{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:23:40Z","timestamp":1791156220113,"version":"4.1.0"},"reference-count":178,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:p>\u03b11-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes \u03b11-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant \u03b11-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (\u03b11-antitrypsin and \u03b11-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of \u03b11-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.<\/jats:p>","DOI":"10.1042\/cs20080484","type":"journal-article","created":{"date-parts":[[2009,5,15]],"date-time":"2009-05-15T16:06:56Z","timestamp":1242403616000},"page":"837-850","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["\u03b11-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies"],"prefix":"10.1042","volume":"116","author":[{"given":"Ugo\u00a0I.","family":"Ekeowa","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibek","family":"Gooptu","sequence":"additional","affiliation":[{"name":"School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Belorgey","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"H\u00e4ggl\u00f6f","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Karlsson-Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular, Gen\u00e9tica y Fisiolog\u00eda, Universidad de M\u00e1laga, Facultad de Ciencias, Campus de Teatinos, M\u00e1laga, 29071, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."},{"name":"Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Kroger","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan\u00a0J.","family":"Marciniak","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."},{"name":"Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian\u00a0C.","family":"Crowther","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."},{"name":"Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David\u00a0A.","family":"Lomas","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust\/MRC Building, Cambridge CB2 0XY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2009,5,14]]},"reference":[{"key":"2021113010071371100_B1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1073\/pnas.82.3.795","article-title":"Expression of \u03b11-proteinase inhibitor gene in human monocytes and macrophages","volume":"82","author":"Perlmutter","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1046\/j.1365-2249.2002.01843.x","article-title":"Regulation of \u03b11-proteinase inhibitor release by proinflammatory cytokines in human intestinal epithelial cells","volume":"128","author":"Faust","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"2021113010071371100_B3","doi-asserted-by":"crossref","first-page":"8250","DOI":"10.1074\/jbc.272.13.8250","article-title":"Biosynthesis of \u03b11-proteinase inhibitor by human lung-derived epithelial cells","volume":"272","author":"Cichy","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B4","first-page":"10","article-title":"Warm hearts in a cold land, New Scientist, 4 March","author":"Kiernan","year":"1995"},{"key":"2021113010071371100_B5","first-page":"769","article-title":"Chopin's illnesses","volume":"87","author":"Kuzemko","year":"1994","journal-title":"J. R. Soc. Med."},{"key":"2021113010071371100_B6","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1378\/chest.113.1.210","article-title":"The long-suffering of Frederic Chopin","volume":"113","author":"Kubba","year":"1997","journal-title":"Chest"},{"key":"2021113010071371100_B7","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/00365516309051324","article-title":"The electrophoretic \u03b11-globulin pattern of serum in \u03b11-antitrypsin deficiency","volume":"15","author":"Laurell","year":"1963","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"2021113010071371100_B8","first-page":"397","article-title":"\u03b11-Antitrypsin deficiency: memorandum from a WHO meeting","volume":"75","year":"1997","journal-title":"Bull. World Health Organ."},{"key":"2021113010071371100_B9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0002-9343(88)80066-4","article-title":"Molecular basis of \u03b11-antitrypsin deficiency","volume":"84","author":"Brantly","year":"1988","journal-title":"Am. J. Med."},{"key":"2021113010071371100_B10","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/sj.ejhg.5201127","article-title":"Practical genetics: \u03b11-antitrypsin deficiency and the serpinopathies","volume":"12","author":"Crowther","year":"2004","journal-title":"Eur. J. Hum. Genet."},{"key":"2021113010071371100_B11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1034\/j.1399-0004.2001.600105.x","article-title":"\u03b11-antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys","volume":"60","author":"Blanco","year":"2001","journal-title":"Clin. Genet."},{"key":"2021113010071371100_B12","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3109\/15513818909022371","article-title":"The fetal liver in PiZZ \u03b11-antitrypsin deficiency: a report of 5 cases","volume":"9","author":"Malone","year":"1989","journal-title":"Pediatr. Pathol."},{"key":"2021113010071371100_B13","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1056\/NEJM197606102942404","article-title":"Liver disease in \u03b11-antitrypsin deficiency detected by screening of 200,000 infants","volume":"294","author":"Sveger","year":"1976","journal-title":"N. Engl. J. Med."},{"key":"2021113010071371100_B14","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1542\/peds.62.1.22","article-title":"\u03b11-Antitrypsin deficiency in early childhood","volume":"62","author":"Sveger","year":"1978","journal-title":"Pediatrics"},{"key":"2021113010071371100_B15","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1111\/j.1651-2227.1988.tb10767.x","article-title":"The natural history of liver disease in \u03b11-antitrypsin deficient children","volume":"77","author":"Sveger","year":"1988","journal-title":"Acta Paediatr. Scand."},{"key":"2021113010071371100_B16","first-page":"514","article-title":"The liver in adolescents with \u03b11-antitrypsin deficiency","volume":"22","author":"Sveger","year":"1995","journal-title":"Hepatology"},{"key":"2021113010071371100_B17","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.0954-6820.1987.tb01281.x","article-title":"\u03b11-Antitrypsin deficiency and liver cirrhosis in adults: an analysis of 35 Swedish autopsied cases","volume":"221","author":"Eriksson","year":"1987","journal-title":"Acta Med. Scand."