title: 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.
  
  
  RESULTS
  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.
authors: Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Peter A
authors: PA
authors: Sloane
authors: Suresh
authors: S
authors: Shastry
authors: Andrew
authors: A
authors: Wilhelm
authors: Clifford
authors: C
authors: Courville
authors: Li Ping
authors: LP
authors: Tang
authors: Kyle
authors: K
authors: Backer
authors: Elina
authors: E
authors: Levin
authors: S Vamsee
authors: SV
authors: Raju
authors: Yao
authors: Y
authors: Li
authors: Marina
authors: M
authors: Mazur
authors: Suzanne
authors: S
authors: Byan-Parker
authors: William
authors: W
authors: Grizzle
authors: Eric J
authors: EJ
authors: Sorscher
authors: Mark T
authors: MT
authors: Dransfield
authors: Steven M
authors: SM
authors: Rowe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000627:Aminophenols / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003710:Demography; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D012907:Smoking / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000627:Aminophenols; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor