The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency

References

• Mason DY, Cramer EM, Masse JM, Crystal R, Bassot JM, Breton-Gorius J. α1-antitrypsin is present within the primary granules of human polymorphonuclear leukocytes. Am. J. Pathol.139(3), 623–628 (1991).
   PubMed Web of Science ®Google Scholar
• Travis J, Shieh BH, Potempa J. The functional role of acute phase plasma proteinase inhibitors. Tokai J. Exp. Clin. Med.13(6), 313–320 (1988).
   PubMedGoogle Scholar
• Hu C, Perlmutter DH. Cell-specific involvement of HNF-1β in α(1)-antitrypsin gene expression in human respiratory epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol.282(4), L757–L765 (2002).
   Google Scholar
• McCracken AA, Kruse KB, Brown JL. Molecular basis for defective secretion of the Z variant of human α-1-proteinase inhibitor: secretion of variants having altered potential for salt bridge formation between amino acids 290 and 342. Mol. Cell Biol.9(4), 1406–1414 (1989).
   PubMed Web of Science ®Google Scholar
• Lomas DA, Mahadeva R. α1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J. Clin. Invest.110(11), 1585–1590 (2002).
   PubMed Web of Science ®Google Scholar
• Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z α 1-antitrypsin accumulation in the liver. Nature357(6379), 605–607 (1992).
   PubMed Web of Science ®Google Scholar
• Zimmerman MR, Jensen AM, Sheehan GW. Agnaiyaaq: the autopsy of a frozen Thule mummy. Arctic Anthropol.37(2), 52–59 (2000).
   PubMed Web of Science ®Google Scholar
• Blanco I, de Serres FJ, Fernandez-Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of α1-antitrypsin deficiency in European countries. Eur. Respir. J.27(1), 77–84 (2006).
   PubMed Web of Science ®Google Scholar
• de Serres FJ. Worldwide racial and ethnic distribution of α1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest122(5), 1818–1829 (2002).
   PubMed Web of Science ®Google Scholar
• Seyama K, Nukiwa T, Souma S, Shimizu K, Kira S. A 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of α 1-antitrypsin deficiency in Japan. Am. J. Respir. Crit. Care Med.152(6 Pt 1), 2119–2126 (1995).
   PubMed Web of Science ®Google Scholar
• Luisetti M, Seersholm N. A1-antitrypsin deficiency. 1: epidemiology of α1-antitrypsin deficiency. Thorax59(2), 164–169 (2004).
   PubMed Web of Science ®Google Scholar
• Cox DW, Woo SL, Mansfield T. DNA restriction fragments associated with α1-antitrypsin indicate a single origin for deficiency allele PI Z. Nature316(6023), 79–81 (1985).
   PubMed Web of Science ®Google Scholar
• Lomas DA. The selective advantage of α1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med.173(10), 1072–1077 (2006).
   PubMed Web of Science ®Google Scholar
• Lace B, Sveger T, Krams A, Cernevska G, Krumina A. Age of SERPINA1 gene PI Z mutation: Swedish and Latvian population analysis. Ann. Hum. Genet.72(Pt 3), 300–304 (2008).
   PubMed Web of Science ®Google Scholar
• Campos MA, Wanner A, Zhang G, Sandhaus RA. Trends in the diagnosis of symptomatic patients with α1-antitrypsin deficiency between 1968 and 2003. Chest128(3), 1179–1186 (2005).
   PubMed Web of Science ®Google Scholar
• Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C. Delay in diagnosis of α1-antitrypsin deficiency: a continuing problem. Chest128(4), 1989–1994 (2005).
   PubMed Web of Science ®Google Scholar
• Silverman EK, Sandhaus RA. Clinical practice. A1-antitrypsin deficiency. N. Engl. J. Med.360(26), 2749–2757 (2009).
   PubMed Web of Science ®Google Scholar
• Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on opsonized Pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J. Clin. Invest.86(1), 300–308 (1990).
   PubMed Web of Science ®Google Scholar
• Fick RB Jr, Naegel GP, Squier SU, Wood RE, Gee JB, Reynolds HY. Proteins of the cystic fibrosis respiratory tract. Fragmented immunoglobulin G opsonic antibody causing defective opsonophagocytosis. J. Clin. Invest.74(1), 236–248 (1984).
