title: Alpha-1 antitrypsin augmentation therapy corrects accelerated neutrophil apoptosis in deficient individuals.
abstract: Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by neutrophil-driven lung destruction and early emphysema in a low AAT, and high neutrophil elastase environment in the lungs of affected individuals. In this study, we examined peripheral blood neutrophil apoptosis and showed it to be accelerated in individuals with AATD by a mechanism involving endoplasmic reticulum stress and aberrant TNF-α signaling. We reveal that neutrophil apoptosis in individuals homozygous for the Z allele (PiZZ) is increased nearly 2-fold compared with healthy controls and is associated with activation of the external death pathway. We demonstrate that in AATD, misfolded AAT protein accumulates in the endoplasmic reticulum of neutrophils, leading to endoplasmic reticulum stress and the expression of proapoptotic signals, including TNF-α, resulting in increased apoptosis and defective bacterial killing. In addition, treatment of AATD individuals with AAT augmentation therapy decreased neutrophil ADAM-17 activity and apoptosis in vivo and increased bacterial killing by treated cells. In summary, this study demonstrates that AAT can regulate neutrophil apoptosis by a previously unidentified and novel mechanism and highlights the role of AAT augmentation therapy in ameliorating inflammation in AATD.
authors.affiliation: Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
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.
authors.forename: Noreen
authors.initials: N
authors.lastname: Lacey
authors.affiliation: Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
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.
authors.forename: David A
authors.initials: DA
authors.lastname: Bergin
authors.affiliation: Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Oliver J
authors.initials: OJ
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.
authors.forename: M Emmet
authors.initials: ME
authors.lastname: O'Brien
authors.affiliation: Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Oisín F
authors.initials: OF
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 emerreeves@rcsi.ie.
authors.forename: Emer P
authors.initials: EP
authors.lastname: Reeves
authors.affiliation: Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000276:immunology*; D004646:Emphysema / Q000150:complications / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D019272:Leukocyte Elastase / Q000096:biosynthesis / Q000378:metabolism; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000627:therapeutic use*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human