{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:20:21Z","timestamp":1790796021167,"version":"4.1.0"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["1R01HL166828"],"award-info":[{"award-number":["1R01HL166828"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001448","name":"Alpha-1 Foundation","doi-asserted-by":"crossref","award":["1037649"],"award-info":[{"award-number":["1037649"]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001448","name":"Alpha-1 Foundation","doi-asserted-by":"crossref","award":["1249387"],"award-info":[{"award-number":["1249387"]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,10]]},"abstract":"<jats:p>\n                    In\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -1 antitrypsin (AAT) deficiency (AATD), emphysema is classically linked to protease-antiprotease imbalance caused by decreased antiprotease AAT due levels and function. This decrease is secondary to the impaired release of Z-AAT polymers from hepatocytes carrying Pi*Z, E342K mutation in\n                    <jats:italic>SERPENA1<\/jats:italic>\n                    gene. Whether the accumulation of Z-AAT polymers in distal lungs contributes directly to emphysema pathogenesis has remained unexplored due to the lack of suitable model systems. We characterized lung injury and airspace enlargement in a Z-AAT\u2013overexpressing murine model. We generated Z-AAT\n                    <jats:italic>Serpina1<\/jats:italic>\n                    <jats:sup>Null<\/jats:sup>\n                    mice overexpressing human (E342K)\n                    <jats:italic>SERPENA1<\/jats:italic>\n                    in\n                    <jats:italic>Serpina1<\/jats:italic>\n                    <jats:sup>Null<\/jats:sup>\n                    mice and analyzed pulmonary phenotypes in young and aged animals, complemented by translational studies using primary cells, bronchoalveolar lavage fluid (BALf), and lung tissue from individuals who have never smoked and individuals with AATD. Young Z-AAT\n                    <jats:italic>Serpina1<\/jats:italic>\n                    <jats:sup>Null<\/jats:sup>\n                    mice accumulated Z-AAT polymers in hepatocytes, plasma, and BALf, exhibited spontaneous neutrophilic lung inflammation, increased alveolo-capillary permeability, and premature airspace enlargement, which was worse in older Z-AAT\n                    <jats:italic>Serpina1<\/jats:italic>\n                    <jats:sup>Null<\/jats:sup>\n                    mice. Moreover, Z-AAT polymers accumulated in alveolar type-2 epithelial (AT2) cells and lung macrophages, associated with endoplasmic reticulum (ER) stress, mitochondria dysfunction, and incomplete autophago-lysosomal fusion, which we recapitulated in lung samples from individuals with AATD. These findings support the pathogenic role of Z-AAT polymer accumulation in distal lung epithelium as a driver of epithelial, endothelial, and macrophage dysfunction linked to AATD emphysema.\n                  <\/jats:p>\n                  <jats:p\/>\n                  <jats:p>Mouse model lacking normal Alpha-1 Antitrypsin and overexpressing Z Alpha-1 Antitrypsin protein recapitulates human lung injury seen in Alpha-1 Antitrypsin Deficiency.<\/jats:p>","DOI":"10.1172\/jci.insight.199029","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:51:14Z","timestamp":1786463474000},"source":"Crossref","is-referenced-by-count":1,"title":["Polymerized Z-\u03b1-1 antitrypsin leads to lung injury in a murine model of emphysema"],"prefix":"10.1172","volume":"11","author":[{"given":"Maria","family":"Magall\u00f3n Serrano","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1586-2151","authenticated-orcid":true,"given":"Xinran","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Cellular & Molecular Imaging, Electron Microscopy Core Facility, Yale University School of Medicine, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungnam","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy O.","family":"Flagg","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida, 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Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divay","family":"Chandra","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1005-1552","authenticated-orcid":true,"given":"Susan M.","family":"Majka","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-2600","authenticated-orcid":true,"given":"Irina","family":"Petrache","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, 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