   PubMed Web of Science ®Google Scholar
• Smallman LA, Hill SL, Stockley RA. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax39(9), 663–667 (1984).
   PubMed Web of Science ®Google Scholar
• Weldon S, McNally P, McElvaney NG et al. Decreased levels of secretory leucoprotease inhibitor in the Pseudomonas-infected cystic fibrosis lung are due to neutrophil elastase degradation. J. Immunol.183(12), 8148–8156 (2009).
   PubMed Web of Science ®Google Scholar
• Guyot N, Butler MW, McNally P et al. Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. J. Biol. Chem.283(47), 32377–32385 (2008).
   PubMed Web of Science ®Google Scholar
• Wu MC, Eriksson S. Lung function, smoking and survival in severe α1-antitrypsin deficiency, PiZZ. J. Clin. Epidemiol.41(12), 1157–1165 (1988).
   PubMed Web of Science ®Google Scholar
• Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in α1-antitrypsin deficiency influences lung function impairment. Am. J. Respir. Crit. Care Med.170(11), 1172–1178 (2004).
   PubMed Web of Science ®Google Scholar
• Bernspang E, Sveger T, Piitulainen E. Respiratory symptoms and lung function in 30‑year-old individuals with α-1-antitrypsin deficiency. Respir. Med.101(9), 1971–1976 (2007).
   PubMed Web of Science ®Google Scholar
• Larsson C. Natural history and life expectancy in severe α1-antitrypsin deficiency, Pi Z. Acta Med. Scand.204(5), 345–351 (1978).
   PubMed Web of Science ®Google Scholar
• McElvaney NG, Stoller JK, Buist AS et al. Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of α1-antitrypsin deficiency. α1-Antitrypsin Deficiency Registry Study Group. Chest111(2), 394–403 (1997).
   PubMed Web of Science ®Google Scholar
• Gishen P, Saunders AJ, Tobin MJ, Hutchison DC. α 1-antitrypsin deficiency: the radiological features of pulmonary emphysema in subjects of Pi type Z and Pi type SZ: a survey by the British Thoracic Association. Clin. Radiol.33(4), 371–377 (1982).
   PubMed Web of Science ®Google Scholar
• Stolk J, Ng WH, Bakker ME et al. Correlation between annual change in health status and computer tomography derived lung density in subjects with α1-antitrypsin deficiency. Thorax58(12), 1027–1030 (2003).
   PubMed Web of Science ®Google Scholar
• Tobin MJ, Cook PJ, Hutchison DC. α1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br. J. Dis. Chest77(1), 14–27 (1983).
   PubMedGoogle Scholar
• Seersholm N, Kok-Jensen A, Dirksen A. Decline in FEV1 among patients with severe hereditary α1-antitrypsin deficiency type PiZ. Am. J. Respir. Crit. Care Med.152(6 Pt 1), 1922–1925 (1995).
   PubMed Web of Science ®Google Scholar
• Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, Crystal RG. Clinical features and history of the destructive lung disease associated with α-1-antitrypsin deficiency of adults with pulmonary symptoms. Am. Rev. Respir. Dis.138(2), 327–336 (1988).
   PubMed Web of Science ®Google Scholar
• Demeo DL, Campbell EJ, Barker AF et al. IL10 polymorphisms are associated with airflow obstruction in severe α1-antitrypsin deficiency. Am. J. Respir. Cell Mol. Biol.38(1), 114–120 (2008).
   PubMed Web of Science ®Google Scholar
• Sapey E, Wood AM, Ahmad A, Stockley RA. Tumor necrosis factor-{α} rs361525 polymorphism is associated with increased local production and downstream inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.182(2), 192–199 (2010).
   PubMed Web of Science ®Google Scholar
• The A-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of α1-antitrypsin. Am. J. Respir. Crit. Care Med.158(1), 49–59 (1988).
   Google Scholar
• Dawkins PA, Dowson LJ, Guest PJ, Stockley RA. Predictors of mortality in α1-antitrypsin deficiency. Thorax58(12), 1020–1026 (2003).