},{"key":"2021113010071371100_B18","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1097\/00042737-199610000-00010","article-title":"Risk of hepatobiliary disease in adults with severe \u03b11-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?","volume":"8","author":"Elzouki","year":"1996","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"2021113010071371100_B19","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1056\/NEJM198603203141202","article-title":"Risk of cirrhosis and primary liver cancer in \u03b11-antitrypsin deficiency","volume":"314","author":"Eriksson","year":"1986","journal-title":"N. Engl. J. Med."},{"key":"2021113010071371100_B20","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S1542-3565(05)00082-0","article-title":"Factors associated with advanced liver disease in adults with \u03b11-antitrypsin deficiency","volume":"3","author":"Bowlus","year":"2005","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"2021113010071371100_B21","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1378\/chest.89.3.370","article-title":"\u03b11-antitrypsin Pi-types in 925 COPD patients","volume":"89","author":"Lieberman","year":"1986","journal-title":"Chest"},{"key":"2021113010071371100_B22","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1164\/rccm.168.7.818","article-title":"American Thoracic Society\/European Respiratory Society statement: standards for the diagnosis and management of individuals with \u03b11-antitrypsin deficiency","volume":"168","author":"American Thoracic Society\/European Respiratory Society","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1164\/ajrccm.158.1.9712017","article-title":"Survival and FEV1 decline in individuals with severe deficiency of \u03b11-antitrypsin","volume":"158","author":"\u03b11-Antitrypsin deficiency registry study group","year":"1998","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B24","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/thorax.58.12.1020","article-title":"Predictors of mortality in \u03b11-antitrypsin deficiency","volume":"58","author":"Dawkins","year":"2003","journal-title":"Thorax"},{"key":"2021113010071371100_B25","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/thx.2006.075846","article-title":"Determinants of airflow obstruction in severe \u03b11-antitrypsin deficiency","volume":"62","author":"Demeo","year":"2007","journal-title":"Thorax"},{"key":"2021113010071371100_B26","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.0954-6820.1978.tb08452.x","article-title":"Natural history and life expectancy in severe \u03b11-antitrypsin deficiency, Pi Z","volume":"204","author":"Larsson","year":"1978","journal-title":"Acta Med. Scand."},{"key":"2021113010071371100_B27","doi-asserted-by":"crossref","first-page":"12627","DOI":"10.1016\/S0021-9258(18)98945-3","article-title":"Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)): a new \u03b11-antitrypsin- deficient variant with mutation on a predicted conserved residue of the serpin backbone","volume":"266","author":"Seyama","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B28","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1164\/ajrccm.152.6.8520784","article-title":"\u03b11-antitrypsin-deficient variant Siiyama (Ser53(TCC) to Phe53(TTC)) is prevalent in Japan. Status of \u03b11-antitrysin deficiency in Japan","volume":"152","author":"Seyama","year":"1995","journal-title":"Am. Rev. Respir. Dis."},{"key":"2021113010071371100_B29","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1093\/ajcp\/82.4.424","article-title":"Occurrence of \u03b11-antitrypsin deficiency in 155 patients with alcoholic liver disease","volume":"82","author":"Roberts","year":"1984","journal-title":"Am. J. Clin. Pathol."},{"key":"2021113010071371100_B30","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1053\/rmed.2000.0851","article-title":"Molecular mechanisms of \u03b11-antitrypsin null alleles","volume":"94","author":"Lee","year":"2000","journal-title":"Respir. Med."},{"key":"2021113010071371100_B31","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S0025-7753(04)74661-8","article-title":"PI*S and PI*Z \u03b11-antitrypsin deficiency: estimated prevalence and number of deficient subjects in Spain","volume":"123","author":"Blanco","year":"2004","journal-title":"Med. Clin."},{"key":"2021113010071371100_B32","first-page":"73","article-title":"The genetics of \u03b11-antitrypsin and its implications","volume":"52","author":"Fagerhol","year":"1976","journal-title":"Postgrad. Med. J."},{"key":"2021113010071371100_B33","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1034\/j.1399-0004.2001.600605.x","article-title":"Distribution of \u03b11-antitrypsin PI*S and PI*Z frequencies in countries outside Europe: a meta-analysis","volume":"60","author":"Blanco","year":"2001","journal-title":"Clin. Genet."},{"key":"2021113010071371100_B34","doi-asserted-by":"crossref","first-page":"4751","DOI":"10.1021\/cr010170+","article-title":"Serpin structure, mechanism and function","volume":"102","author":"Gettins","year":"2002","journal-title":"Chem. Rev."},{"key":"2021113010071371100_B35","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0968-0004(97)01172-9","article-title":"An atlas of serpin conformations","volume":"23","author":"Whisstock","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"2021113010071371100_B36","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.sbi.2006.10.005","article-title":"Molecular gymnastics: serpin structure, folding and misfolding","volume":"16","author":"Whisstock","year":"2006","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2021113010071371100_B37","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1006\/jmbi.1997.1458","article-title":"Wildtype \u03b11-antitrypsin is in the canonical inhibitory conformation","volume":"275","author":"Elliott","year":"1998","journal-title":"J. Mol. Biol."},{"key":"2021113010071371100_B38","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nsb0896-676","article-title":"Inhibitory conformation of the reactive loop of \u03b11-antitrypsin","volume":"3","author":"Elliott","year":"1996","journal-title":"Nat. Struct. Biol."},{"key":"2021113010071371100_B39","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1110\/ps.9.7.1274","article-title":"Topography of a 2.0\u00a0\u00c5 structure of \u03b11-antitrypsin reveals targets for rational drug design to prevent conformational disease","volume":"9","author":"Elliott","year":"2000","journal-title":"Protein Sci."