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COPD lungs exhibit an influx of circulating innate immune cells, which, when isolated, display impaired functions, including imbalanced protease secretion. In addition to immune cells, the extracellular matrix (ECM) plays a crucial role in COPD pathology. Remodeling of the ECM can generate ECM fragments, which can be released into circulation and subsequently induce pro-inflammatory responses. COPD is a heterogeneous disease, and serological biomarkers can be used to sub-categorize COPD patients for targeted treatments and optimal recruitment in clinical trials. This study evaluated fragments of calprotectin, collagen type VI, and versican, generated by neutrophil elastase and matrix metalloproteinases (MMP-) 2 and 12, respectively, as potential biomarkers of COPD disease, severity, and endotypes. Lower plasma levels of a neoepitope marker of calprotectin, indicative of activated neutrophils (nordicCPa9-HNETM), were detected in COPD donors compared to controls. CPa9-HNE was associated with milder disease, higher degree of air-trapping, and higher serum levels of MMP-2. Deposition of CPa9-HNE levels in lung tissue revealed no differences between groups. Taken together, CPa9-HNE was found to be a potential marker of mild COPD, but further studies are warranted to validate our findings.<\/jats:p>","DOI":"10.3390\/cells14151155","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T07:57:24Z","timestamp":1753689444000},"page":"1155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Calprotectin Fragment, CPa9-HNE, Is a Plasma Biomarker of Mild Chronic Obstructive Pulmonary Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Mugdha M.","family":"Joglekar","sequence":"first","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannie M. B.","family":"Sand","sequence":"additional","affiliation":[{"name":"Nordic Bioscience A\/S, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Borghuis","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4256-140X","authenticated-orcid":false,"given":"Diana J.","family":"Leeming","sequence":"additional","affiliation":[{"name":"Nordic Bioscience A\/S, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-8740","authenticated-orcid":false,"given":"Morten","family":"Karsdal","sequence":"additional","affiliation":[{"name":"Nordic Bioscience A\/S, 2730 Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3503-1694","authenticated-orcid":false,"given":"Frank","family":"Klont","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, Epidemiology, and Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"},{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P.","family":"Bowler","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7091-907X","authenticated-orcid":false,"given":"Barbro N.","family":"Melgert","sequence":"additional","affiliation":[{"name":"Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9868-9966","authenticated-orcid":false,"given":"Janette K.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7345-8061","authenticated-orcid":false,"given":"Simon D.","family":"Pouwels","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev.pathol.4.110807.092145","article-title":"The pathology of chronic obstructive pulmonary disease","volume":"4","author":"Hogg","year":"2009","journal-title":"Annu. 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