   PubMed Web of Science ®Google Scholar
• Schenkein JG, Nahm MH, Dransfield MT. Pneumococcal vaccination for patients with COPD: current practice and future directions. Chest133(3), 767–774 (2008).
   PubMed Web of Science ®Google Scholar
• O’Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax55(8), 635–642 (2000).
   PubMed Web of Science ®Google Scholar
• Parr DG, Guest PG, Reynolds JH, Dowson LJ, Stockley RA. Prevalence and impact of bronchiectasis in α1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med.176(12), 1215–1221 (2007).
   PubMed Web of Science ®Google Scholar
• Fallat RJ. Reactive airways disease and α 1-antitrypsin deficiency. In: α1-Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestation, Therapy. Crystal R (Ed.). Marcel Dekker, NY, USA, 259–279 (1996).
   Google Scholar
• Cuvelier A, Muir JF, Hellot MF et al. Distribution of α(1)-antitrypsin alleles in patients with bronchiectasis. Chest117(2), 415–419 (2000).
   PubMed Web of Science ®Google Scholar
• Chan ED, Kaminska AM, Gill W et al. α-1-antitrypsin (AAT) anomalies are associated with lung disease due to rapidly growing mycobacteria and AAT inhibits Mycobacterium abscessus infection of macrophages. Scand. J. Infect. Dis.39(8), 690–696 (2007).
   PubMed Web of Science ®Google Scholar
• Eden E, Hammel J, Rouhani FN et al. Asthma features in severe α1-antitrypsin deficiency: experience of the National Heart, Lung, and Blood Institute Registry. Chest123(3), 765–771 (2003).
   PubMed Web of Science ®Google Scholar
• Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA. Exercise capacity predicts health status in α(1)-antitrypsin deficiency. Am. J. Respir. Crit. Care Med.163(4), 936–941 (2001).
   PubMed Web of Science ®Google Scholar
• Eden E, Mitchell D, Mehlman B et al. Atopy, asthma, and emphysema in patients with severe α-1-antitrypysin deficiency. Am. J. Respir. Crit. Care Med.156(1), 68–74 (1997).
   PubMed Web of Science ®Google Scholar
• Sigsgaard T, Brandslund I, Omland O et al. S and Z α1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction. Eur. Respir. J.16(1), 50–55 (2000).
   PubMed Web of Science ®Google Scholar
• Dycaico MJ, Grant SG, Felts K et al. Neonatal hepatitis induced by α1-antitrypsin: a transgenic mouse model. Science242(4884), 1409–1412 (1988).
   PubMed Web of Science ®Google Scholar
• Carlson JA, Rogers BB, Sifers RN et al. Accumulation of PiZ α 1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest.83(4), 1183–1190 (1989).
   PubMed Web of Science ®Google Scholar
• Jeppsson JO, Larsson C, Eriksson S. Characterization of α1-antitrypsin in the inclusion bodies from the liver in α 1-antitrypsin deficiency. N. Engl. J. Med.293(12), 576–579 (1975).
   PubMed Web of Science ®Google Scholar
• Sveger T. Liver disease in α1-antitrypsin deficiency detected by screening of 200,000 infants. N. Engl. J. Med.294(24), 1316–1321 (1976).
   PubMed Web of Science ®Google Scholar
• Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in α 1-antitrypsin deficiency. N. Engl. J. Med.314(12), 736–739 (1986).
   PubMed Web of Science ®Google Scholar
• Sharp HL, Bridges RA, Krivit W, Freier EF. Cirrhosis associated with α-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J. Lab. Clin. Med.73(6), 934–939 (1969).
   PubMed Web of Science ®Google Scholar
• Sveger T, Eriksson S. The liver in adolescents with α1-antitrypsin deficiency. Hepatology22(2), 514–517 (1995).
   PubMed Web of Science ®Google Scholar
• Eriksson S. α1-antitrypsin deficiency and liver cirrhosis in adults. An analysis of 35 Swedish autopsied cases. Acta Med. Scand.221(5), 461–467 (1987).
   PubMedGoogle Scholar
• Piitulainen E, Carlson J, Ohlsson K, Sveger T. α1-antitrypsin deficiency in 26‑year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest128(4), 2076–2081 (2005).