},{"key":"2021113010071371100_B40","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1006\/jmbi.2000.4357","article-title":"A 2.1\u00a0\u00c5 resolution structure of an uncleaved \u03b11-antitrypsin shows variability of the reactive centre and other loops","volume":"306","author":"Kim","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2021113010071371100_B41","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S0969-2126(96)00126-8","article-title":"The native strains in the hydrophobic core and flexible reactive loop of a serine protease inhibitor: crystal structure of an uncleaved \u03b11-antitrypsin at 2.7\u00a0\u00c5","volume":"4","author":"Ryu","year":"1996","journal-title":"Structure"},{"key":"2021113010071371100_B42","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/35038119","article-title":"Structure of a serpin-protease complex shows inhibition by deformation","volume":"407","author":"Huntington","year":"2000","journal-title":"Nature"},{"key":"2021113010071371100_B43","doi-asserted-by":"crossref","first-page":"29652","DOI":"10.1074\/jbc.270.50.29652","article-title":"The inhibition mechanism of serpins. Evidence that the mobile reactive centre loop is cleaved in the native protease-inhibitor complex","volume":"270","author":"Wilczynska","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B44","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/nsb0597-354","article-title":"Structural insights into serpin-protease complexes reveal the inhibitory mechanism of serpins","volume":"4","author":"Wilczynska","year":"1997","journal-title":"Nat. Struct. Biol."},{"key":"2021113010071371100_B45","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1073\/pnas.94.2.453","article-title":"Major proteinase movement upon stable serpin-proteinase complex formation","volume":"4","author":"Stratikos","year":"1997","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B46","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1073\/pnas.87.10.3753","article-title":"Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes","volume":"87","author":"Perlmutter","year":"1990","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B47","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/pro.5560060110","article-title":"Importance of release of strand 1C to the polymer mechanism of inhibitory serpins","volume":"6","author":"Chang","year":"1997","journal-title":"Protein Sci."},{"key":"2021113010071371100_B48","doi-asserted-by":"crossref","first-page":"4575","DOI":"10.1021\/bi0158932","article-title":"Probing the role of the F helix in serpin stability through a single tryptophan substitution","volume":"41","author":"Cabrita","year":"2002","journal-title":"Biochemistry"},{"key":"2021113010071371100_B49","doi-asserted-by":"crossref","unstructured":"Gooptu B. Nobeli I. Purkiss A. Phillips R. Mallya M. Lomas D.\u00a0A. Barrett T.\u00a0E. Probing the structural transitions required to form a pathogenic intermediate in \u03b11-antitrypsin deficiency: implications for rational drug design J. Mol. Biol. 2009 doi:10.1016\/j.jmb.2009.01.069","DOI":"10.1016\/j.jmb.2009.01.069"},{"key":"2021113010071371100_B50","doi-asserted-by":"crossref","first-page":"9548","DOI":"10.1074\/jbc.274.14.9548","article-title":"A kinetic mechanism for the polymerisation of \u03b11-antitrypsin","volume":"274","author":"Dafforn","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B51","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1073\/pnas.97.1.67","article-title":"Inactive conformation of the serpin \u03b11-antichymotrypsin indicates two stage insertion of the reactive loop; implications for inhibitory function and conformational disease","volume":"97","author":"Gooptu","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B52","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1074\/jbc.C100722200","article-title":"6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerisation: implications for the prevention of Z \u03b11-antitrypsin related cirrhosis","volume":"277","author":"Mahadeva","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B53","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jmb.2007.10.055","article-title":"Dimers initiate and propagate serine protease inhibitor polymerisation","volume":"375","author":"Zhou","year":"2008","journal-title":"J. Mol. Biol."},{"key":"2021113010071371100_B54","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/357605a0","article-title":"The mechanism of Z \u03b11-antitrypsin accumulation in the liver","volume":"357","author":"Lomas","year":"1992","journal-title":"Nature"},{"key":"2021113010071371100_B55","doi-asserted-by":"crossref","first-page":"26540","DOI":"10.1074\/jbc.M203832200","article-title":"Detection of circulating and endothelial cell polymers of Z and wildtype \u03b11-antitrypsin by a monoclonal antibody","volume":"277","author":"Janciauskiene","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B56","doi-asserted-by":"crossref","first-page":"33663","DOI":"10.1074\/jbc.M004054200","article-title":"Pathogenic \u03b11-antitrypsin polymers are formed by reactive loop-\u03b2-sheet A linkage","volume":"275","author":"Sivasothy","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B57","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1006\/abbi.1998.0751","article-title":"The mechanism of \u03b11-antitrypsin polymerization probed by fluorescence spectroscopy","volume":"356","author":"James","year":"1998","journal-title":"Arch. Biochem. Biophys."},{"key":"2021113010071371100_B58","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1021\/bi048662e","article-title":"\u03b11-Antitrypsin polymerisation: a fluorescence correlation spectroscopic study","volume":"44","author":"Purkayastha","year":"2005","journal-title":"Biochemistry"},{"key":"2021113010071371100_B59","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/nature07394","article-title":"Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization","volume":"455","author":"Yamasaki","year":"2008","journal-title":"Nature"},{"key":"2021113010071371100_B60","doi-asserted-by":"crossref","first-page":"15116","DOI":"10.1074\/jbc.M211663200","article-title":"Serpin polymerisation is prevented by a hydrogen bond network that is centered on His-334 and stabilized by glycerol","volume":"278","author":"Zhou","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B61","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1074\/jbc.272.1.510","article-title":"Folding and stability of the Z and Siiyama genetic variants of human \u03b11-antitrypsin","volume":"272","author":"Kang","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B62","doi-asserted-by":"crossref","first-page":"15333","DOI":"10.1016\/S0021-9258(18)82258-X","article-title":"\u03b11-Antitrypsin Siiyama (Ser53\u2192Phe); further evidence for intracellular loop-sheet polymerization","volume":"268","author":"Lomas","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B63","doi-asserted-by":"crossref","first-page":"16864","DOI":"10.1074\/jbc.270.28.16864","article-title":"\u03b11-antitrypsin Mmalton (52Phe deleted) forms loop-sheet polymers in vivo: evidence for the C sheet mechanism of polymerisation","volume":"270","author":"Lomas","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B64","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/nsb1196-910","article-title":"Structural explanation for the deficiency of S \u03b11-antitrypsin","volume":"3","author":"Elliot","year":"1996","journal-title":"Nat. Struct. Biol."},{"key":"2021113010071371100_B65","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1172\/JCI4874","article-title":"Heteropolymerisation of S, I and Z \u03b11-antitrypsin and liver cirrhosis","volume":"103","author":"Mahadeva","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B66","first-page":"501","article-title":"Cirrhosis and heterozygous \u03b11-antitrypsin deficiency in a 4 year old girl","volume":"30","author":"Cruz","year":"1975","journal-title":"Helv. Paediatr. Acta"},{"key":"2021113010071371100_B67","doi-asserted-by":"crossref","first-page":"233","DOI":"10.7326\/0003-4819-78-2-233","article-title":"Cirrhosis associated with partial deficiency of \u03b11-antitrypsin in an adult","volume":"78","author":"Campra","year":"1973","journal-title":"Ann. Intern. Med."},{"key":"2021113010071371100_B68","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1042\/bst0300098","article-title":"Proteinases in chronic obstructive pulmonary disease","volume":"30","author":"Shapiro","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"2021113010071371100_B69","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1515\/BC.1999.153","article-title":"Comparative cleavage sites within the reactive-site loop of native and oxidized \u03b11-proteinase inhibitor by selected bacterial proteinases","volume":"380","author":"Rapala-Kozik","year":"1999","journal-title":"Biol. Chem."},{"key":"2021113010071371100_B70","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1172\/JCI113214","article-title":"Z-type \u03b11-antitrypsin is less competent than M1-type \u03b11-antitrypsin as an inhibitor of neutrophil elastase","volume":"80","author":"Ogushi","year":"1987","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B71","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0014-5793(90)80464-T","article-title":"Comparative properties of human \u03b11-proteinase inhibitor glycosylation variants","volume":"272","author":"Guzdek","year":"1990","journal-title":"FEBS Lett."},{"key":"2021113010071371100_B72","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1021\/bi00053a014","article-title":"Effect of the Z mutation on the physical and inhibitory properties of \u03b11-antitrypsin","volume":"32","author":"Lomas","year":"1993","journal-title":"Biochemistry"},{"key":"2021113010071371100_B73","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0925-4439(94)90089-2","article-title":"The effect of the Z mutation on the ability of \u03b11-antitrypsin to prevent neutrophil mediated tissue damage","volume":"1227","author":"Llewellyn-Jones","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"2021113010071371100_B74","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1165\/rcmb.4791","article-title":"Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice","volume":"27","author":"Churg","year":"2002","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B75","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1006\/bbrc.1994.2503","article-title":"Matrilysin is much more efficient than other matrix metalloproteinases in the proteolytic inactivation of \u03b11-antitrypsin","volume":"204","author":"Sires","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021113010071371100_B76","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1165\/ajrcmb.18.5.3065","article-title":"Lung polymers in Z \u03b11-antitrypsin deficiency-related emphysema","volume":"18","author":"Elliott","year":"1998","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B77","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0002-9440(10)62261-4","article-title":"Polymers of Z \u03b11-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo","volume":"166","author":"Mahadeva","year":"2005","journal-title":"Am. J. Pathol."},{"key":"2021113010071371100_B78","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1378\/chest.125.5.1952","article-title":"Z \u03b11-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant","volume":"125","author":"Mulgrew","year":"2004","journal-title":"Chest"},{"key":"2021113010071371100_B79","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1165\/ajrcmb.26.6.4739","article-title":"Polymers of \u03b11-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema","volume":"26","author":"Parmar","year":"2002","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B80","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1084\/jem.167.5.1608","article-title":"The inhibitory complex of human \u03b11-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant","volume":"167","author":"Banda","year":"1988","journal-title":"J. Exp. Med."},{"key":"2021113010071371100_B81","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1172\/JCI109926","article-title":"Chemotactic activity of elastin-derived peptides","volume":"66","author":"Senior","year":"1980","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B82","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1042\/cs0720373","article-title":"Lung lavage fluid from patients with \u03b11-protease inhibitor deficiency or chronic obstructive bronchitis: anti-elastase function and cell profile","volume":"72","author":"Morrison","year":"1987","journal-title":"Clin. Sci."},{"key":"2021113010071371100_B83","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1084\/jem.20072080","article-title":"Polymers and inflammation: disease mechanisms of the serpinopathies","volume":"205","author":"Gooptu","year":"2008","journal-title":"J. Exp. Med."},{"key":"2021113010071371100_B84","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1172\/JCI10259","article-title":"Inhibition of VEGF receptors causes lung cell apoptosis and emphysema","volume":"106","author":"Kasahara","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B85","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1164\/ajrccm.163.3.2002117","article-title":"Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema","volume":"163","author":"Kasahara","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B86","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1161\/01.CIR.102.12.1420","article-title":"Functional protection by acute phase proteins \u03b11-acid glycoprotein and \u03b11-antitrypsin against ischemia\/reperfusion injury by preventing apoptosis and inflammation","volume":"102","author":"Deamen","year":"2000","journal-title":"Circulation"},{"key":"2021113010071371100_B87","doi-asserted-by":"crossref","first-page":"11798","DOI":"10.1074\/jbc.M008503200","article-title":"\u03b11-Proteinase inhibitor, \u03b11-antichymotrypsin and \u03b12-macroglobulin are the antiapoptotic factors of vascular smooth muscle cells","volume":"276","author":"Ikari","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B88","doi-asserted-by":"crossref","first-page":"12153","DOI":"10.1073\/pnas.0505579102","article-title":"\u03b11-Antitrypsin monotherapy prolongs islet allograft survival in mice","volume":"102","author":"Lewis","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B89","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2353\/ajpath.2006.060058","article-title":"\u03b11-Antitrypsin inhibits caspase-3 activity preventing lung endothelial cell apoptosis","volume":"169","author":"Petrache","year":"2006","journal-title":"Am. J. Pathol."