title: Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR.
abstract: BACKGROUND
  Cystic fibrosis transmembrane conductance regulator plays a key role in maintenance of lung fluid homeostasis. Cigarette smoke decreases CFTR expression in the lung but neither the mechanisms leading to CFTR loss, nor potential ways to prevent its loss have been identified to date.
  
  
  METHODS
  The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing ribonucleic acids (RNAs).
  
  
  RESULTS
  Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK (MEK: mitogen-activated protein kinase/ERK kinase Erk1/2: extracellular signal-regulated kinase 1/2 MAPK: Mitogen-activated protein kinase) pathway regulating cell survival. Interestingly, pharmacological inhibition of the MEK/Erk1/2 MAPK pathway prevented the loss of plasma membrane CFTR upon cigarette smoke exposure. Similarly, decreased expression of Erk1/2 using silencing RNAs prevented the suppression of CFTR protein by cigarette smoke. Conversely, specific inhibitors of the c-Jun N-terminal kinase (JNK) or p38 MAPK pathways had no effect on CFTR decrease after cigarette smoke exposure. In addition, inhibition of the MEK/Erk1/2 MAPK pathway prevented the reduction of the airway surface liquid observed upon cigarette smoke exposure of primary human airway epithelial cells. Finally, addition of the antioxidant N-acetylcysteine inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR.
  
  
  CONCLUSIONS
  These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells.
  
  
  CONCLUSIONS
  The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Balsiger
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Prosper N
authors.initials: PN
authors.lastname: Boyaka
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tarran
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA. Electronic address: boyaka.2@osu.edu.
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D034622:RNA Interference; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014162:Transfection
chemical_list: D000975:Antioxidants; C505032:CFTR protein, human; D047428:Protein Kinase Inhibitors; D012906:Smoke; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D050721:Proto-Oncogene Proteins c-cbl; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C067419:CBL protein, human
keywords: Airway epithelial cell; CFTR; Cigarette smoke; MAPK pathway