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 Ca2+ 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.

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

“…New insights into the diverse functions of AAT have demonstrated that AAT possesses unique anti-inflammatory properties independent of anti-protease function, affecting several cell types through the modulation of inflammation caused by leukotriene B 4 ,9 tumour necrosis factor alpha,10 CXCL-8,11 interferon gamma12 and interleukin-1β 13. Mechanisms of immune-regulation include direct binding of AAT to either receptors or antagonists, as demonstrated by AAT binding to CXCL-8 thereby controlling neutrophil migration 11.…”

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

“…Blood was drawn in 7.5-ml heparinized S-Monovette tubes (10 U/ml of heparin; Sarstedt, Germany). Neutrophils were purified by dextran sedimentation and Lymphoprep centrifugation (34). In brief, a 4-ml aliquot of 10% (wt/vol) dextran (M r , 500,000; Sigma, Ireland) was added to 40 ml of freshly collected blood; these components were gently mixed and allowed to settle.…”

Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association?

“…In particular, Jonigk et al [10] demonstrated that exogenous AAT, independent of its anti-elastase activity, can significantly lower the lipopolysaccharide (LPS)-induced release of two molecules involved in different inflammatory pathways: Tumor Necrosis Factor-α (TNF-α) and Interleukin-8 (IL-8). Bergin et al [11] and O'Dwyer et al [12] showed that AAT can directly bind IL-8 and leukotriene-B4 (LTB4), inhibiting their chemoattractant activities. In addition, AAT downregulates TNF-α gene expression by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling [13] and reduces LPS-induced synthesis and the release of active IL-1β [14], which is an important inflammatory mediator.…”