{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:47:27Z","timestamp":1779238047877,"version":"3.51.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T00:00:00Z","timestamp":1501545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alpha-1 antitrypsin (AAT) deficiency\u2013associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (M\u0278) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises M\u0278 function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, M\u0278 from individuals with Z-AAT (Z-M\u0278) have greater proteolytic activity on ECM than do normal M\u0278. This abnormal Z-M\u0278 activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-M\u0278. Importantly, compared with normal M\u0278, the membrane-bound serine protease, matriptase, is present in Z-M\u0278 at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-M\u0278, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in M\u0278 confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency\u2013associated emphysema.<\/jats:p>","DOI":"10.1165\/rcmb.2016-0366oc","type":"journal-article","created":{"date-parts":[[2017,3,31]],"date-time":"2017-03-31T10:11:46Z","timestamp":1490955106000},"page":"238-247","source":"Crossref","is-referenced-by-count":20,"title":["Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity"],"prefix":"10.1093","volume":"57","author":[{"given":"Karina","family":"Krotova","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George W.","family":"Marek","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rejean L.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Aslanidi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Florida, Gainesville, Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brad E.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Florida, Gainesville, Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazli","family":"Khodayari","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farshid N.","family":"Rouhani","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark L.","family":"Brantly","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,8,1]]},"reference":[{"key":"2026021122460138800_bib1","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.molmed.2013.10.007","article-title":"The molecular and cellular pathology of \u03b11-antitrypsin deficiency","volume":"20","author":"Gooptu","year":"2014","journal-title":"Trends Mol Med"},{"key":"2026021122460138800_bib2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3109\/15412555.2013.771956","article-title":"The electrophoretic \u03b11-globulin pattern of serum in \u03b11-antitrypsin deficiency. 1963","volume":"10","author":"Laurell","year":"2013","journal-title":"COPD"},{"key":"2026021122460138800_bib3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/j.0954-6820.1964.tb00567.x","article-title":"Pulmonary emphysema and alpha1-antitrypsin deficiency","volume":"175","author":"Eriksson","year":"1964","journal-title":"Acta Med Scand"},{"key":"2026021122460138800_bib4","first-page":"934","article-title":"Cirrhosis associated with alpha-1\u2013antitrypsin deficiency: a previously unrecognized inherited disorder","volume":"73","author":"Sharp","year":"1969","journal-title":"J Lab Clin Med"},{"key":"2026021122460138800_bib5","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI114578","article-title":"Alpha 1\u2013antitrypsin deficiency, emphysema, and liver disease: genetic basis and strategies for therapy","volume":"85","author":"Crystal","year":"1990","journal-title":"J Clin Invest"},{"key":"2026021122460138800_bib6","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S0140-6736(15)60860-1","article-title":"Intravenous augmentation treatment and lung density in severe \u03b11 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial","volume":"386","author":"Chapman","year":"2015","journal-title":"Lancet"},{"key":"2026021122460138800_bib7","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.immuni.2006.03.008","article-title":"Alveolar macrophage in the driver\u2019s seat","volume":"24","author":"Lambrecht","year":"2006","journal-title":"Immunity"},{"issue":"5","key":"2026021122460138800_bib8","doi-asserted-by":"crossref","first-page":"156S","DOI":"10.1378\/chest.121.5_suppl.156S","article-title":"Macrophages and the pathogenesis of COPD","volume":"121","author":"Tetley","year":"2002","journal-title":"Chest"},{"key":"2026021122460138800_bib9","doi-asserted-by":"crossref","first-page":"6332","DOI":"10.1038\/ncomms7332","article-title":"Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages","volume":"6","author":"Ueno","year":"2015","journal-title":"Nat Commun"},{"key":"2026021122460138800_bib10","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1136\/thorax.57.8.709","article-title":"Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of \u03b1(1)-antitrypsin deficiency and the role of leukotriene B(4) and interleukin 8","volume":"57","author":"Woolhouse","year":"2002","journal-title":"Thorax"},{"key":"2026021122460138800_bib11","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1172\/JCI115391","article-title":"Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency: spontaneous release of leukotriene B4 by alveolar macrophages","volume":"88","author":"Hubbard","year":"1991","journal-title":"J Clin Invest"},{"key":"2026021122460138800_bib12","doi-asserted-by":"crossref","first-page":"L514","DOI":"10.1152\/ajplung.00099.2003","article-title":"Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency","volume":"286","author":"Spencer","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021122460138800_bib13","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1126\/science.277.5334.2002","article-title":"Requirement