},{"key":"2021113010071371100_B90","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1164\/rccm.200512-1842OC","article-title":"A novel antiapoptotic role for \u03b11-antitrypsin in the prevention of pulmonary emphysema","volume":"173","author":"Petrache","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B91","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1001\/archderm.1987.01660360083017","article-title":"Panniculitis associated with severe \u03b11-antitrypsin deficiency","volume":"123","author":"Smith","year":"1987","journal-title":"Arch. Dermatol."},{"key":"2021113010071371100_B92","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1093\/oxfordjournals.ndt.a027308","article-title":"C-antineutrophil cytoplasmic antibody positivity in vasculitis patients is associated with the Z allele of \u03b11-antitrypsin, and P-antineutrophil cytoplasmic antibody positivity with the S allele","volume":"11","author":"Griffith","year":"1996","journal-title":"Nephrol. Dial. Transplant."},{"key":"2021113010071371100_B93","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1046\/j.1365-2362.1996.2070553.x","article-title":"Complexes between proteinase 3, \u03b11-antitrypsin and proteinase 3 anti-neutrophil cytoplasmic autoantibodies: a comparison between \u03b11-antitrypsin PiZ allele carriers and non-carriers with Wegener's granulomatosis","volume":"26","author":"Baslund","year":"1996","journal-title":"Eur. J. Clin. Invest."},{"key":"2021113010071371100_B94","first-page":"232","article-title":"Membranoproliferative glomerulonephritis in childhood cirrhosis is associated with \u03b11-antitrypsin deficiency","volume":"57","author":"Moroz","year":"1976","journal-title":"Pediatrics"},{"key":"2021113010071371100_B95","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1378\/chest.103.3.812","article-title":"Variants of \u03b11-antitrypsin in Puerto Rican children with asthma","volume":"103","author":"Colp","year":"1993","journal-title":"Chest"},{"key":"2021113010071371100_B96","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1164\/ajrccm.156.1.9508014","article-title":"Atopy, asthma, and emphysema in patients with severe \u03b11-antitrypsin deficiency","volume":"156","author":"Eden","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B97","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/S0140-6736(75)90728-X","article-title":"Chronic pancreatitis and \u03b11-antitrypsin","volume":"ii","author":"Novis","year":"1975","journal-title":"Lancet"},{"key":"2021113010071371100_B98","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1148\/radiology.199.1.8633137","article-title":"\u03b11-Antitrypsin deficiency: evaluation of bronchiectasis with CT","volume":"199","author":"King","year":"1996","journal-title":"Radiology"},{"key":"2021113010071371100_B99","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1136\/thx.50.4.424","article-title":"Bronchiectasis and homozygous (PiZZ) \u03b11-antitrypsin deficiency in a young man","volume":"50","author":"Rodriguez-Cintron","year":"1995","journal-title":"Thorax"},{"key":"2021113010071371100_B100","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1378\/chest.117.2.415","article-title":"Distribution of \u03b11-antitrypsin alleles in patients with bronchiectasis","volume":"117","author":"Cuvelier","year":"2000","journal-title":"Chest"},{"key":"2021113010071371100_B101","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1164\/rccm.200511-1797PP","article-title":"The selective advantage of \u03b11-antitrypsin deficiency","volume":"173","author":"Lomas","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B102","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1399-0004.1979.tb02026.x","article-title":"\u03b11-Antitrypsin deficiency in twins and parents-of-twins","volume":"15","author":"Lieberman","year":"1979","journal-title":"Clin. Genet."},{"key":"2021113010071371100_B103","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.1021\/bi00011a024","article-title":"Inhibition of acrosin by serpins: a suicide substrate mechanism","volume":"34","author":"Hermans","year":"1995","journal-title":"Biochemistry"},{"key":"2021113010071371100_B104","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF00220552","article-title":"Protease inhibitor (Pi) locus, fertility and twinning","volume":"89","author":"Boomsma","year":"1992","journal-title":"Hum. Genet."},{"key":"2021113010071371100_B105","doi-asserted-by":"crossref","first-page":"33293","DOI":"10.1074\/jbc.R100016200","article-title":"The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition novel functions and a revised nomenclature","volume":"276","author":"Silverman","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B106","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2174\/0929867043455936","article-title":"Promiscuous beta-strand interactions and the conformational disease","volume":"11","author":"Chow","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"2021113010071371100_B107","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrg907","article-title":"Serpinopathies and the conformational dementias","volume":"3","author":"Lomas","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"2021113010071371100_B108","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1042\/BST0330321","article-title":"Molecular mousetraps and the serpinopathies","volume":"33","author":"Lomas","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"2021113010071371100_B109","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/43894","article-title":"Familial dementia caused by polymerization of mutant neuroserpin","volume":"401","author":"Davis","year":"1999","journal-title":"Nature"},{"key":"2021113010071371100_B110","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1161\/01.CIR.0000140763.51679.D9","article-title":"Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis","volume":"110","author":"Corral","year":"2004","journal-title":"Circulation"},{"key":"2021113010071371100_B111","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1172\/JCI0216782","article-title":"\u03b11-Antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy","volume":"110","author":"Lomas","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B112","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.1002\/j.1460-2075.1996.tb00657.x","article-title":"Neuroserpin, an axonally secreted serine protease inhibitor","volume":"15","author":"Osterwalder","year":"1996","journal-title":"EMBO J."