   PubMed Web of Science ®Google Scholar
• Bernspang E, Carlson J, Piitulainen E. The liver in 30‑year-old individuals with α(1)-antitrypsin deficiency. Scand. J. Gastroenterol.44(11), 1349–1355 (2009).
   PubMed Web of Science ®Google Scholar
• Kok KF, Wahab PJ, Houwen RH et al. Heterozygous α-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth. J. Med.65(5), 160–166 (2007).
   PubMed Web of Science ®Google Scholar
• Rakela J, Goldschmiedt M, Ludwig J. Late manifestation of chronic liver disease in adults with α-1-antitrypsin deficiency. Dig. Dis. Sci.32(12), 1358–1362 (1987).
   PubMed Web of Science ®Google Scholar
• Voide N, Ardigo S, Morris M et al. α-1-antitrypsin deficiency in a 78‑year-old woman with isolated liver cirrhosis. J. Am. Geriatr. Soc.58(2), 415–416 (2010).
   PubMed Web of Science ®Google Scholar
• Pan S, Huang L, McPherson J et al. Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in α1-antitrypsin deficiency. Hepatology50(1), 275–281 (2009).
   PubMed Web of Science ®Google Scholar
• Bartlett JR, Friedman KJ, Ling SC et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA302(10), 1076–1083 (2009).
   PubMed Web of Science ®Google Scholar
• Edmonds BK, Hodge JA, Rietschel RL. α1-antitrypsin deficiency-associated panniculitis: case report and review of the literature. Pediatr. Dermatol.8(4), 296–299 (1991).
   PubMed Web of Science ®Google Scholar
• Fortin PR, Fraser RS, Watts CS, Esdaile JM. α-1 antitrypsin deficiency and systemic necrotizing vasculitis. J. Rheumatol.18(10), 1613–1616 (1991).
   PubMed Web of Science ®Google Scholar
• Barnett VT, Sekosan M, Khurshid A. Wegener’s granulomatosis and α1-antitrypsin-deficiency emphysema: proteinase-related diseases. Chest116(1), 253–255 (1999).
   PubMed Web of Science ®Google Scholar
• Schievink WI, Puumala MR, Meyer FB, Raffel C, Katzmann JA, Parisi JE. Giant intracranial aneurysm and fibromuscular dysplasia in an adolescent with α1-antitrypsin deficiency. J. Neurosurg.85(3), 503–506 (1996).
   PubMed Web of Science ®Google Scholar
• Yang P, Bamlet WR, Sun Z et al. α1-antitrypsin and neutrophil elastase imbalance and lung cancer risk. Chest128(1), 445–452 (2005).
   PubMed Web of Science ®Google Scholar
• Davis ID, Burke B, Freese D, Sharp HL, Kim Y. The pathologic spectrum of the nephropathy associated with α1-antitrypsin deficiency. Hum. Pathol.23(1), 57–62 (1992).
   PubMed Web of Science ®Google Scholar
• Schievink WI, Björnsson J, Parisi JE, Prakash UB. Arterial fibromuscular dysplasia associated with severe α1-antitrypsin deficiency. Mayo Clin. Proc.69(11), 1040–1043 (1994).
   PubMed Web of Science ®Google Scholar
• Novis BH, Young GO, Bank S, Marks IN. Chronic pancreatitis and α-1 antitrypsin. Lancet2(7938), 748–749 (1975).
   PubMed Web of Science ®Google Scholar
• Schmechel DE, Browndyke J, Ghio A. Strategies for dissecting genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology27(5), 637–657 (2006).
   PubMed Web of Science ®Google Scholar
• Russo AJ, Neville L, Wroge C. Low Serum α-1 Antitrypsin (AAT) in Family Members of Individuals with Autism Correlates with PiMZ Genotype. Biomark. Insights4(1), 45–56 (2009).
   PubMedGoogle Scholar
• Schmechel DE. Art, α-1-antitrypsin polymorphisms and intense creative energy: blessing or curse? Neurotoxicology28(5), 899–914 (2007).
