{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:55:26Z","timestamp":1792788926910,"version":"4.5.0"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T00:00:00Z","timestamp":1725235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2017 Sociedad Valenciana de Neumologi\u00eda","award":["ISCIII #PI17\/01250"],"award-info":[{"award-number":["ISCIII #PI17\/01250"]}]},{"name":"2017 Sociedad Valenciana de Neumologi\u00eda","award":["ACIF\/2019\/231"],"award-info":[{"award-number":["ACIF\/2019\/231"]}]},{"name":"European Regional Development Funds (FEDER)","award":["ISCIII #PI17\/01250"],"award-info":[{"award-number":["ISCIII #PI17\/01250"]}]},{"name":"European Regional Development Funds (FEDER)","award":["ACIF\/2019\/231"],"award-info":[{"award-number":["ACIF\/2019\/231"]}]},{"name":"2021 Amadeu Monteiro","award":["ISCIII #PI17\/01250"],"award-info":[{"award-number":["ISCIII #PI17\/01250"]}]},{"name":"2021 Amadeu Monteiro","award":["ACIF\/2019\/231"],"award-info":[{"award-number":["ACIF\/2019\/231"]}]},{"DOI":"10.13039\/501100003359","name":"GVA","doi-asserted-by":"publisher","award":["ISCIII #PI17\/01250"],"award-info":[{"award-number":["ISCIII #PI17\/01250"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"GVA","doi-asserted-by":"publisher","award":["ACIF\/2019\/231"],"award-info":[{"award-number":["ACIF\/2019\/231"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Alpha-1 antitrypsin deficiency (AATD) is an inflammatory disorder where neutrophils play a key role. Excessive neutrophil activation leads to local hypoxia and tissue damage. Most research on neutrophil function has been conducted under atmospheric conditions (21% O2), which may not represent physiological or pathological conditions. This study aimed to determine the effects of hypoxia on neutrophil degranulation and cytokine production in AATD patients. Methods: Neutrophils isolated from 54 AATD patients (31 MZ; 8 SZ; 15 ZZ) and 7 controls (MM) were exposed to hypoxia (1% O2) for 4 h. Neutrophil degranulation was assessed by measuring elastase (NE), myeloperoxidase (MPO), lactoferrin, and matrix metalloproteinase-9 (MMP-9) levels using immunoassay-based methods. Pro-inflammatory (IL-8, IL-1 beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-4 and IL-10) cytokine levels were assessed by a Luminex-based method. Results: Our results indicate a significantly increased release of NE (p = 0.015), MPO (p = 0.042), lactoferrin (p = 0.015), and MMP-9 (p = 0.001) compared to controls. Pro-inflammatory cytokines show a significant rise in IL-8 (p = 0.019), a trend towards increased IL-1 beta (p = 0.3196), no change in IL-6 (p = 0.7329), and reduced TNF-alpha (p = 0.006). Anti-inflammatory cytokines show increased IL-4 (p = 0.057) and decreased IL-10 (p = 0.05703). Conclusions: Increased neutrophil degranulation and inflammatory phenotype are observed in AATD neutrophils under physiological hypoxia.<\/jats:p>","DOI":"10.3390\/antiox13091071","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T06:51:17Z","timestamp":1725259877000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Impact of Hypoxia on Neutrophil Degranulation and Inflammatory Response in Alpha-1 Antitrypsin Deficiency Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Mar\u00eda","family":"Magall\u00f3n","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0121-2676","authenticated-orcid":false,"given":"Silvia","family":"Castillo-Corull\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"},{"name":"Paediatrics Unit, Hospital Cl\u00ednico Universitario de Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 17, 46010 Valencia, Spain"},{"name":"Department of Paediatrics, School of Medicine, University of Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Ba\u00f1uls","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Romero","sequence":"additional","affiliation":[{"name":"Pediatrics Unit, Hospital de Manises, Avda. Generalitat Valenciana, 50, 46940 Manises, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3285-2609","authenticated-orcid":false,"given":"Daniel","family":"Pellicer","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Herrej\u00f3n","sequence":"additional","affiliation":[{"name":"Pulmonology