wilson
A1 Taruna Joshi
A1 Christopher Rider
A1 Pawan Sharma
A1 Dong Yan
A1 Robert Newton
A1 Mark A Giembycz
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/02/06/mol.112.083493.abstract
AB Post hoc analysis of two phase III clinical studies found that the phosphodiesterase (PDE) 4 inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) that were taking inhaled corticosteroids (ICS) concomitantly whereas patients not taking ICS derived no such benefit. In contrast, in two different trials, also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realised. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease that will inevitably be taking a LABA/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells (both BEAS-2B cells and primary cultures), roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the long-acting β2-adrenoecoptor agonist (LABA), formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD.