{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T02:27:37Z","timestamp":1775960857007,"version":"3.50.1"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-\u03b1 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-\u03b1, 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1400132","type":"journal-article","created":{"date-parts":[[2014,9,13]],"date-time":"2014-09-13T02:59:41Z","timestamp":1410577181000},"page":"3978-3991","source":"Crossref","is-referenced-by-count":59,"title":["Alpha-1 Antitrypsin Augmentation Therapy Corrects Accelerated Neutrophil Apoptosis in Deficient Individuals"],"prefix":"10.1093","volume":"193","author":[{"given":"Killian","family":"Hurley","sequence":"first","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noreen","family":"Lacey","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciara A","family":"O\u2019Dwyer","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Bergin","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver J","family":"McElvaney","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Emmet","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ois\u00edn F","family":"McElvaney","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emer P","family":"Reeves","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noel G","family":"McElvaney","sequence":"additional","affiliation":[{"name":"Respiratory Research Division, Department of Medicine Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin 9 ,","place":["Ireland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,10,15]]},"reference":[{"key":"2025030707405619900_r1","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1172\/JCI110360","article-title":"Replacement therapy of alpha 1-antitrypsin deficiency: reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects","volume":"68","author":"Gadek","year":"1981","journal-title":"J. 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