},{"key":"2021113010071371100_B113","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1074\/jbc.273.4.2312","article-title":"The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin","volume":"237","author":"Osterwalder","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B114","doi-asserted-by":"crossref","first-page":"33062","DOI":"10.1074\/jbc.272.52.33062","article-title":"Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurones","volume":"272","author":"Hastings","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B115","doi-asserted-by":"crossref","first-page":"17367","DOI":"10.1074\/jbc.M200680200","article-title":"Mutant neuroserpin (Ser49Pro) that causes the familial dementia FENIB is a poor proteinase inhibitor and readily forms polymers in vitro","volume":"277","author":"Belorgey","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B116","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1046\/j.1471-4159.2002.01100.x","article-title":"Neuroserpin regulates neurite outgrowth in nerve growth factor treated PC12 cells","volume":"82","author":"Parmar","year":"2002","journal-title":"J. Neurochem."},{"key":"2021113010071371100_B117","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1182\/blood.V96.2.569","article-title":"Neuroserpin reduces cerebral infarct volume and protects neurones from ischaemia-induced apoptosis","volume":"96","author":"Yepes","year":"2000","journal-title":"Blood"},{"key":"2021113010071371100_B118","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1172\/JCI0214308","article-title":"Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen independent","volume":"109","author":"Yepes","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B119","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S1044-7431(03)00077-0","article-title":"Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine proteinase inhibitor neuroserpin","volume":"23","author":"Madani","year":"2003","journal-title":"Mol. Cell. Neurosci."},{"key":"2021113010071371100_B120","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1016\/S0140-6736(02)09293-0","article-title":"Association between conformational mutations in neuroserpin and onset and severity of dementia","volume":"359","author":"Davis","year":"2002","journal-title":"Lancet"},{"key":"2021113010071371100_B121","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1212\/01.wnl.0000316306.08751.28","article-title":"Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep","volume":"71","author":"Coutelier","year":"2008","journal-title":"Neurology"},{"key":"2021113010071371100_B122","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1016\/S0002-9440(10)65510-1","article-title":"Familial encephalopathy with neuroserpin inclusion bodies (FENIB)","volume":"155","author":"Davis","year":"1999","journal-title":"Am. J. Pathol."},{"key":"2021113010071371100_B123","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1001\/archneur.58.9.1429","article-title":"Cognitive deficits associated with a recently reported familial neurodegenerative disease","volume":"58","author":"Bradshaw","year":"2001","journal-title":"Arch. Neurol."},{"key":"2021113010071371100_B124","doi-asserted-by":"crossref","first-page":"13735","DOI":"10.1074\/jbc.M413282200","article-title":"Latent S49P neuroserpin spontaneously forms polymers: identification of a novel pathway of polymerization and implications for the dementia FENIB","volume":"280","author":"Onda","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B125","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1111\/j.1432-1033.2004.04270.x","article-title":"Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB","volume":"271","author":"Belorgey","year":"2004","journal-title":"Eur. J. Biochem."},{"key":"2021113010071371100_B126","doi-asserted-by":"crossref","first-page":"28283","DOI":"10.1074\/jbc.M313166200","article-title":"Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum","volume":"279","author":"Miranda","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B127","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1093\/hmg\/ddn041","article-title":"The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB","volume":"17","author":"Miranda","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2021113010071371100_B128","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1172\/JCI0216787","article-title":"Liver injury in \u03b11-antitrypsin deficiency: an aggregated protein induces mitochondrial injury","volume":"110","author":"Perlmutter","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2021113010071371100_B129","doi-asserted-by":"crossref","first-page":"9014","DOI":"10.1073\/pnas.91.19.9014","article-title":"A lag in intracellular degradation of mutant \u03b11-antitrypsin correlates with liver disease phenotype in homozygous PiZZ \u03b11-antitrypsin deficiency","volume":"91","author":"Wu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B130","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1152\/physrev.00015.2006","article-title":"Endoplasmic reticulum stress signaling in disease","volume":"86","author":"Marciniak","year":"2006","journal-title":"Physiol. Rev."},{"key":"2021113010071371100_B131","doi-asserted-by":"crossref","first-page":"39002","DOI":"10.1074\/jbc.M508652200","article-title":"Accumulation of mutant \u03b11-antitrypsin Z in the endoplasmic reticulum activates capases-4 and -12, NF\u03baB, and BAP31 but not the unfolded protein response","volume":"280","author":"Hidvegi","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B132","doi-asserted-by":"crossref","first-page":"5722","DOI":"10.4049\/jimmunol.172.9.5722","article-title":"Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z \u03b11-antitrypsin deficiency","volume":"172","author":"Lawless","year":"2004","journal-title":"J. Immunol."