Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

被引:67
作者
Lambert, James A. [1 ,7 ]
Raju, S. Vamsee [1 ]
Tang, Li Ping [1 ,6 ]
McNicholas, Carmel M. [3 ]
Li, Yao [1 ,6 ]
Courville, Clifford A. [1 ]
Farris, Roopan F. [1 ,2 ]
Coricor, George E. [7 ]
Smoot, Lisa H. [1 ]
Mazur, Marina M. [6 ]
Dransfield, Mark T. [1 ,5 ]
Bolger, Graeme B. [1 ,4 ]
Rowe, Steven M. [1 ,2 ,3 ,5 ,6 ]
机构
[1] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA
[3] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA
[4] Univ Alabama Birmingham, Dept Pharmacol, Birmingham, AL 35294 USA
[5] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Birmingham, AL USA
[6] Univ Alabama Birmingham, Cyst Fibrosis Res Ctr, Birmingham, AL USA
[7] Univ Alabama Birmingham, Dept Biochem & Struct Biol, Birmingham, AL USA
基金
美国国家卫生研究院;
关键词
chronic obstructive pulmonary disease; cigarette; smoke; cystic fibrosis transmembrane conductance regulator; roflumilast; ion transport; OBSTRUCTIVE PULMONARY-DISEASE; FUNCTION IN-VITRO; EPITHELIAL-CELLS; PHOSPHODIESTERASE INHIBITORS; PERICILIARY LIQUID; CFTR POTENTIATOR; PDE4; INHIBITOR; CL-SECRETION; CYCLIC-AMP; EXPRESSION;
D O I
10.1165/rcmb.2013-0228OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. CFTRdependent 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 mu A/ cm(2) vs. 1.2 +/- 0.2 mu A/ 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 toWCS (9.0 +/- 3.1mmvs. 5.6 +/- 2.0 mu m [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.
引用
收藏
页码:549 / 558
页数:10
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