Back to Search
Start Over
Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2014 Mar; Vol. 50 (3), pp. 549-58. - Publication Year :
- 2014
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 50
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 24106801
- Full Text :
- https://doi.org/10.1165/rcmb.2013-0228OC