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

• Published in: The Journal of immunology (1950) Vol. 195; no. 8; pp. 3628 - 3641
• Main Authors: O'Dwyer, Ciara A, O'Brien, M Emmet, Wormald, Mark R, White, Michelle M, Banville, Nessa, Hurley, Killian, McCarthy, Cormac, McElvaney, Noel G, Reeves, Emer P
• Format: Journal Article
• Language: English
• Published: United States 15.10.2015
• Subjects: Adult; alpha 1-Antitrypsin - immunology; alpha 1-Antitrypsin - therapeutic use; alpha 1-Antitrypsin Deficiency - drug therapy; alpha 1-Antitrypsin Deficiency - immunology; alpha 1-Antitrypsin Deficiency - pathology; Calcium Signaling - immunology; Cell Degranulation - immunology; Female; Humans; Leukocyte Elastase - immunology; Leukotriene B4 - immunology; Lung - immunology; Lung - pathology; Male; Neutrophils - immunology; Neutrophils - pathology; Receptors, Leukotriene B4 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500038

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.