Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo

Am J Respir Crit Care Med. 2013 Jan 15;187(2):170-9. doi: 10.1164/rccm.201205-0875OC. Epub 2012 Dec 6.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calpain / metabolism
  • Calpain / physiology*
  • Chloride Channels / physiology
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Epithelium / physiology
  • Humans
  • Leukocyte Elastase / metabolism
  • Leukocyte Elastase / physiology*
  • Lung / metabolism
  • Lung / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Patch-Clamp Techniques
  • Pneumonia, Bacterial / etiology
  • Pneumonia, Bacterial / physiopathology
  • Pseudomonas Infections / etiology
  • Pseudomonas Infections / physiopathology


  • Chloride Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Leukocyte Elastase
  • Calpain