},{"key":"2021113010071371100_B133","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.biocel.2007.12.017","article-title":"The molecular aetiology of the serpinopathies","volume":"40","author":"Davies","year":"2008","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"2021113010071371100_B134"},{"key":"2021113010071371100_B135","doi-asserted-by":"crossref","first-page":"22791","DOI":"10.1074\/jbc.271.37.22791","article-title":"Degradation of a mutant secretory protein, \u03b11-antitrypsin Z, in the endoplamic reticulum requires proteasome activity","volume":"271","author":"Qu","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B136","doi-asserted-by":"crossref","first-page":"G39","DOI":"10.1152\/ajpgi.2000.278.1.G39","article-title":"The role of ubiquitin in proteasomal degradation of mutant \u03b11-antitrypsin Z in the endoplasmic reticulum","volume":"278","author":"Teckman","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021113010071371100_B137","doi-asserted-by":"crossref","first-page":"G961","DOI":"10.1152\/ajpgi.2000.279.5.G961","article-title":"Retention of mutant \u03b11-antitrypsin Z in the endoplasmic reticulum is associated with an autophagic response","volume":"279","author":"Teckman","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021113010071371100_B138","doi-asserted-by":"crossref","first-page":"8229","DOI":"10.1073\/pnas.1430537100","article-title":"Elucidation of the molecular logic by which misfolded \u03b11-antitrypsin is preferentially selected for degradation","volume":"100","author":"Wu","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B139","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/glycob\/cwi014","article-title":"EDEM2, a novel homolog of family 47 glycosidases is involved in ER-associated degradation of glycoproteins","volume":"15","author":"Mast","year":"2005","journal-title":"Glycobiology"},{"key":"2021113010071371100_B140","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1079181","article-title":"EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin","volume":"299","author":"Oda","year":"2003","journal-title":"Science"},{"key":"2021113010071371100_B141","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1126\/science.1079474","article-title":"Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle","volume":"299","author":"Molinari","year":"2003","journal-title":"Science"},{"key":"2021113010071371100_B142","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1091\/mbc.e02-11-0717","article-title":"Stress tolerance of misfolded carboxypeptidase Y requires maintenance of protein trafficking and degradative pathways","volume":"14","author":"Spear","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"2021113010071371100_B143","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1074\/jbc.M509409200","article-title":"Intracellular inclusions containing mutant \u03b11-antitrypsin Z are propagated in the absence of autophagic activity","volume":"281","author":"Kamimoto","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B144","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1091\/mbc.e04-09-0779","article-title":"Characterization of an ERAD gene as VPS30\/ATG6 reveal two alternative and functionally distinct quality control pathways: one for soluble Z variant of human \u03b11-proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ","volume":"17","author":"Kruse","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"2021113010071371100_B145","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.2353\/ajpath.2006.051097","article-title":"Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation of liver disease","volume":"168","author":"Kruse","year":"2006","journal-title":"Am. J. Pathol."},{"key":"2021113010071371100_B146","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1016\/j.biocel.2004.03.009","article-title":"Aging as a catabolic malfunction","volume":"36","author":"Terman","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021113010071371100_B147","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.cell.2005.04.014","article-title":"IKK\u03b2 couples hepatocytes death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis","volume":"121","author":"Maeda","year":"2005","journal-title":"Cell"},{"key":"2021113010071371100_B148","doi-asserted-by":"crossref","first-page":"G851","DOI":"10.1152\/ajpgi.00175.2003","article-title":"Mitochondrial autophagy an injury in the liver in \u03b11-antitrypsin deficiency","volume":"286","author":"Teckman","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021113010071371100_B149","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1136\/gut.2003.024935","article-title":"Cytokines and the pathogenesis of nonalcoholic steatohepatitis","volume":"54","author":"Diehl","year":"2005","journal-title":"Gut"},{"key":"2021113010071371100_B150","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature02924","article-title":"NF-\u03baB functions as a tumour promoter in inflammation-associated cancer","volume":"431","author":"Pikarsky","year":"2004","journal-title":"Nature"},{"key":"2021113010071371100_B151","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/hep.20815","article-title":"\u03b11-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease","volume":"42","author":"Rudnick","year":"2005","journal-title":"Hepatology"},{"key":"2021113010071371100_B152","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1056\/NEJMcp012477","article-title":"Clinical practice: acute exacerbations of COPD","volume":"346","author":"Stoller","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"2021113010071371100_B153","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1056\/NEJMra030415","article-title":"Management of COPD","volume":"350","author":"Sutherland","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"2021113010071371100_B154","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.jtcvs.2004.03.040","article-title":"Long-term results after lung volume reduction surgery in patients with \u03b11-antitrypsin deficiency","volume":"128","author":"Tutic","year":"2004","journal-title":"J. Thoracic Cardiovasc. Surg."},{"key":"2021113010071371100_B155","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1183\/09031936.05.00021605","article-title":"\u03b11-Antitrypsin deficiency and lung disease: risk modification by occupational and enviromental inhalants","volume":"26","author":"Senn","year":"2005","journal-title":"Eur. Respir. J."