Chest
Volume 144, Issue 2, August 2013, Pages 498-506
Journal home page for Chest

Original Research
COPD
Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in the Lower Airways in COPD

https://doi.org/10.1378/chest.13-0274Get rights and content

Background

Cigarette smoke and smoking-induced inflammation decrease cystic fibrosis transmembrane conductance regulator (CFTR) activity and mucociliary transport in the nasal airway and cultured bronchial epithelial cells. This raises the possibility that lower airway CFTR dysfunction may contribute to the pathophysiology of COPD. We compared lower airway CFTR activity in current and former smokers with COPD, current smokers without COPD, and lifelong nonsmokers to examine the relationships between clinical characteristics and CFTR expression and function.

Methods

Demographic, spirometry, and symptom questionnaire data were collected. CFTR activity was determined by nasal potential difference (NPD) and lower airway potential difference (LAPD) assays. The primary measure of CFTR function was the total change in chloride transport (Δchloride-free isoproterenol). CFTR protein expression in endobronchial biopsy specimens was measured by Western blot.

Results

Compared with healthy nonsmokers (n = 11), current smokers (n = 17) showed a significant reduction in LAPD CFTR activity (Δchloride-free isoproterenol, −8.70 mV vs −15.9 mV; P = .003). Similar reductions were observed in smokers with and without COPD. Former smokers with COPD (n = 7) showed a nonsignificant reduction in chloride conductance (−12.7 mV). A similar pattern was observed for CFTR protein expression. Univariate analysis demonstrated correlations between LAPD CFTR activity and current smoking, the presence of chronic bronchitis, and dyspnea scores.

Conclusions

Smokers with and without COPD have reduced lower airway CFTR activity compared with healthy nonsmokers, and this finding correlates with disease phenotype. Acquired CFTR dysfunction may contribute to COPD pathogenesis.

Section snippets

Study Subjects and Study Protocol

The study was approved by the University of Alabama at Birmingham Institutional Review Board (approval number F090626003), and all patients provided written informed consent. Patients aged 40 to 80 years were categorized into four subgroups by smoking status and the presence or absence of airflow obstruction (FEV1/FVC below the lower limit of normal for age, race, sex, and height). A minimum of 10 pack-years tobacco use was required for patients with COPD, and abstinence was confirmed with

Study Subjects

We enrolled 48 patients of whom eight did not meet spirometric inclusion criteria or were excluded because of comorbid illnesses that increased the risk of bronchoscopy complications (e-Fig 1). Of the remaining 40 patients, 35 had acceptable LAPD tracings. Tracings were not available for five patients because of technical issues with the perfusion catheter (n = 3), leakage of perfusion fluids (n = 1), or patient intolerance of bronchoscopy (n = 1). Three patients (two COPD smokers and one

Discussion

The results demonstrate that smokers with and without COPD have reduced chloride conductance in the lower airway and that this ion transport abnormality is associated with the presence of chronic bronchitis and dyspnea. These results extend previous findings, suggesting that cigarette smoke has deleterious effects on CFTR activity and epithelial function,12, 13, 14, 15, 27 and establish a link between CFTR dysfunction in the lung and clinically relevant COPD symptoms. Detection of this ion

Acknowledgments

Author contributions: Drs Dransfield and Rowe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Dransfield: contributed to the study design, study procedures, data analysis, manuscript writing, and manuscript editing.

Dr Wilhelm: contributed to the study procedures, data analysis, and manuscript editing.

Dr Flanagan: contributed to the study procedures, data analysis, and manuscript editing.

Dr Courville:

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    Funding/Support: This research is sponsored by the National Institutes of Health [R01 HL105487 to Dr Rowe, R01 HL07783, P30 DK072482, and 5UL1 RR025777] and the Cystic Fibrosis Foundation (CLANCY09Y0 to Dr Rowe and R464-CF). Dr Rowe is supported by American Lung Association Senior Research Fellowship (RT-219427-N).

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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