for macrophage elastase for cigarette smoke\u2013induced emphysema in mice","volume":"277","author":"Hautamaki","year":"1997","journal-title":"Science"},{"key":"2026021122460138800_bib14","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1084\/jem.20030626","article-title":"Matrilysin-dependent elastolysis by human macrophages","volume":"198","author":"Filippov","year":"2003","journal-title":"J Exp Med"},{"key":"2026021122460138800_bib15","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.4049\/jimmunol.1302864","article-title":"Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion","volume":"192","author":"Fleetwood","year":"2014","journal-title":"J Immunol"},{"key":"2026021122460138800_bib16","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1084\/jem.152.5.1340","article-title":"Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages","volume":"152","author":"Werb","year":"1980","journal-title":"J Exp Med"},{"key":"2026021122460138800_bib17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1749-6632.1991.tb17009.x","article-title":"Role of enzyme receptors and inhibitors in regulating proteolytic activities of macrophages","volume":"624","author":"Chapman","year":"1991","journal-title":"Ann N Y Acad Sci"},{"key":"2026021122460138800_bib18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0304-4165(01)00190-8","article-title":"Matrix remodelling enzymes, the protease cascade and glycosylation","volume":"1528","author":"Van den Steen","year":"2001","journal-title":"Biochim Biophys Acta"},{"key":"2026021122460138800_bib19","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1084\/jem.152.6.1527","article-title":"Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture","volume":"152","author":"Jones","year":"1980","journal-title":"J Exp Med"},{"key":"2026021122460138800_bib20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1177\/002215540305100805","article-title":"Characterization of matriptase expression in normal human tissues","volume":"51","author":"Oberst","year":"2003","journal-title":"J Histochem Cytochem"},{"key":"2026021122460138800_bib21","doi-asserted-by":"crossref","first-page":"C423","DOI":"10.1152\/ajpcell.00164.2008","article-title":"Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1","volume":"295","author":"Tseng","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021122460138800_bib22","first-page":"1409","article-title":"Identification and characterization of a novel matrix-degrading protease from hormone-dependent human breast cancer cells","volume":"53","author":"Shi","year":"1993","journal-title":"Cancer Res"},{"key":"2026021122460138800_bib23","doi-asserted-by":"crossref","first-page":"26333","DOI":"10.1074\/jbc.M002941200","article-title":"Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates","volume":"275","author":"Takeuchi","year":"2000","journal-title":"J Biol Chem"},{"key":"2026021122460138800_bib24","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1046\/j.1432-1327.2001.02016.x","article-title":"Regulation of the activity of matriptase on epithelial cell surfaces by a blood-derived factor","volume":"268","author":"Benaud","year":"2001","journal-title":"Eur J Biochem"},{"key":"2026021122460138800_bib25","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1165\/rcmb.2008-0015RC","article-title":"\u03b11-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro","volume":"39","author":"Janciauskiene","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122460138800_bib26","doi-asserted-by":"crossref","first-page":"C95","DOI":"10.1152\/ajpcell.00611.2006","article-title":"Autoactivation of matriptase in vitro: requirement for biomembrane and LDL receptor domain","volume":"293","author":"Lee","year":"2007","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021122460138800_bib27","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1111\/j.1742-4658.2009.06950.x","article-title":"Probing the substrate specificities of matriptase, matriptase-2, hepsin and DESC1 with internally quenched fluorescent peptides","volume":"276","author":"B\u00e9liveau","year":"2009","journal-title":"FEBS J"},{"key":"2026021122460138800_bib28","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1091\/mbc.11.7.2387","article-title":"Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases","volume":"11","author":"Yana","year":"2000","journal-title":"Mol Biol Cell"},{"key":"2026021122460138800_bib29","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1038\/sj.onc.1209572","article-title":"Furin regulates the intracellular activation and the uptake rate of cell surface\u2013associated MT1-MMP","volume":"25","author":"Remacle","year":"2006","journal-title":"Oncogene"},{"key":"2026021122460138800_bib30","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1172\/JCI112524","article-title":"Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin\u2013deficient individuals","volume":"77","author":"Mornex","year":"1986","journal-title":"J Clin Invest"},{"key":"2026021122460138800_bib31","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1073\/pnas.82.3.795","article-title":"Expression of the alpha 1-proteinase inhibitor gene in human monocytes and