{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:40:20Z","timestamp":1792118420745,"version":"4.4.0"},"reference-count":52,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,11,16]],"date-time":"2025-11-16T00:00:00Z","timestamp":1763251200000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23HL173570"],"award-info":[{"award-number":["K23HL173570"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL127349"],"award-info":[{"award-number":["R01HL127349"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL141852"],"award-info":[{"award-number":["R01HL141852"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL112707"],"award-info":[{"award-number":["U01HL112707"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["UH2HL123886"],"award-info":[{"award-number":["UH2HL123886"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open Resp Res"],"accepted":{"date-parts":[[2025,10,26]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>There is an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygotes for the alpha-1 antitrypsin (AAT) Z allele (PI*MZ), but there is significant variation in outcomes. Matrix metalloproteinases (MMPs) contribute to worse airway disease and emphysema. Given that the AAT protein is an antiprotease, we hypothesised that MMPs play a modifying role among AAT-deficient individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied PI*MZ (n=39) and PI*ZZ (n=27) individuals from the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study cohort. MMP (MMP3, MMP9, MMP10, MMP12 and MMP15) gene expression was assessed in bronchoalveolar lavage cells and peripheral blood mononuclear cells. Plasma protein MMP (MMP3, MMP9, MMP10 and MMP12) expression was assessed using SomaScan and BAL MMP15 protein using ELISA. MMP values were log-transformed, and linear regression analyses were used to assess lung function, patient-reported outcomes and CT emphysema adjusted for age, body mass index, sex and duration of smoking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Alveolar MMP3 and MMP15 were uniquely associated with worse lung function, patient-reported outcomes and emphysema among PI*MZ individuals. MMP10 was associated with less disease severity among PI*MZ individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study shows that alveolar MMP3 and MMP15 may uniquely contribute to disease among PI*MZ individuals, raising the possibility that they could serve as biomarkers or therapeutic targets in this highly prevalent COPD phenotype. Furthermore, we show that MMP10 may serve a protective effect. In aggregate, these data support further studies of the MMP pathway among lung-affected PI*MZ individuals, as they may serve as biomarkers or pharmacological targets in future studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjresp-2025-003585","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T07:40:25Z","timestamp":1763451625000},"page":"e003585","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Matrix metalloproteinases and disease severity among PI*MZ and PI*ZZ individuals in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) cohort"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2100-6148","authenticated-orcid":false,"given":"Vickram","family":"Tejwani","sequence":"first","affiliation":[{"name":"Department of Pulmonary, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, Ohio, USA"},{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P","family":"Bowler","sequence":"additional","affiliation":[{"name":"Department of Pulmonary, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, Ohio, USA"},{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina A","family":"Serban","sequence":"additional","affiliation":[{"name":"University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Pratte","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, National Jewish Health, Denver, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor E","family":"Ortega","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K","family":"Stoller","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-4601","authenticated-orcid":false,"given":"Naftali","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Yale School of Medicine Shield Education Patient Care Research Internal Medicine, Yale School of Medicine Shield Education Patient Care Research, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Strange","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Medical University of SC, Charleston, SC, South Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"2026010701520112000_12.1.e003585.1","unstructured":"Kochanek KD , Murphy SL , Xu J , et al . Mortality in the United States. NCHS Data Brief, 2016:1\u20138."