Unit, Hospital Universitario Doctor Peset, Avda. Gaspar Aguilar, 90, 46017 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Mercedes","family":"Navarro-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-5832","authenticated-orcid":false,"given":"Cruz","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"},{"name":"Pulmonology Unit, Hospital Cl\u00ednico Universitario de Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 17, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2938-2965","authenticated-orcid":false,"given":"Francisco","family":"Das\u00ed","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, University of Valencia, Avda. Blasco Ib\u00e1\u00f1ez, 15, 46010 Valencia, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria INCLIVA, Rare Respiratory Diseases Group, Avda. Men\u00e9ndez y Pelayo, 4, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13023-018-0856-9","article-title":"Alpha-1 Antitrypsin Deficiency: Outstanding Questions and Future Directions","volume":"13","author":"Barrecheguren","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","first-page":"3183","article-title":"Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency","volume":"15","author":"Belchamber","year":"2020","journal-title":"Int. J. Chronic Obstr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S297","DOI":"10.1513\/AnnalsATS.201509-634KV","article-title":"The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency","volume":"13","author":"McCarthy","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S305","DOI":"10.1513\/AnnalsATS.201510-671KV","article-title":"Alpha-1 Antitrypsin Deficiency: Beyond the Protease\/Antiprotease Paradigm","volume":"13","author":"Cosio","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S280","DOI":"10.1513\/AnnalsATS.201507-468KV","article-title":"Well-Known and Less Well-Known Functions of Alpha-1 Antitrypsin. Its Role in Chronic Obstructive Pulmonary Disease and Other Disease Developments","volume":"13","author":"Janciauskiene","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1136\/thoraxjnl-2016-208879","article-title":"Neutrophils and Tissue Damage: Is Hypoxia the Key to Excessive Degranulation?","volume":"71","author":"Williams","year":"2016","journal-title":"Thorax"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8238459","DOI":"10.1155\/2018\/8238459","article-title":"How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen-Consuming Reactions","volume":"2018","author":"Stuart","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Alva, R., Gardner, G.L., Liang, P., and Stuart, J.A. (2022). Supraphysiological Oxygen Levels in Mammalian Cell Culture: Current State and Future Perspectives. Cells, 11.","DOI":"10.3390\/cells11193123"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1136\/thoraxjnl-2015-207604","article-title":"Hypoxia Upregulates Neutrophil Degranulation and Potential for Tissue Injury","volume":"71","author":"Hoenderdos","year":"2016","journal-title":"Thorax"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1164\/rccm.201305-0986OC","article-title":"Hypoxia Promotes Danger-Mediated Inflammation via Receptor for Advanced Glycation End Products in Cystic Fibrosis","volume":"188","author":"Iannitti","year":"2013","journal-title":"Am. J. Resp. Crit. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1053\/rmed.2000.0947","article-title":"Blood Gases at Rest and during Exercise in Patients with Alpha1-Pi Deficiency","volume":"94","author":"Wencker","year":"2000","journal-title":"Resp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1378\/chest.100.5.1323","article-title":"Hypoxia and Cyanosis in Alpha-1-Antitrypsin Deficiency Cirrhosis as an Unusual Etiologic Factor","volume":"100","author":"Feuerstein","year":"1991","journal-title":"Chest"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lodge, K.M., Cowburn, A.S., Li, W., and Condliffe, A.M. (2020). The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041183"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1515\/hsz-2012-0335","article-title":"Hypoxia, the HIF Pathway and Neutrophilic Inflammatory Responses","volume":"394","author":"Thompson","year":"2013","journal-title":"Bchm"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1165\/rcmb.2012-0492TR","article-title":"The