Type

Journal Article

Authors

Noel G McElvaney
Emer P Reeves
Martin Clynes
Michelle M White
Oliver J McElvaney
Cormac McCarthy
David A Bergin
Bakr Jundi
Kevin Molloy
Paula Meleady
and 4 others

Subjects

Microbiology

Topics
mutation cell degranulation female rab gtp binding proteins cystic fibrosis transmembrane conductance regulator tumor necrosis factor alpha genetics neutrophils metabolism sodium drug therapy magnesium proteomics rab27a protein human male quinolones electrophoresis gel two dimensional young adult chlorides homeostasis physiology pharmacology proteome immunoblotting aminophenols cftr protein human cells cultured therapeutic use drug effects humans adult protein transport cystic fibrosis

A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. (2014)

Abstract Studies have endeavored to reconcile whether dysfunction of neutrophils in people with cystic fibrosis (CF) is a result of the genetic defect or is secondary due to infection and inflammation. In this study, we illustrate that disrupted function of the CF transmembrane conductance regulator (CFTR), such as that which occurs in patients with ∆F508 and/or G551D mutations, correlates with impaired degranulation of antimicrobial proteins. We demonstrate that CF blood neutrophils release less secondary and tertiary granule components compared with control cells and that activation of the low-molecular-mass GTP-binding protein Rab27a, involved in the regulation of granule trafficking, is defective. The mechanism leading to impaired degranulation involves altered ion homeostasis caused by defective CFTR function with increased cytosolic levels of chloride and sodium, yet decreased magnesium measured in CF neutrophils. Decreased magnesium concentration in vivo and in vitro resulted in significantly decreased levels of GTP-bound Rab27a. Treatment of G551D patients with the ion channel potentiator ivacaftor resulted in normalized neutrophil cytosolic ion levels and activation of Rab27a, thereby leading to increased degranulation and bacterial killing. Our results confirm that intrinsic alterations of circulating neutrophils from patients with CF are corrected by ivacaftor, thus illustrating additional clinical benefits for CFTR modulator therapy.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Noel G McElvaney, Emer P Reeves, Martin Clynes, Michelle M White, Oliver J McElvaney, Cormac McCarthy, David A Bergin, Bakr Jundi, Kevin Molloy, Paula Meleady and 4 others

Experts in our system

1
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 190
 
2
Emer P Reeves
Royal College of Surgeons in Ireland
Total Publications: 58
 
3
Martin Clynes
Dublin City University
Total Publications: 209
 
4
Michelle M White
Royal College of Surgeons in Ireland
Total Publications: 10
 
5
Oliver J McElvaney
Royal College of Surgeons in Ireland
 
6
Cormac McCarthy
Royal College of Surgeons in Ireland
Total Publications: 19
 
7
David A Bergin
Royal College of Surgeons in Ireland
Total Publications: 27
 
8
Kevin Molloy
Royal College of Surgeons in Ireland
Total Publications: 19
 
9
Paula Meleady
Dublin City University
Total Publications: 95