},{"key":"2026010701520112000_12.1.e003585.2","doi-asserted-by":"crossref","DOI":"10.1177\/2040622321995691","article-title":"The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency","volume":"12_suppl","author":"Tejwani","year":"2021","journal-title":"Ther Adv Chronic Dis"},{"key":"2026010701520112000_12.1.e003585.3","doi-asserted-by":"publisher","DOI":"10.1177\/1753465812457113"},{"key":"2026010701520112000_12.1.e003585.4","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.2147\/COPD.S327803","article-title":"Estimated Prevalence and Number of PiMZ Genotypes of Alpha-1 Antitrypsin in Seventy-Four Countries Worldwide","volume":"Volume 16","author":"Martinez-Gonz\u00e1lez","year":"2021","journal-title":"COPD"},{"key":"2026010701520112000_12.1.e003585.5","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-136-4-200202190-00006"},{"key":"2026010701520112000_12.1.e003585.6","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1164\/rccm.202106-1404OC","article-title":"Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease","volume":"205","author":"Ghosh","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"key":"2026010701520112000_12.1.e003585.7","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201611-838OC"},{"key":"2026010701520112000_12.1.e003585.8","doi-asserted-by":"crossref","DOI":"10.1186\/s12931-025-03322-6","article-title":"Increased exacerbations and hospitalizations among PI*MZ compared to PI*MM individuals: an electronic health record analysis","volume":"26","author":"Tejwani","year":"2025","journal-title":"Respir Res"},{"key":"2026010701520112000_12.1.e003585.9","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1513\/AnnalsATS.202411-1209OC","article-title":"Longitudinal Outcomes in Pi*MZ Alpha-1 Antitrypsin-Deficient Individuals with Tobacco Smoking History from the SPIROMICS Cohort","volume":"22","author":"Barjaktarevic","year":"2025","journal-title":"Ann Am Thorac Soc"},{"key":"2026010701520112000_12.1.e003585.10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201904-0769OC"},{"key":"2026010701520112000_12.1.e003585.11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.matbio.2018.01.018","article-title":"Matrix metalloproteinases in emphysema","volume":"73","author":"Gharib","year":"2018","journal-title":"Matrix Biol"},{"key":"2026010701520112000_12.1.e003585.12","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207428"},{"key":"2026010701520112000_12.1.e003585.13","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00212114"},{"key":"2026010701520112000_12.1.e003585.14","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/febs.16127","article-title":"Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis","volume":"289","author":"Wilkinson","year":"2022","journal-title":"FEBS J"},{"key":"2026010701520112000_12.1.e003585.15","doi-asserted-by":"crossref","unstructured":"Bchir S , Ben Nasr H , Garrouch A , et al . MMP-3 (-1171 5A\/6A; Lys45Glu) variants affect serum levels of matrix metalloproteinase (MMP)-3 and correlate with severity of COPD: A study of MMP-3, MMP-7 and MMP-12 in a Tunisian population. J Gene Med 2018;20. doi:10.1002\/jgm.2999","DOI":"10.1002\/jgm.2999"},{"key":"2026010701520112000_12.1.e003585.16","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3787"},{"key":"2026010701520112000_12.1.e003585.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904006"},{"key":"2026010701520112000_12.1.e003585.18","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00481.2007"},{"key":"2026010701520112000_12.1.e003585.19","doi-asserted-by":"crossref","first-page":"899","DOI":"10.4049\/jimmunol.1600502","article-title":"Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation","volume":"197","author":"McMahan","year":"2016","journal-title":"The Journal of Immunology"},{"key":"2026010701520112000_12.1.e003585.20","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201503-143OC"},{"key":"2026010701520112000_12.1.e003585.21","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2019-214301"},{"key":"2026010701520112000_12.1.e003585.22","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2022.104262","article-title":"Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease","volume":"84","author":"Serban","year":"2022","journal-title":"EBioMedicine"},{"key":"2026010701520112000_12.1.e003585.23","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2006-0345OC"},{"key":"2026010701520112000_12.1.e003585.24","doi-asserted-by":"crossref","DOI":"10.1096\/fj.202001801R","article-title":"Alpha\u20101\u2010antitrypsin reduces inflammation and exerts chondroprotection in arthritis","volume":"35","author":"Kaneva","year":"2021","journal-title":"The FASEB Journal"},{"key":"2026010701520112000_12.1.e003585.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00087-8"},{"key":"2026010701520112000_12.1.e003585.26","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.088559"},{"key":"2026010701520112000_12.1.e003585.27","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1148\/radiol.2020191429","article-title":"Five-year Progression of Emphysema and Air Trapping at CT in Smokers with and Those without Chronic Obstructive Pulmonary Disease: Results from the COPDGene Study","volume":"295","author":"Pompe","year":"2020","journal-title":"Radiology"},{"key":"2026010701520112000_12.1.e003585.28","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2010-11-12-220","article-title":"From RNA-seq reads to differential expression results","volume":"11","author":"Oshlack","year":"2010","journal-title":"Genome Biol"},{"key":"2026010701520112000_12.1.e003585.29","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/nature08872","article-title":"Understanding mechanisms underlying human gene expression variation with RNA sequencing","volume":"464","author":"Pickrell","year":"2010","journal-title":"Nature New