macrophages","volume":"82","author":"Perlmutter","year":"1985","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021122460138800_bib32","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1164\/rccm.200901-0023OC","article-title":"Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1","volume":"180","author":"Rouhani","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021122460138800_bib33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/S1074-7613(01)00218-7","article-title":"GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1","volume":"15","author":"Shibata","year":"2001","journal-title":"Immunity"},{"key":"2026021122460138800_bib34","doi-asserted-by":"crossref","first-page":"22793","DOI":"10.1074\/jbc.M109.027102","article-title":"Endoplasmic reticulum\u2013associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins","volume":"284","author":"Kroeger","year":"2009","journal-title":"J Biol Chem"},{"key":"2026021122460138800_bib35","doi-asserted-by":"crossref","first-page":"39002","DOI":"10.1074\/jbc.M508652200","article-title":"Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response","volume":"280","author":"Hidvegi","year":"2005","journal-title":"J Biol Chem"},{"key":"2026021122460138800_bib36","doi-asserted-by":"crossref","first-page":"258","DOI":"10.4161\/auto.2882","article-title":"The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins","volume":"2","author":"Perlmutter","year":"2006","journal-title":"Autophagy"},{"key":"2026021122460138800_bib37","doi-asserted-by":"crossref","first-page":"5722","DOI":"10.4049\/jimmunol.172.9.5722","article-title":"Activation of endoplasmic reticulum\u2013specific stress responses associated with the conformational disease Z \u03b1 1-antitrypsin deficiency","volume":"172","author":"Lawless","year":"2004","journal-title":"J Immunol"},{"key":"2026021122460138800_bib38","doi-asserted-by":"crossref","first-page":"4538","DOI":"10.4049\/jimmunol.0802864","article-title":"Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency","volume":"184","author":"Carroll","year":"2010","journal-title":"J Immunol"},{"key":"2026021122460138800_bib39","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nrm2120","article-title":"In search of partners: linking extracellular proteases to substrates","volume":"8","author":"Overall","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026021122460138800_bib40","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.4049\/jimmunol.175.5.3329","article-title":"Inhibition of neutrophil elastase by alpha1-protease inhibitor at the surface of human polymorphonuclear neutrophils","volume":"175","author":"Korkmaz","year":"2005","journal-title":"J Immunol"},{"key":"2026021122460138800_bib41","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1083\/jcb.131.3.775","article-title":"Cell surface\u2013bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases","volume":"131","author":"Owen","year":"1995","journal-title":"J Cell Biol"},{"key":"2026021122460138800_bib42","doi-asserted-by":"crossref","first-page":"5793","DOI":"10.1074\/jbc.M110.186874","article-title":"Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase","volume":"286","author":"Friis","year":"2011","journal-title":"J Biol Chem"},{"key":"2026021122460138800_bib43","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1182\/blood-2006-02-001073","article-title":"Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase","volume":"108","author":"Kilpatrick","year":"2006","journal-title":"Blood"},{"key":"2026021122460138800_bib44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/glycob\/cwh013","article-title":"Addition of \u03b21-6 GlcNAc branching to the oligosaccharide attached to Asn 772 in the serine protease domain of matriptase plays a pivotal role in its stability and resistance against trypsin","volume":"14","author":"Ihara","year":"2004","journal-title":"Glycobiology"},{"key":"2026021122460138800_bib45","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1002\/art.27476","article-title":"Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis","volume":"62","author":"Milner","year":"2010","journal-title":"Arthritis Rheum"},{"key":"2026021122460138800_bib46","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/j.1349-7006.2006.00328.x","article-title":"Matriptase activates stromelysin (MMP-3) and promotes tumor growth and angiogenesis","volume":"97","author":"Jin","year":"2006","journal-title":"Cancer Sci"},{"key":"2026021122460138800_bib47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcp.20431","article-title":"MT1-MMP: a potent modifier of pericellular microenvironment","volume":"206","author":"Itoh","year":"2006","journal-title":"J Cell Physiol"},{"key":"2026021122460138800_bib48","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jcp.20064","article-title":"Processing, shedding, and endocytosis of membrane type 1-matrix metalloproteinase (MT1-MMP)","volume":"200","author":"Osenkowski","year":"2004","journal-title":"J Cell Physiol"},{"key":"2026021122460138800_bib49","first-page":"4707","article-title":"ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis and increased tumor growth","volume":"126","author":"Albrechtsen","year":"2013","journal-title":"J Cell Sci"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/57\/2\/238\/66805303\/ajrcmb_57_2_238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/57\/2\/238\/66805303\/ajrcmb_57_2_238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:51:53Z","timestamp":1770868313000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/57\/2\/238\/8467272"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,1]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,8,1]]},"published-print":{"date-parts":[[2017,8,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2016-0366oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,8]]},"published":{"date-parts":[[2017,8,1]]}}}