Neutrophil Elastase Degrades Cystic Fibrosis Transmembrane Conductance Regulator via Calpains and Disables Channel Function<i>In Vitro</i>and<i>In Vivo</i>

Gars, Mathieu Le; Descamps, Delphyne; Roussel, Delphine; Saussereau, Emilie; Guillot, Loïc; Ruffin, Manon; Tabary, Olivier; Hong, Saw-See; Boulanger, Pierre; Paulais, Marc; Malleret, Laurette; Belaaouaj, Abderrazzaq; Edelman, Aleksander; Huerre, Michel; Chignard, Michel; Sallenave, Jean–Michel

doi:10.1164/rccm.201205-0875oc

Cited by 94 publications

(72 citation statements)

References 48 publications

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“…Importantly, we validated these data in vivo, by showing : a) that the intranasal instillation of NE in WT C57/Bl6 mice inactivated CFTR structure and Cl -channel function, and b) that P.a lung infection also led to WT-CFTR inactivation, the latter being partly dependent on host NE activity (34). Indeed, following P.a lung infection, NE KO mice were still sensitive (albeit less than WT) to P.a-mediated CFTR degradation, compared to WT mice.…”

Section: Impaired Mucosal Innate Immune Response In Cf: a Role For Prsupporting

confidence: 58%

“…Mechanistically, we also demonstrated that NE cleaved CFTR through the activation of intracellular calpains (34).…”

Section: Impaired Mucosal Innate Immune Response In Cf: a Role For Prmentioning

confidence: 56%

“…We demonstrated that NE (in concentrations not affecting cell viability) was able to degrade both WT and ΔF508 CFTR in bronchial epithelial cells (34), and that this degradation resulted in complete loss of function, as assessed by patch-clamp analysis.…”

Section: Impaired Mucosal Innate Immune Response In Cf: a Role For Prmentioning

confidence: 84%

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2013

Pediatric Pulmonology

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Section: Impaired Mucosal Innate Immune Response In Cf: a Role For Prsupporting

confidence: 58%

“…Mechanistically, we also demonstrated that NE cleaved CFTR through the activation of intracellular calpains (34).…”

Section: Impaired Mucosal Innate Immune Response In Cf: a Role For Prmentioning

confidence: 56%

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2013

Pediatric Pulmonology

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“…Furthermore, recent studies demonstrated that NE leads to degradation and loss of CFTR Cl -channel function through a pathway involving the activation of intracellular calpains ( fig. 1) [47]. Therefore, an imbalance between NE and potentially other proteases released from inflammatory cells or bacteria on the one hand, and protective anti-proteases on the other hand [44], may inevitably aggravate airway surface dehydration and also impede therapeutic approaches targeting the basic ion transport defect in CF airways once chronic inflammation and infection are established.…”

Section: Airway Proteases Aggravate Basic Cf Ion Transport Defectmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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“…However, the consequences of exposure to infections on CFTR channel expression and function have not been clearly defined. In fact, contradictory results have been reported depending on the bacterial strain, the duration of exposure to infection, as well as the cellular models tested [6][7][8][9]. However, it is crucial to understand the outcomes of microbial infection on CFTR.…”

Section: Introductionmentioning

confidence: 99%

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

et al. 2015

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The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells.CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements.A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells.These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors. @ERSpublications Exposure of airway epithelial cell to P. aeruginosa impairs CFTR function, expression and rescue by correctors http://ow.ly/IleTw

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Neutrophil Elastase Degrades Cystic Fibrosis Transmembrane Conductance Regulator via Calpains and Disables Channel FunctionIn VitroandIn Vivo

Abstract: 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.

Cited by 94 publications

References 48 publications

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Symposium Session Summaries

CFTR: cystic fibrosis and beyond

Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells

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