   PubMed Web of Science ®Google Scholar
• Zandi PP, Willour VL, Huo Y et al. National Institute of Mental Health Genetics Initiative Bipolar Group. Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X. Am. J. Med. Genet. B Neuropsychiatr. Genet.119B(1), 69–76 (2003).
   PubMed Web of Science ®Google Scholar
• Beyer J, Kuchibhatla M, Gersing K, Krishnan KR. Medical comorbidity in a bipolar outpatient clinical population. Neuropsychopharmacology30(2), 401–404 (2005).
   PubMed Web of Science ®Google Scholar
• Baugh RJ, Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry15(4), 836–841 (1976).
   PubMed Web of Science ®Google Scholar
• Lee WL, Downey GP. Leukocyte elastase: physiological functions and role in acute lung injury. Am. J. Respir. Crit. Care Med.164(5), 896–904 (2001).
   PubMed Web of Science ®Google Scholar
• Cooley J, Takayama TK, Shapiro SD, Schechter NM, Remold-O’Donnell E. The serpin MNEI inhibits elastase-like and chymotrypsin-like serine proteases through efficient reactions at two active sites. Biochemistry40(51), 15762–15770 (2001).
   PubMed Web of Science ®Google Scholar
• Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res.69(3), 562–573 (2006).
   PubMed Web of Science ®Google Scholar
• Gaggar A, Jackson PL, Noerager BD et al. A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J. Immunol.180(8), 5662–5669 (2008).
   PubMed Web of Science ®Google Scholar
• Lin M, Jackson P, Tester AM et al. Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro. Am. J. Pathol.173(1), 144–153 (2008).
   PubMed Web of Science ®Google Scholar
• Berger M, Sorensen RU, Tosi MF, Dearborn DG, Doring G. Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. J. Clin. Invest.84(4), 1302–1313 (1989).
   PubMed Web of Science ®Google Scholar
• Zhu YK, Liu XD, Skold CM et al. Synergistic neutrophil elastase-cytokine interaction degrades collagen in three-dimensional culture. Am. J. Physiol. Lung Cell Mol. Physiol.281(4), L868–L878 (2001).
   PubMed Web of Science ®Google Scholar
• Abrahamson M, Mason RW, Hansson H, Buttle DJ, Grubb A, Ohlsson K. Human cystatin C. role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase. Biochem. J.273(Pt 3), 621–626 (1991).
   PubMed Web of Science ®Google Scholar
• Hirche TO, Benabid R, Deslee G et al. Neutrophil elastase mediates innate host protection against Pseudomonas aeruginosa. J. Immunol.181(7), 4945–4954 (2008).
   PubMed Web of Science ®Google Scholar
• Belaaouaj A, McCarthy R, Baumann M et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat. Med.4(5), 615–618 (1998).
   PubMed Web of Science ®Google Scholar
• Rogan MP, Taggart CC, Greene CM, Murphy PG, O’Neill SJ, McElvaney NG. Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis. J. Infect. Dis.190(7), 1245–1253 (2004).
   PubMed Web of Science ®Google Scholar
• Hartl D, Latzin P, Hordijk P et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat. Med.13(12), 1423–1430 (2007).
   PubMed Web of Science ®Google Scholar
• Nemoto E, Sugawara S, Tada H, Takada H, Shimauchi H, Horiuchi H. Cleavage of CD14 on human gingival fibroblasts cocultured with activated neutrophils is mediated by human leukocyte elastase resulting in down-regulation of lipopolysaccharide-induced IL-8 production. J. Immunol.165(10), 5807–5813 (2000).
   PubMed Web of Science ®Google Scholar
• Campbell EJ, Campbell MA, Owen CA. Bioactive proteinase 3 on the cell surface of human neutrophils: quantification, catalytic activity, and susceptibility to inhibition. J. Immunol.165(6), 3366–3374 (2000).
   PubMed Web of Science ®Google Scholar
• Geraghty P, Rogan MP, Greene CM et al. α-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro. Thorax63(7), 621–626 (2008).
   PubMed Web of Science ®Google Scholar
• Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood96(8), 2673–2681 (2000).