},{"key":"2021113010071371100_B156","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1016\/S0140-6736(05)66781-5","article-title":"\u03b11-Antitrypsin deficiency","volume":"365","author":"Stoller","year":"2005","journal-title":"Lancet"},{"key":"2021113010071371100_B157","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1056\/NEJM198704233161704","article-title":"Replacement therapy for \u03b11-antitrypsin deficiency associated with emphysema","volume":"316","author":"Wewers","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"2021113010071371100_B158","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1378\/chest.118.5.1480","article-title":"Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data","volume":"118","author":"Liebermann","year":"2000","journal-title":"Chest"},{"key":"2021113010071371100_B159","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1378\/chest.123.5.1425","article-title":"Augmentation therapy with \u03b11-antitrypsin: patterns of use and adverse effects","volume":"123","author":"Stoller","year":"2003","journal-title":"Chest"},{"key":"2021113010071371100_B160","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1164\/rccm.2109013","article-title":"The effect of augmentation therapy on bronchial inflammation in \u03b11-antitrypsin deficiency","volume":"165","author":"Stockley","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B161","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1164\/ajrccm.160.5.9901055","article-title":"A randomized clinical trial of \u03b11-antitrypsin augmentation therapy","volume":"160","author":"Dirksen","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B162","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1378\/chest.117.3.875","article-title":"Should health care systems pay for replacement therapy in patients with \u03b11-antitrypsin deficiency? A critical review and cost-effectiveness analysis","volume":"117","author":"Alkins","year":"2000","journal-title":"Chest"},{"key":"2021113010071371100_B163","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1164\/rccm.200209-1035OC","article-title":"Cost effectiveness analysis of augmentation therapy for severe \u03b11-antitrypsin deficiency","volume":"167","author":"Gildea","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021113010071371100_B164","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2105\/AJPH.81.4.427","article-title":"Cost-effectiveness of \u03b11-antitrypsin replacement therapy in treatment of congenital COPD","volume":"81","author":"Hay","year":"1991","journal-title":"Am. J. Public Health"},{"key":"2021113010071371100_B165","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1073\/pnas.97.4.1796","article-title":"Chemical chaperones mediate increased secretion of mutant \u03b11-antitrypsin Z: a potential pharmacological strategy for prevention of liver injury and emphysema in \u03b11-antitrypsin deficiency","volume":"97","author":"Burrows","year":"2000","journal-title":"Prot. Natl. Acad. Sci. U.S.A."},{"key":"2021113010071371100_B166","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1165\/ajrcmb.24.6.4407","article-title":"Prevention of polymerization of M and Z \u03b11-antitrypsin (\u03b11-AT) with trimethylamine N-oxide. Implications for the treatment of \u03b11-AT deficiency","volume":"24","author":"Devlin","year":"2001","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B167","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1111\/j.1742-4658.2006.05262.x","article-title":"Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis","volume":"273","author":"Sharp","year":"2006","journal-title":"FEBS J."},{"key":"2021113010071371100_B168","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1097\/00005176-200407000-00007","article-title":"Lack of effect of oral 4-phenylbutyrate on serum \u03b11-antitrypsin in patients with \u03b11-antitrypsin deficiency: a preliminary study","volume":"39","author":"Teckman","year":"2004","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"2021113010071371100_B169","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1165\/rcmb.2003-0276OC","article-title":"Inhibiting polymerization: new therapeutic strategies for Z \u03b11-antitrypsin-related emphysema","volume":"31","author":"Parfey","year":"2004","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B170","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.jmb.2004.07.078","article-title":"How small peptides block and reverse serpin polymerisation","volume":"342","author":"Zhou","year":"2004","journal-title":"J. Mol. Biol."},{"key":"2021113010071371100_B171","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1165\/rcmb.2005-0207OC","article-title":"Identification of 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z \u03b11-antitrypsin","volume":"35","author":"Chang","year":"2006","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"2021113010071371100_B172","doi-asserted-by":"crossref","first-page":"5357","DOI":"10.1021\/jm070687z","article-title":"Small molecules block the polymerization of Z \u03b11-antitrypsin and increase the clearance of intracellular aggregates","volume":"50","author":"Mallya","year":"2007","journal-title":"J. Med. Chem."},{"key":"2021113010071371100_B173","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1110\/ps.840101","article-title":"Cavities of \u03b11-antitrypsin that play structural and functional roles","volume":"10","author":"Lee","year":"2001","journal-title":"Protein Sci."},{"key":"2021113010071371100_B174","doi-asserted-by":"crossref","first-page":"33060","DOI":"10.1074\/jbc.M302646200","article-title":"Targeting a surface cavity of \u03b11-antitrypsin to prevent conformational disease","volume":"278","author":"Parfrey","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B175","article-title":"Probing and modulating the conformation of the flexible joints region of plasminogen activator inhibitor-1 with a fluorescent ligand","volume-title":"2nd International Symposium on the Structure and Biology of Serpins, Cambridge","author":"Egelund","year":"1999"},{"key":"2021113010071371100_B176","doi-asserted-by":"crossref","first-page":"13077","DOI":"10.1074\/jbc.M009024200","article-title":"A regulatory hydrophobic area in the flexible joint region of plasminogen activator inhibitor-1, defined with fluorescent activity-neutralizing ligands. Ligand-induced serpin polymerization","volume":"276","author":"Egelund","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021113010071371100_B177","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1042\/bj20021868","article-title":"Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands","volume":"372","author":"Pedersen","year":"2003","journal-title":"Biochem. J."},{"key":"2021113010071371100_B178","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1006\/jmbi.1998.2083","article-title":"Implications for function and therapy of a 2.9\u00a0\u00c5 structure of binary-complexed antithrombin","volume":"283","author":"Skinner","year":"1998","journal-title":"J. Mol. Biol."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/116\/12\/837\/439653\/cs1160837.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/116\/12\/837\/439653\/cs1160837.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T05:02:01Z","timestamp":1684990921000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/116\/12\/837\/68503\/1-Antitrypsin-deficiency-chronic-obstructive"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,14]]},"references-count":178,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2009,6,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20080484","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,14]]}}}