title: Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function.
abstract: BACKGROUND
  Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR.
  
  
  OBJECTIVE
  To study the effect of cigarette smoke on extrapulmonary CFTR function.
  
  
  METHODS
  Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy.
  
  
  RESULTS
  Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke-exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein.
  
  
  CONCLUSIONS
  Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.
authors.affiliation: 1 Department of Medicine.
authors.forename: S Vamsee
authors.initials: SV
authors.lastname: Raju
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Courville
authors.forename: Carmel M
authors.initials: CM
authors.lastname: McNicholas
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sloane
authors.forename: Gina
authors.initials: G
authors.lastname: Sabbatini
authors.forename: Sherry
authors.initials: S
authors.lastname: Tidwell
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Tang
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: James A
authors.initials: JA
authors.lastname: Fortenberry
authors.forename: Caleb W
authors.initials: CW
authors.lastname: Jones
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Boydston
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
authors.forename: Larry E
authors.initials: LE
authors.lastname: Bowen
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Accurso
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dransfield
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
mesh_terms: D000171:Acrolein / Q000097:blood*; D000368:Aged; D000818:Animals; D002712:Chlorides / Q000097:blood; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000378:metabolism; D017079:Exercise Tolerance / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D009297:Nasal Mucosa / Q000737:chemistry; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000503:physiopathology; D012964:Sodium / Q000097:blood; D013147:Spirometry; D013542:Sweat / Q000737:chemistry*
chemical_list: D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000171:Acrolein; D012964:Sodium
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