A Pharmacologic Approach to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Smoking Related Lung Disease

Abstract

Background Mucus stasis in chronic obstructive pulmonary disease (COPD) is a significant contributor to morbidity and mortality. Potentiators of cystic fibrosis transmembrane conductance regulator (CFTR) activity pharmacologically enhance CFTR function; ivacaftor is one such agent approved to treat CF patients with the G551D-CFTR gating mutation. CFTR potentiators may also be useful for other diseases of mucus stasis, including COPD. Methods and Findings In primary human bronchial epithelial cells, exposure to cigarette smoke extract diminished CFTR-mediated anion transport (65.8±0.2% of control, P<0.005) and mucociliary transport (0.17±0.05 µm/sec vs. 2.4±0.47 µm/sec control, P<0.05) by reducing airway surface liquid depth (7.3±0.6 µm vs. 13.0±0.6 µm control, P<0.005) and augmenting mucus expression (by 64%, P<0.05) without altering transepithelial resistance. Smokers with or without COPD had reduced CFTR activity measured by nasal potential difference compared to age-matched non-smokers (−6.3±1.4 and −8.0±2.0 mV, respectively vs. −15.2±2.7 mV control, each P<0.005, n = 12–14/group); this CFTR decrement was associated with symptoms of chronic bronchitis as measured by the Breathlessness Cough and Sputum Score (r = 0.30, P<0.05) despite controlling for smoking (r = 0.31, P<0.05). Ivacaftor activated CFTR-dependent chloride transport in non-CF epithelia and ameliorated the functional CFTR defect induced by smoke to 185±36% of non-CF control (P<0.05), thereby increasing airway surface liquid (from 7.3±0.6 µm to 10.1±0.4 µm, P<0.005) and mucociliary transport (from 0.27±0.11 µm/s to 2.7±0.28 µm/s, P<0.005). Conclusions Cigarette smoking reduces CFTR activity and is causally related to reduced mucus transport in smokers due to inhibition of CFTR dependent fluid transport. These effects are reversible by the CFTR potentiator ivacaftor, representing a potential therapeutic strategy to augment mucociliary clearance in patients with smoking related lung disease.

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

“…Our laboratory and others have reported that cigarette smoke exposure reduces CFTR expression, function, and mucociliary transport [12][13][14][15] in vitro and that smokers with and without COPD exhibit reduced CFTR-dependent nasal potential difference (NPD) in the upper airway. 15 However, CFTR activity has not been previously measured in the lungs of individuals with COPD.…”

“…15 However, CFTR activity has not been previously measured in the lungs of individuals with COPD. We hypothesized that CFTR dysfunction would be present in the lower airway of individuals with COPD and that the abnormality would correlate with the presence of chronic bronchitis and markers of disease severity.…”

“…19 NPD Measurements: NPD studies were performed according to the description by Solomon et al 20 with Electronic Data Capture (ADInstruments), KCl calomel electrodes (Thermo Fisher Scientifi c Inc), and 3% agar nasal catheter and reference bridges. 15,21 Lower Airway Potential Difference Measurements: During bronchoscopy under conscious sedation with limited topical analgesia (1% lidocaine to the vocal cords and right mainstem bronchus), lower airway potential difference (LAPD) measurements were performed to quantify CFTR activity in the lower airway ( Fig 1 ). The equipment and conditions for measuring bioelectric changes across the airway mucosa were based on the standard NPD protocol adapted to the bronchoscopic technique, including use of agar-fi lled PE90 tubing for the probing electrode and limiting perfusion solutions to Ringer, Ringer plus amiloride (100 m M), and chloride-free gluconate with amiloride plus isoproterenol (100 m M).…”

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

“…Taken together, these data strongly suggest that CFTR could be a therapeutic target in smoking-related diseases. In fact, drugs which increase CFTR function (the CFTR potentiator ivacaftor and the phosphodiesterase 4 inhibitor roflumilast) were found to have beneficial effects on cigarette smoke-induced Cl − channel inhibition [71,72]. …”

Signature Motifs Identify an Acinetobacter Cif Virulence Factor with Epoxide Hydrolase Activity

“…The resulting breakdown of airway clearance permits colonization by bacteria such as Pseudomonas aeruginosa and Burkholderia cepacia complex, leading to cycles of infection and inflammation that impair respiratory function and lead ultimately to death (2). Smoking also suppresses airway epithelial CFTR (3)(4)(5)(6) and contributes to the etiology of chronic obstructive pulmonary disease, the third leading cause of mortality in the United States (7). Although the role of P. aeruginosa in chronic obstructive pulmonary disease is complex, it has been associated with exacerbations, reduced lung function, and increased mortality (8 -11).…”