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Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.<\/jats:p>","DOI":"10.4049\/jimmunol.2300658","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T14:11:51Z","timestamp":1715955111000},"page":"75-85","source":"Crossref","is-referenced-by-count":11,"title":["Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation"],"prefix":"10.1093","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5624-1338","authenticated-orcid":false,"given":"Mark P","family":"Murphy","sequence":"first","affiliation":[{"name":"Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5527-7427","authenticated-orcid":false,"given":"David","family":"Hunt","sequence":"additional","affiliation":[{"name":"Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8117-2311","authenticated-orcid":false,"given":"Malcolm","family":"Herron","sequence":"additional","affiliation":[{"name":"Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"McDonnell","sequence":"additional","affiliation":[{"name":"Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashed","family":"Alshuhoumi","sequence":"additional","affiliation":[{"name":"Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2860-0302","authenticated-orcid":false,"given":"Lorcan P","family":"McGarvey","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Royal Victoria Hospital; Belfast Health Social Care Trust , Belfast ,","place":["United Kingdom"]},{"name":"Wellcome\u2013Wolfson Centre for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen\u2019s University Belfast , Belfast ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelie","family":"Fabr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Histopathology, St. Vincent\u2019s University Hospital and Department of Medicine, University College Dublin , Dublin ,","place":["Ireland"]},{"name":"School of Medicine, University College Dublin , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6406-1860","authenticated-orcid":false,"given":"Helen","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, St. Vincent\u2019s University Hospital , Elm Park, Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac","family":"McCarthy","sequence":"additional","affiliation":[{"name":"School of Medicine, University College Dublin , Dublin ,","place":["Ireland"]},{"name":"Department of Respiratory Medicine, St. Vincent\u2019s University Hospital , Elm Park, Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-0610","authenticated-orcid":false,"given":"S Lorraine","family":"Martin","sequence":"additional","affiliation":[{"name":"Biomolecular Sciences Research Group, School of Pharmacy, Queen\u2019s University Belfast , Belfast ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel G","family":"McElvaney","sequence":"additional","affiliation":[{"name":"Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-0447","authenticated-orcid":false,"given":"Emer P","family":"Reeves","sequence":"additional","affiliation":[{"name":"Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"2025012305004093900_r1","volume-title":"Global Health Estimates 2020: deaths by cause, age, sex, by country and region, 2000\u20132019","author":"WHO","year":"2012"},{"key":"2025012305004093900_r2","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1172\/JCI60324","article-title":"Pathogenesis of chronic obstructive pulmonary disease","volume":"122","author":"Tuder","year":"2012","journal-title":"J. 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