title: The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling.
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.
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Ciara A
authors.initials: CA
authors.lastname: O'Dwyer
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: M Emmet
authors.initials: ME
authors.lastname: O'Brien
authors.affiliation: Department of Biochemistry, Oxford Glycobiology Institute, University of Oxford, Oxford OX1 3QU, United Kingdom.
authors.forename: Mark R
authors.identifier: http://orcid.org/0000-0002-4853-2773
authors.initials: MR
authors.lastname: Wormald
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: White
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Nessa
authors.initials: N
authors.lastname: Banville
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Killian
authors.initials: K
authors.lastname: Hurley
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Cormac
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and.
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; and emerreeves@rcsi.ie.
authors.forename: Emer P
authors.initials: EP
authors.lastname: Reeves
mesh_terms: D000328:Adult; D020013:Calcium Signaling / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology*; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D018102:Receptors, Leukotriene B4 / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000276:immunology* / Q000627:therapeutic use; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: C513240:LTB4R protein, human; D018102:Receptors, Leukotriene B4; D000515:alpha 1-Antitrypsin; D007975:Leukotriene B4; D019272:Leukocyte Elastase