{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:54:35Z","timestamp":1793314475143,"version":"4.5.0"},"reference-count":61,"publisher":"Baishideng Publishing Group Inc.","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["WJGPT"],"published-print":{"date-parts":[[2010]]},"DOI":"10.4292\/wjgpt.v1.i5.94","type":"journal-article","created":{"date-parts":[[2010,10,26]],"date-time":"2010-10-26T20:27:01Z","timestamp":1288124821000},"page":"94","source":"Crossref","is-referenced-by-count":39,"title":["Z \u03b1-1 antitrypsin deficiency and the endoplasmic reticulum stress response"],"prefix":"10.4292","volume":"1","author":[{"given":"Catherine M","family":"Greene","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2060","reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Greene CM, Miller SD, Carroll T, McLean C, O'Mahony M, Lawless MW, O'Neill SJ, Taggart CC, McElvaney NG. Alpha-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations. J Inherit Metab Dis 2008;31:21-34.","DOI":"10.1007\/s10545-007-0748-y"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"McCracken AA, Kruse KB, Brown JL. Molecular basis for defective secretion of the Z variant of human alpha-1-proteinase inhibitor: secretion of variants having altered potential for salt bridge formation between amino acids 290 and 342. Mol Cell Biol 1989;9:1406-1414.","DOI":"10.1128\/MCB.9.4.1406"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002;110:1585-1590.","DOI":"10.1172\/JCI0216782"},{"key":"ref4","unstructured":"Laurell CB, Sveger T. Mass screening of newborn Swedish infants for alpha antitrypsin deficiency. Am J Hum Genet 1975;27:213-217."},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"American Thoracic Society, European Respiratory Society. American Thoracic Society\/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818-900.","DOI":"10.1164\/rccm.168.7.818"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Perlmutter DH. Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J Clin Invest 2002;110:1579-1583.","DOI":"10.1172\/JCI0216787"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res 2006;60:233-238.","DOI":"10.1203\/01.pdr.0000228350.61496.90"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 1986;314:736-739.","DOI":"10.1056\/NEJM198603203141202"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 2007;45:1313-1323.","DOI":"10.1002\/hep.21628"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Dycaico MJ, Grant SG, Felts K, Nichols WS, Geller SA, Hager JH, Pollard AJ, Kohler SW, Short HP, Jirik FR. Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model. Science 1988;242:1409-1412.","DOI":"10.1126\/science.3264419"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Carlson JA, Rogers BB, Sifers RN, Finegold MJ, Clift SM, DeMayo FJ, Bullock DW, Woo SL. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 1989;83:1183-1190.","DOI":"10.1172\/JCI113999"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ 2009;16:39-45.","DOI":"10.1038\/cdd.2008.103"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Rudnick DA, Liao Y, An JK, Muglia LJ, Perlmutter DH, Teckman JH. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004;39:1048-1055.","DOI":"10.1002\/hep.20118"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Geller SA, Nichols WS, Kim S, Tolmachoff T, Lee S, Dycaico MJ, Felts K, Sorge JA. Hepatocarcinogenesis is the sequel to hepatitis in Z#2 alpha 1-antitrypsin transgenic mice: histopathological and DNA ploidy studies. Hepatology 1994;19:389-397.","DOI":"10.1002\/hep.1840190218"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Taggart CC, Greene CM, Carroll TP, O'Neill SJ, McElvaney NG. Elastolytic proteases: inflammation resolution and dysregulation in chronic infective lung disease. Am J Respir Crit Care Med 2005;171:1070-1076.","DOI":"10.1164\/rccm.200407-881PP"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Taggart CC, Lowe GJ, Greene CM, Mulgrew AT, O'Neill SJ, Levine RL, McElvaney NG. Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor. J Biol Chem 2001;276:33345-33352.","DOI":"10.1074\/jbc.M103220200"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316-1321.","DOI":"10.1056\/NEJM197606102942404"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Wu Y, Whitman I, Molmenti E, Moore K, Hippenmeyer P, Perlmutter DH. A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc Natl Acad Sci USA 1994;91:9014-9018.","DOI":"10.1073\/pnas.91.19.9014"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Pan S, Huang L, McPherson J, Muzny D, Rouhani F, Brantly M, Gibbs R, Sifers RN. Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology 2009;50:275-281.","DOI":"10.1002\/hep.22974"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Hidvegi T, Mirnics K, Hale P, Ewing M, Beckett C, Perlmutter DH. Regulator of G Signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant alpha1-antitrypsin Z in the classical form of alpha1-antitrypsin deficiency. J Biol Chem 2007;282:27769-27780.","DOI":"10.1074\/jbc.M704330200"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Malhotra JD, Kaufman RJ. The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 2007;18:716-731.","DOI":"10.1016\/j.semcdb.2007.09.003"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Teckman JH, An JK, Loethen S, Perlmutter DH. Fasting in alpha1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am J Physiol Gastrointest Liver Physiol 2002;283:G1156-G1165.","DOI":"10.1152\/ajpgi.00041.2002"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Carroll TP, Greene CM, O'Connor CA, Nolan AM, O'Neill SJ, McElvaney NG. Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. J Immunol 2010;184:4538-4546.","DOI":"10.4049\/jimmunol.0802864"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Teckman JH, An JK, Blomenkamp K, Schmidt B, Perlmutter D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2004;286:G851-G862.","DOI":"10.1152\/ajpgi.00175.2003"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Teckman JH, Perlmutter DH. Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 2000;279:G961-G974.","DOI":"10.1152\/ajpgi.2000.279.5.G961"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem 2005;280:39002-39015.","DOI":"10.1074\/jbc.M508652200"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Lawless MW, Greene CM, Mulgrew A, Taggart CC, O'Neill SJ, McElvaney NG. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 2004;172:5722-5726.","DOI":"10.4049\/jimmunol.172.9.5722"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Miller SD, Greene CM, McLean C, Lawless MW, Taggart CC, O'Neill SJ, McElvaney NG. Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of Bad. Hepatology 2007;46:496-503.","DOI":"10.1002\/hep.21689"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Kelly E, Greene CM, Carroll TP, McElvaney NG, O'Neill SJ. Selenoprotein S\/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency. J Biol Chem 2009;284:16891-16897.","DOI":"10.1074\/jbc.M109.006288"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Greene CM, Miller SD, Carroll TP, Oglesby IK, Ahmed F, O'Mahony M, Taggart CC, McElvaney NG, O'Neill SJ. Anti-apoptotic effects of Z alpha1-antitrypsin in human bronchial epithelial cells. Eur Respir J 2010;35:1155-1163.","DOI":"10.1183\/09031936.00191908"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005;121:977-990.","DOI":"10.1016\/j.cell.2005.04.014"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 2004;165:347-356.","DOI":"10.1083\/jcb.200310015"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte TR, Tuder RM. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol 2006;169:1155-1166.","DOI":"10.2353\/ajpath.2006.060058"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Wiseman RL, Haynes CM, Ron D. SnapShot: The unfolded protein response. Cell 2010;140:590-590.e2.","DOI":"10.1016\/j.cell.2010.02.006"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000;6:1099-1108.","DOI":"10.1016\/S1097-2765(00)00108-8"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001;153:1011-1022.","DOI":"10.1083\/jcb.153.5.1011"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 2001;21:1249-1259.","DOI":"10.1128\/MCB.21.4.1249-1259.2001"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 2003;23:7198-7209.","DOI":"10.1128\/MCB.23.20.7198-7209.2003"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 2004;36:1199-1207.","DOI":"10.1016\/j.freeradbiomed.2004.02.074"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Malhotra D, Thimmulappa R, Vij N, Navas-Acien A, Sussan T, Merali S, Zhang L, Kelsen SG, Myers A, Wise R. Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease: the role of Nrf2-regulated proteasomal activity. Am J Respir Crit Care Med 2009;180:1196-1207.","DOI":"10.1164\/rccm.200903-0324OC"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Ye J, Rawson RB, Komuro R, Chen X, Dav&eacute; UP, Prywes R, Brown MS, Goldstein JL. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000;6:1355-1364.","DOI":"10.1016\/S1097-2765(00)00133-7"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001;107:881-891.","DOI":"10.1016\/S0092-8674(01)00611-0"},{"key":"ref43","doi-asserted-by":"crossref","unstructured":"Brodsky JL, McCracken AA. ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 1999;10:507-513.","DOI":"10.1006\/scdb.1999.0321"},{"key":"ref44","doi-asserted-by":"crossref","unstructured":"Perlmutter DH. The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy 2006;2:258-263.","DOI":"10.4161\/auto.2882"},{"key":"ref45","doi-asserted-by":"crossref","unstructured":"Bathurst IC, Travis J, George PM, Carrell RW. Structural and functional characterization of the abnormal Z alpha 1-antitrypsin isolated from human liver. FEBS Lett 1984;177:179-183.","DOI":"10.1016\/0014-5793(84)81279-X"},{"key":"ref46","doi-asserted-by":"crossref","unstructured":"Katsoulieris E, Mabley JG, Samai M, Green IC, Chatterjee PK. alpha-Linolenic acid protects renal cells against palmitic acid lipotoxicity via inhibition of endoplasmic reticulum stress. Eur J Pharmacol 2009;623:107-112.","DOI":"10.1016\/j.ejphar.2009.09.015"},{"key":"ref47","doi-asserted-by":"crossref","unstructured":"Diakogiannaki E, Welters HJ, Morgan NG. Differential regulation of the endoplasmic reticulum stress response in pancreatic beta-cells exposed to long-chain saturated and monounsaturated fatty acids. J Endocrinol 2008;197:553-563.","DOI":"10.1677\/JOE-08-0041"},{"key":"ref48","doi-asserted-by":"crossref","unstructured":"Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005;307:935-939.","DOI":"10.1126\/science.1101902"},{"key":"ref49","unstructured":"McLean C, Greene CM, McElvaney NG. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency. Biologics 2009;3:63-75."},{"key":"ref50","doi-asserted-by":"crossref","unstructured":"Kruger K, Grabowski PJ, Zaug AJ, Sands J, Gottschling DE, Cech TR. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell 1982;31:147-157.","DOI":"10.1016\/0092-8674(82)90414-7"},{"key":"ref51","doi-asserted-by":"crossref","unstructured":"Ozaki I, Zern MA, Liu S, Wei DL, Pomerantz RJ, Duan L. Ribozyme-mediated specific gene replacement of the alpha1-antitrypsin gene in human hepatoma cells. J Hepatol 1999;31:53-60.","DOI":"10.1016\/S0168-8278(99)80163-9"},{"key":"ref52","doi-asserted-by":"crossref","unstructured":"Nielsen PE, Egholm M, Berg RH, Buchardt O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991;254:1497-1500.","DOI":"10.1126\/science.1962210"},{"key":"ref53","unstructured":"McLean C. Gene targeted inhibition in alpha-1 antitrypsin deficiency. Ph.D. Thesis Dublin: Royal College of Surgeons; Ireland; 2009;."},{"key":"ref54","doi-asserted-by":"crossref","unstructured":"Cruz PE, Mueller C, Cossette TL, Golant A, Tang Q, Beattie SG, Brantly M, Campbell-Thompson M, Blomenkamp KS, Teckman JH. In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest 2007;87:893-902.","DOI":"10.1038\/labinvest.3700629"},{"key":"ref55","doi-asserted-by":"crossref","unstructured":"Mahadeva R, Dafforn TR, Carrell RW, Lomas DA. 6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis. J Biol Chem 2002;277:6771-6774.","DOI":"10.1074\/jbc.C100722200"},{"key":"ref56","doi-asserted-by":"crossref","unstructured":"Parfrey H, Dafforn TR, Belorgey D, Lomas DA, Mahadeva R. Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema. Am J Respir Cell Mol Biol 2004;31:133-139.","DOI":"10.1165\/rcmb.2003-0276OC"},{"key":"ref57","doi-asserted-by":"crossref","unstructured":"Chang YP, Mahadeva R, Chang WS, Shukla A, Dafforn TR, Chu YH. Identification of a 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z alpha1-antitrypsin. Am J Respir Cell Mol Biol 2006;35:540-548.","DOI":"10.1165\/rcmb.2005-0207OC"},{"key":"ref58","doi-asserted-by":"crossref","unstructured":"Chang YP, Mahadeva R, Chang WS, Lin SC, Chu YH. Small-molecule peptides inhibit Z alpha1-antitrypsin polymerization. J Cell Mol Med 2009;13:2304-2316.","DOI":"10.1111\/j.1582-4934.2008.00608.x"},{"key":"ref59","doi-asserted-by":"crossref","unstructured":"Sharp LK, Mallya M, Kinghorn KJ, Wang Z, Crowther DC, Huntington JA, Belorgey D, Lomas DA. Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis. FEBS J 2006;273:2540-2552.","DOI":"10.1111\/j.1742-4658.2006.05262.x"},{"key":"ref60","doi-asserted-by":"crossref","unstructured":"Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA 2000;97:1796-1801.","DOI":"10.1073\/pnas.97.4.1796"},{"key":"ref61","doi-asserted-by":"crossref","unstructured":"Marcus NY, Perlmutter DH. Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. J Biol Chem 2000;275:1987-1992.","DOI":"10.1074\/jbc.275.3.1987"}],"container-title":["World Journal of Gastrointestinal Pharmacology and Therapeutics"],"original-title":[],"language":"en","deposited":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T18:32:46Z","timestamp":1559759566000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.wjgnet.com\/2150-5349\/full\/v1\/i5\/94.htm"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010]]},"references-count":61,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2010]]}},"URL":"https:\/\/doi.org\/10.4292\/wjgpt.v1.i5.94","relation":{},"ISSN":["2150-5349"],"issn-type":[{"value":"2150-5349","type":"print"}],"subject":[],"published":{"date-parts":[[2010]]}}}