1. Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis.
- Author
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Lambert JA, Raju SV, Tang LP, McNicholas CM, Li Y, Courville CA, Farris RF, Coricor GE, Smoot LH, Mazur MM, Dransfield MT, Bolger GB, and Rowe SM
- Subjects
- Aminophenols pharmacology, Aminopyridines toxicity, Animals, Benzamides toxicity, Bronchi metabolism, Bronchi physiopathology, Bronchitis, Chronic metabolism, Bronchitis, Chronic physiopathology, Cells, Cultured, Cyclic AMP, Cyclopropanes pharmacology, Cyclopropanes toxicity, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Diarrhea chemically induced, Diarrhea metabolism, Dose-Response Relationship, Drug, Epithelial Cells metabolism, Humans, Intestinal Secretions metabolism, Intestine, Small drug effects, Intestine, Small metabolism, Membrane Potentials, Mice, Mucociliary Clearance drug effects, Phosphodiesterase 4 Inhibitors toxicity, Quinolones pharmacology, Smoke adverse effects, Smoking adverse effects, Time Factors, Aminopyridines pharmacology, Benzamides pharmacology, Bronchi drug effects, Bronchitis, Chronic drug therapy, Cystic Fibrosis Transmembrane Conductance Regulator agonists, Epithelial Cells drug effects, Phosphodiesterase 4 Inhibitors pharmacology
- Abstract
Cigarette smoking causes acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction and is associated with delayed mucociliary clearance and chronic bronchitis. Roflumilast is a clinically approved phosphodiesterase 4 inhibitor that improves lung function in patients with chronic bronchitis. We hypothesized that its therapeutic benefit was related in part to activation of CFTR. Primary human bronchial epithelial (HBE) cells, Calu-3, and T84 monolayers were exposed to whole cigarette smoke (WCS) or air with or without roflumilast treatment. CFTR-dependent ion transport was measured in modified Ussing chambers. Airway surface liquid (ASL) was determined by confocal microscopy. Intestinal fluid secretion of ligated murine intestine was monitored ex vivo. Roflumilast activated CFTR-dependent anion transport in normal HBE cells with a half maximal effective concentration of 2.9 nM. Roflumilast partially restored CFTR activity in WCS-exposed HBE cells (5.3 ± 1.1 μA/cm(2) vs. 1.2 ± 0.2 μA/cm(2) [control]; P < 0.05) and was additive with ivacaftor, a specific CFTR potentiator approved for the treatment of CF. Roflumilast improved the depleted ASL depth of HBE monolayers exposed to WCS (9.0 ± 3.1 μm vs. 5.6 ± 2.0 μm [control]; P < 0.05), achieving 79% of that observed in air controls. CFTR activation by roflumilast also induced CFTR-dependent fluid secretion in murine intestine, increasing the wet:dry ratio and the diameter of ligated murine segments. Roflumilast activates CFTR-mediated anion transport in airway and intestinal epithelia via a cyclic adenosine monophosphate-dependent pathway and partially reverses the deleterious effects of WCS, resulting in augmented ASL depth. Roflumilast may benefit patients with chronic obstructive pulmonary disease with chronic bronchitis by activating CFTR, which may also underlie noninfectious diarrhea caused by roflumilast.
- Published
- 2014
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