• Mathieu Le Gars, Delphyne Descamps, Delphine Roussel, Emilie Saussereau, Loïc Guillot, Manon Ruffin, Olivier Tabary, Saw-See Hong, Pierre Boulanger, Marc Paulais, Laurette Malleret, Azzaq Belaaouaj, Aleksander Edelman, Michel Huerre, Michel Chignard, and Jean-Michel Sallenave.
• Institut Pasteur,Unité de Défense Innée et Inflammation, 25 rue du Dr Roux, 75724 Paris, France.
• Am. J. Respir. Crit. Care Med.. 2013 Jan 15;187(2):170-9.

RationaleCystic 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.ObjectivesTo test whether neutrophil elastase (NE) and neutrophil-mediated inflammation negatively impact CFTR structure and function, in vitro and in vivo.MethodsUsing 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 ResultsCFTR 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.ConclusionsThese 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.

26 keywords...

hide…