Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice

Respiratory Research

Research

Emily Falk Libby¹  Peter A. Sloane²  Lawrence Rasmussen³  Li Ping Tang³  S. Vamsee Raju⁴  Steven M. Rowe⁵ 

[1] Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA;Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Cell, Integrative, and Developmental Biology, University of Alabama at Birmingham, Birmingham, AL, USA;Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Cell, Integrative, and Developmental Biology, University of Alabama at Birmingham, Birmingham, AL, USA;UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA;Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA;MCLM 702, 1918 University Blvd, 35294-0006, Birmingham, AL, USA;

关键词: CFTR;    Roflumilast;    cAMP;    COPD;    Chronic bronchitis;   

DOI  :  10.1186/s12931-017-0656-0

 received in 2017-08-12, accepted in 2017-09-12,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) can be elicited by cigarette smoke and is observed in patients with chronic bronchitis. We have previously demonstrated in human airway epithelial cell monolayers that roflumilast, a clinically approved phosphodiesterase 4 inhibitor that reduces the risk of exacerbations in chronic obstructive pulmonary disease patients with chronic bronchitis and a history of exacerbations, activates CFTR-dependent chloride secretion via a cAMP-mediated pathway, partially restores the detrimental effects of cigarette smoke on CFTR-mediated ion transport, and increases CFTR-dependent gastrointestinal fluid secretion in isolated murine intestine segments. Based on these findings, we hypothesized that roflumilast could improve CFTR-mediated chloride transport and induce secretory diarrhea in mice exhibiting cigarette smoke-induced CFTR dysfunction.MethodsA/J mice expressing wild type CFTR (+/+) were exposed to cigarette smoke or air with or without roflumilast and the effect of treatment on CFTR-dependent chloride transport was quantified using nasal potential difference (NPD) measurements in vivo and short-circuit current (Isc) analysis of trachea ex vivo. Stool specimen were collected and the wet/dry ratio measured to assess the effect of roflumilast on secretory diarrhea.ResultsAcute roflumilast treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice (smoke, −2.0 ± 0.4 mV, 131.3 ± 29.3 μA/cm2, P < 0.01 and air, 3.9 ± 0.8 mV, 147.7 ± 38.0 μA/cm2, P < 0.01 vs. vehicle −0.3 ± 0.7 mV, 10.4 ± 7.0 μA/cm2). Oral administration of roflumilast over five weeks completely reversed the deleterious effects of cigarette smoke on CFTR function in smoke-exposed animals, in which CFTR-dependent chloride transport was 64% that of air controls (roflumilast, −15.22 ± 2.7 mV vs. air, −14.45 ± 1.4 mV, P < 0.05). Smoke exposure increased the wet/dry ratio of stool specimen to a level beyond which roflumilast had little additional effect.ConclusionsRoflumilast effectively rescues CFTR-mediated chloride transport in vivo, further implicating CFTR activation as a mechanism through which roflumilast benefits patients with bronchitis.

【 授权许可】

CC BY   
© The Author(s). 2017