Type

Journal Article

Authors

Emer P Reeves
Noel G McElvaney
Cormac McCarthy
Killian Hurley
Nessa Banville
Michelle M White
Mark R Wormald
M Emmet O'Brien
Ciara A O'Dwyer

Subjects

Veterinary

Topics
therapy plasma concentrations neutrophil elastase clinical applications 1 antitrypsin leukotriene b4 inflammatory diseases neutrophil

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling. (2015)

Abstract Leukotriene B4 (LTB4) contributes to many inflammatory diseases, including genetic and nongenetic forms of chronic obstructive pulmonary disease. α-1 Antitrypsin (AAT) deficiency (AATD) is characterized by destruction of lung parenchyma and development of emphysema, caused by low AAT levels and a high neutrophil burden in the airways of affected individuals. In this study we assessed whether AATD is an LTB4-related disease and investigated the ability of serum AAT to control LTB4 signaling in neutrophils. In vitro studies demonstrate that neutrophil elastase is a key player in the LTB4 inflammatory cycle in AATD, causing increased LTB4 production, and associated BLT1 membrane receptor expression. AATD patients homozygous for the Z allele were characterized by increased neutrophil adhesion and degranulation responses to LTB4. We demonstrate that AAT can bind LTB4 and that AAT/LTB4 complex formation modulates BLT1 engagement and downstream signaling events, including 1,4,5-triphosphate production and Ca(2+) flux. Additionally, treatment of ZZ-AATD individuals with AAT augmentation therapy decreased plasma LTB4 concentrations and reduced levels of membrane-bound neutrophil elastase. Collectively, these results provide a mechanism by which AAT augmentation therapy impacts on LTB4 signaling in vivo, and not only reinforces the utility of this therapy for resolving inflammation in AATD, but supports useful future clinical applications in treatment of other LTB4-related diseases.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Emer P Reeves, Noel G McElvaney, Cormac McCarthy, Killian Hurley, Nessa Banville, Michelle M White, Mark R Wormald, M Emmet O'Brien, Ciara A O'Dwyer

Experts in our system

1
Emer P Reeves
Royal College of Surgeons in Ireland
Total Publications: 63
 
2
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
3
Cormac McCarthy
Royal College of Surgeons in Ireland
Total Publications: 19
 
4
Nessa Banville
Maynooth University
Total Publications: 9
 
5
Michelle M White
Royal College of Surgeons in Ireland
Total Publications: 10
 
6
Mark R Wormald
Dublin City University
Total Publications: 5
 
7
M Emmet O'Brien
Royal College of Surgeons in Ireland
Total Publications: 9