   PubMed Web of Science ®Google Scholar
• Rouhani F, Paone G, Smith NK, Krein P, Barnes P, Brantly ML. Lung neutrophil burden correlates with increased pro-inflammatory cytokines and decreased lung function in individuals with α(1)-antitrypsin deficiency. Chest117(5 Suppl. 1), 250S–251S (2000).
   PubMed Web of Science ®Google Scholar
• Devaney JM, Greene CM, Taggart CC, Carroll TP, O’Neill SJ, McElvaney NG. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett.544(1–3), 129–132 (2003).
   PubMed Web of Science ®Google Scholar
• Geraghty P, Rogan MP, Greene CM et al. Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression. J. Immunol.178(9), 5871–5878 (2007).
   PubMed Web of Science ®Google Scholar
• Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br. J. Pharmacol.153(Suppl. 1), S263–S282 (2008).
   Web of Science ®Google Scholar
• Ostrowska E, Sokolova E, Reiser G. PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release. Am. J. Physiol. Lung Cell. Mol. Physiol.293(5), L1208–L1218 (2007).
   Web of Science ®Google Scholar
• Kuwahara I, Lillehoj EP, Lu W et al. Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{κ}B activation via EGFR transactivation in a lung epithelial cell line. Am. J. Physiol. Lung Cell. Mol. Physiol.291(3), L407–L416 (2006).
   PubMed Web of Science ®Google Scholar
• Shao MX, Nadel JA. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc. Natl Acad. Sci. USA102(3), 767–772 (2005).
   PubMed Web of Science ®Google Scholar
• Bergin DA, Greene CM, Sterchi EE et al. Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. J. Biol. Chem.283(46), 31736–31744 (2008).
   PubMed Web of Science ®Google Scholar
• Shao MX, Nadel JA. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-α-converting enzyme. J. Immunol.175(6), 4009–4016 (2005).
   PubMed Web of Science ®Google Scholar
• Griffin S, Carroll TP, Greene CM, O’Neill SJ, Taggart CC, McElvaney NG. Effect of pro-inflammatory stimuli on mucin expression and inhibition by secretory leucoprotease inhibitor. Cell. Microbiol.9(3), 670–679 (2007).
   PubMed Web of Science ®Google Scholar
• Gadek JE, Klein HG, Holland PV, Crystal RG. Replacement therapy of α1 antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J. Clin. Invest.68(5), 1158–1165 (1981).
   PubMed Web of Science ®Google Scholar
• Abboud RT, Ford GT, Chapman KR. α1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Can. Respir. J.8, 81–88 (2001).
   PubMedGoogle Scholar
• Wewers MD, Casolaro MA, Sellers SE et al. Replacement therapy for α-1 antitrypsin deficiency associated with emphysema. N. Engl. J. Med.316, 1055–1062 (1987).
   PubMed Web of Science ®Google Scholar
• Russi EW. α-1 antitrypsin: now available, but do we need it? Swiss Med. Wkly.138, 191–196 (2008).
   PubMed Web of Science ®Google Scholar
• Seersholm N, Wencker M, Banik N et al. Does α1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary α1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) α1-AT study group. Eur. Respir. J.10, 2260–2263 (1997).
   PubMed Web of Science ®Google Scholar
• Dirksen A, Dijkman JH, Madsen F et al. A randomized clinical trial of α(1)-antitrypsin augmentation therapy. Am. J. Respir. Crit. Care Med.160, 1468–1472 (1999).
   PubMed Web of Science ®Google Scholar
• Dirksen A, Piitulainen E, Parr DG et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in α1-antitrypsin deficiency. Eur. Respir. J.33, 1345–1353 (2009).
   PubMed Web of Science ®Google Scholar
• Tonelli AR, Rouhani F, Li N et al. α-1-antitrypsin augmentation therapy in deficient individuals enrolled in the α-1 Foundation DNA and Tissue Bank. Int. J. Chron. Obstruct. Pulmon. Dis.4, 443–452 (2009).
   PubMedGoogle Scholar
• Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in α 1-antitrypsin deficiency. Respir. Res.10, 75 (2009).
   PubMed Web of Science ®Google Scholar
• Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of α-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir. Res.11, 136 (2010)
   PubMed Web of Science ®Google Scholar
• Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ. Augmentation therapy for α1 antitrypsin deficiency: a meta-analysis. COPD6(3), 177–184 (2009).