Biol"},{"key":"2026010701520112000_12.1.e003585.30","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1987.135.6.1276"},{"key":"2026010701520112000_12.1.e003585.31","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2017-210722"},{"key":"2026010701520112000_12.1.e003585.32","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-0868"},{"key":"2026010701520112000_12.1.e003585.33","doi-asserted-by":"crossref","first-page":"196","DOI":"10.5114\/aoms\/114117","article-title":"Association of the MMP-3, MMP-9 and MMP-12 gene polymorphisms with COPD risk: a meta-analysis","volume":"20","author":"Zhao","year":"2024","journal-title":"Arch Med Sci"},{"key":"2026010701520112000_12.1.e003585.34","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1134\/S0026893312020082","article-title":"Association of the MMP3, MMP9, ADAM33 and TIMP3 genes polymorphic markers with development and progression of chronic obstructive pulmonary disease","volume":"46","author":"Korytina","year":"2012","journal-title":"Mol Biol (Mosk)"},{"key":"2026010701520112000_12.1.e003585.35","doi-asserted-by":"publisher","DOI":"10.1177\/1753465809102263"},{"key":"2026010701520112000_12.1.e003585.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2010.06.015"},{"key":"2026010701520112000_12.1.e003585.37","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000070112.80711.3D"},{"key":"2026010701520112000_12.1.e003585.38","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2021.663978","article-title":"Matrix Metalloproteinase 3: A Promoting and Destabilizing Factor in the Pathogenesis of Disease and Cell Differentiation","volume":"12","author":"Wan","year":"2021","journal-title":"Front Physiol"},{"key":"2026010701520112000_12.1.e003585.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0321-7"},{"key":"2026010701520112000_12.1.e003585.40","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1010557","article-title":"Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits","volume":"18","author":"Chun","year":"2022","journal-title":"PLoS Genet"},{"key":"2026010701520112000_12.1.e003585.41","doi-asserted-by":"crossref","first-page":"1386506","DOI":"10.3389\/fcimb.2024.1386506","article-title":"Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease","volume":"14","author":"Wang","year":"2024","journal-title":"Front Cell Infect Microbiol"},{"key":"2026010701520112000_12.1.e003585.42","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.4049\/jimmunol.1500038","article-title":"The BLT1 Inhibitory Function of \u03b1-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling","volume":"195","author":"O\u2019Dwyer","year":"2015","journal-title":"The Journal of Immunology"},{"key":"2026010701520112000_12.1.e003585.43","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00162811"},{"key":"2026010701520112000_12.1.e003585.44","doi-asserted-by":"crossref","first-page":"L1036","DOI":"10.1152\/ajplung.00420.2019","article-title":"Attenuation of pulmonary injury by an inhaled MMP inhibitor in the endotoxin lung injury model","volume":"319","author":"Gerber","year":"2020","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026010701520112000_12.1.e003585.45","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.3390\/ijms24043786","article-title":"Matrix Metalloproteinases in Chronic Obstructive Pulmonary Disease","volume":"24","author":"Christopoulou","year":"2023","journal-title":"IJMS"},{"key":"2026010701520112000_12.1.e003585.46","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5936"},{"key":"2026010701520112000_12.1.e003585.47","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201005-0718OC"},{"key":"2026010701520112000_12.1.e003585.48","doi-asserted-by":"crossref","first-page":"123614","DOI":"10.1172\/jci.insight.123614","article-title":"Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene","volume":"3","author":"Wells","year":"2018","journal-title":"JCI Insight"},{"key":"2026010701520112000_12.1.e003585.49","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.2147\/COPD.S103281","article-title":"Relationship between plasma matrix metalloproteinase levels, pulmonary function, bronchodilator response, and emphysema severity","volume":"11","author":"Koo","year":"2016","journal-title":"COPD"},{"key":"2026010701520112000_12.1.e003585.50","doi-asserted-by":"crossref","DOI":"10.1136\/thx.2009.127936","article-title":"Plasma levels of TIMP-1 are higher in 34-year-old individuals with severe \u03b11-antitrypsin deficiency","volume":"65","author":"Janciauskiene","year":"2010","journal-title":"Thorax"},{"key":"2026010701520112000_12.1.e003585.51","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2005.042432"},{"key":"2026010701520112000_12.1.e003585.52","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-28062-9","article-title":"Characterization of the COPD alveolar niche using single-cell RNA sequencing","volume":"13","author":"Sauler","year":"2022","journal-title":"Nat Commun"}],"container-title":["BMJ Open Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjresp-2025-003585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T09:53:41Z","timestamp":1767779621000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopenrespres.bmj.com\/lookup\/doi\/10.1136\/bmjresp-2025-003585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,11,17]]},"published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1136\/bmjresp-2025-003585"],"URL":"https:\/\/doi.org\/10.1136\/bmjresp-2025-003585","relation":{},"ISSN":["2052-4439"],"issn-type":[{"value":"2052-4439","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]}}}