Neutrophil in Chronic Obstructive Pulmonary Disease","volume":"48","author":"Hoenderdos","year":"2013","journal-title":"Am. J. Resp. Cell. Mol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Magall\u00f3n, M., Castillo-Corull\u00f3n, S., Ba\u00f1uls, L., Pellicer, D., Romero, T., Mart\u00ednez-Ferraro, C., Navarro-Garc\u00eda, M.M., Herrej\u00f3n, A., Gonz\u00e1lez, C., and Das\u00ed, F. (2023). Hypoxia Enhances Oxidative Stress in Neutrophils from ZZ Alpha-1 Antitrypsin Deficiency Patients. Antioxidants, 12.","DOI":"10.3390\/antiox12040872"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1084\/jem.20040624","article-title":"Hypoxia-Induced Neutrophil Survival Is Mediated by HIF-1alpha-Dependent NF-KappaB Activity","volume":"201","author":"Walmsley","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0014-5793(95)00986-J","article-title":"Hypoxia Prolongs Neutrophil Survival in Vitro","volume":"372","author":"Hannah","year":"1995","journal-title":"Febs. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/00024382-200204000-00005","article-title":"Acute Hypoxemia in Humans Enhances the Neutrophil Inflammatory Response","volume":"17","author":"Tamura","year":"2002","journal-title":"Shock"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"453","DOI":"10.4049\/jimmunol.1002213","article-title":"Hypoxia Selectively Inhibits Respiratory Burst Activity and Killing of Staphylococcus Aureus in Human Neutrophils","volume":"186","author":"McGovern","year":"2011","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1901678","DOI":"10.1183\/13993003.01678-2019","article-title":"A1 Antitrypsin Therapy Modulates the Neutrophil Membrane Proteome and Secretome","volume":"55","author":"Murphy","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.bbrc.2005.07.175","article-title":"Hypoxia Reduces Constitutive and TNF-\u03b1-Induced Expression of Monocyte Chemoattractant Protein-1 in Human Proximal Renal Tubular Cells","volume":"335","author":"Li","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/ijo.2011.200","article-title":"Hypoxia Reduces the Response of Human Adipocytes towards TNF\u03b1 Resulting in Reduced NF-\u039aB Signaling and MCP-1 Secretion","volume":"36","author":"Famulla","year":"2012","journal-title":"Int. J. Obes."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1189\/jlb.0208145","article-title":"A-1-Antitrypsin Is an Endogenous Inhibitor of Proinflammatory Cytokine Production in Whole Blood","volume":"85","author":"Pott","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35494","DOI":"10.1074\/jbc.M103543200","article-title":"Interleukin-8 Up-Regulation by Neutrophil Elastase Is Mediated by MyD88\/IRAK\/TRAF-6 in Human Bronchial Epithelium*","volume":"276","author":"Walsh","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1136\/thx.2005.043471","article-title":"Neutrophilic Inflammation and IL-8 Levels in Induced Sputum of Alpha-1-Antitrypsin PiMZ Subjects","volume":"61","author":"Malerba","year":"2006","journal-title":"Thorax"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0014-5793(03)00482-4","article-title":"Neutrophil Elastase Up-regulates Interleukin-8 via Toll-like Receptor","volume":"544","author":"Devaney","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1136\/thorax-2023-221071","article-title":"Monocyte NLRP3 Inflammasome and Interleukin-1\u03b2 Activation Modulated by Alpha-1 Antitrypsin Therapy in Deficient Individuals","volume":"79","author":"Gogoi","year":"2024","journal-title":"Thorax"},{"key":"ref_29","first-page":"203","article-title":"Anti-Cytokines as a Strategy in Alpha-1 Antitrypsin Deficiency","volume":"7","author":"McElvaney","year":"2020","journal-title":"Chronic Obstr. Pulm. Dis. J. COPD Found."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/9\/1071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:47:10Z","timestamp":1760111230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/9\/1071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,2]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["antiox13091071"],"URL":"https:\/\/doi.org\/10.3390\/antiox13091071","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,2]]}}}