title: Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo.
abstract: BACKGROUND
  Cystic fibrosis transmembrane conductance regulator (CFTR) protein is a chloride channel regulating fluid homeostasis at epithelial surfaces. Its loss of function induces hypohydration, mucus accumulation, and bacterial infections in CF and potentially other lung chronic diseases.
  
  
  OBJECTIVE
  To test whether neutrophil elastase (NE) and neutrophil-mediated inflammation negatively impact CFTR structure and function, in vitro and in vivo.
  
  
  METHODS
  Using an adenovirus-CFTR overexpression approach, we showed that NE degrades wild-type (WT)- and ΔF508-CFTR in vitro and WT-CFTR in mice through a new pathway involving the activation of intracellular calpains.
  
  
  RESULTS
  CFTR degradation triggered a loss of function, as measured in vitro by channel patch-clamp and in vivo by nasal potential recording in mice. Importantly, this mechanism was also shown to be operative in a Pseudomonas aeruginosa lung infection murine model, and was NE-dependent, because CFTR integrity was significantly protected in NE(-/-) mice compared with WT mice.
  
  
  CONCLUSIONS
  These data provide a new mechanism and show for the first time a link between NE-calpains activation and CFTR loss of function in bacterial lung infections relevant to CF and to other chronic inflammatory lung conditions.
authors.affiliation: Institut Pasteur,Unité de Défense Innée et Inflammation, 25 rue du Dr Roux, 75724 Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Le Gars
authors.forename: Delphyne
authors.initials: D
authors.lastname: Descamps
authors.forename: Delphine
authors.initials: D
authors.lastname: Roussel
authors.forename: Emilie
authors.initials: E
authors.lastname: Saussereau
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillot
authors.forename: Manon
authors.initials: M
authors.lastname: Ruffin
authors.forename: Olivier
authors.initials: O
authors.lastname: Tabary
authors.forename: Saw-See
authors.initials: SS
authors.lastname: Hong
authors.forename: Pierre
authors.initials: P
authors.lastname: Boulanger
authors.forename: Marc
authors.initials: M
authors.lastname: Paulais
authors.forename: Laurette
authors.initials: L
authors.lastname: Malleret
authors.forename: Azzaq
authors.initials: A
authors.lastname: Belaaouaj
authors.forename: Aleksander
authors.initials: A
authors.lastname: Edelman
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism / Q000502:physiology*; D018118:Chloride Channels / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000503:physiopathology; D011552:Pseudomonas Infections / Q000209:etiology / Q000503:physiopathology
chemical_list: D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019272:Leukocyte Elastase; D002154:Calpain