title: Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein.
abstract: OBJECTIVE
  Evidence indicates that decreased mucociliary clearance (MCC) is a major contributing feature to chronic rhinosinusitis. Tobacco-smoke exposure is thought to inhibit transepithelial Cl(-) secretion, a major determinant of airway surface liquid hydration and MCC. The objective of the current study was to evaluate the effects of acrolein exposure (a prominent tobacco smoke toxin) on vectorial Cl(-) transport through the major apical anion channel cystic fibrosis transmembrane conductance regulator (CFTR) in sinonasal epithelium.
  
  
  METHODS
  In vitro investigation.
  
  
  METHODS
  Primary murine nasal septal epithelia (MNSE; wild-type and transgenic CFTR(-/-)) cultures were exposed to acrolein in Ussing chambers and the effects on Cl(-) secretion investigated using pharmacologic manipulation. Cellular cyclic adenosine monophosphate (cAMP) signaling and cytotoxicity were also investigated.
  
  
  RESULTS
  Acrolein stimulated Cl(-) secretion (ΔI(SC) - change in short-circuit current in μA/cm(2)) at concentrations similar to smoker's airways (100 μM, 15.8 ± 2.2 vs. 2.4 ± 0.8 [control]; P < .0001), suppressed forskolin-stimulated C- transport at 300 μM (13.3 ± 1.2 vs. 19.9 ± 1.0; P < .01), and completely abolished all transport at 500 μM (-1.1 ± 1.6). Stimulated Cl(-) secretion was solely reliant upon the presence of CFTR (confirmed in transgenic CFTR(-/-) MNSE), but independent of cAMP signaling. Inhibition at higher concentrations was not secondary to cellular cytotoxicity.
  
  
  CONCLUSIONS
  The present study demonstrates that acrolein has complex but pronounced interaction with the major apical Cl(-) transport mechanism that uses CFTR. Further investigations are required to determine acrolein's impact as a tobacco smoke constituent on mucociliary transport.
authors.affiliation: Department of Surgery/Division of Otolaryngology, Birmingham, Alabama, USA.
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Alexander
authors.forename: Angela
authors.initials: A
authors.lastname: Blount
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Skinner
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Hicks
authors.forename: Michael
authors.initials: M
authors.lastname: Chestnut
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Kebbel
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Bradford A
authors.initials: BA
authors.lastname: Woodworth
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009079:Mucociliary Clearance / Q000187:drug effects; D009297:Nasal Mucosa / Q000166:cytology; D012016:Reference Values; D015398:Signal Transduction; D012907:Smoking
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000171:Acrolein; D000242:Cyclic AMP