   PubMedGoogle Scholar
• McCarthy C, Dimitrov BD. Augmentation therapy for α-1 antitrypsin deficiency – not enough evidence to support its use yet! COPD7(3), 234 (2010).
   PubMedGoogle Scholar
• Hubbard RC, McElvaney NG, Sellers SE, Healy JT, Czerski DB, Crystal RG. Recombinant DNA-produced α 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with α 1-antitrypsin deficiency. J. Clin. Invest.84(4), 1349–1354 (1989).
   PubMed Web of Science ®Google Scholar
• McElvaney NG, Hubbard RC, Birrer P et al. Aerosol α 1-antitrypsin treatment for cystic fibrosis. Lancet337(8738), 392–394 (1991).
   PubMed Web of Science ®Google Scholar
• Griese M, Latzin P, Kappler M et al. α1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur. Respir. J.29(2), 240–250 (2007).
   PubMed Web of Science ®Google Scholar
• Henriksen PA, Hitt M, Xing Z et al. Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-κ B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. J. Immunol.172(7), 4535–4544 (2004).
   PubMed Web of Science ®Google Scholar
• Simpson AJ, Maxwell AI, Govan JR, Haslett C, Sallenave JM. Elafin (elastase-specific inhibitor) has anti-microbial activity against gram-positive and gram-negative respiratory pathogens. FEBS Lett.452(3), 309–313 (1999).
   PubMed Web of Science ®Google Scholar
• Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infect. Immun.73(3), 1271–1274 (2005).
   PubMed Web of Science ®Google Scholar
• Sallenave JM, Shulmann J, Crossley J, Jordana M, Gauldie J. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am. J. Respir. Cell. Mol. Biol.11(6), 733–741 (1994).
   PubMed Web of Science ®Google Scholar
• Zhang Y, DeWitt DL, McNeely TB, Wahl SM, Wahl LM. Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E2, and matrix metalloproteinases. J. Clin. Invest.99(5), 894–900 (1997).
   PubMed Web of Science ®Google Scholar
• Yang J, Zhu J, Sun D, Ding A. Suppression of macrophage responses to bacterial lipopolysaccharide (LPS) by secretory leukocyte protease inhibitor (SLPI) is independent of its anti-protease function. Biochim. Biophys. Acta1745(3), 310–317 (2005).
   PubMed Web of Science ®Google Scholar
• Birrer P, McElvaney NG, Gillissen A et al. Intravenous recombinant secretory leukoprotease inhibitor augments antineutrophil elastase defense. J. Appl. Physiol.73(1), 317–323 (1992).
   PubMed Web of Science ®Google Scholar
• Vogelmeier C, Buhl R, Hoyt RF et al. Aerosolization of recombinant SLPI to augment antineutrophil elastase protection of pulmonary epithelium. J. Appl. Physiol.69(5), 1843–1848 (1990).
   PubMed Web of Science ®Google Scholar
• McElvaney NG, Nakamura H, Birrer P et al. Modulation of airway inflammation in cystic fibrosis. In vivo suppression of interleukin-8 levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor. J. Clin. Invest.90(4), 1296–1301 (1992).
   PubMed Web of Science ®Google Scholar
• Zani ML, Baranger K, Guyot N, Dallet-Choisy S, Moreau T. Protease inhibitors derived from elafin and SLPI and engineered to have enhanced specificity towards neutrophil serine proteases. Protein Sci.18(3), 579–594 (2009).
   PubMed Web of Science ®Google Scholar
• Delacourt C, Herigault S, Delclaux C et al. Protection against acute lung injury by intravenous or intratracheal pretreatment with EPI-HNE-4, a new potent neutrophil elastase inhibitor. Am. J. Respir. Cell. Mol. Biol.26(3), 290–297 (2002).
   PubMed Web of Science ®Google Scholar
• Greene CM, Miller SD, Carroll T et al. α-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations. J. Inherit. Metab. Dis.31(1), 21–34 (2008).
   PubMed Web of Science ®Google Scholar
• Greene CM, McElvaney NG. Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response. World J. Gastrointest. Pharmacol. Ther.1(5), 94–101 (2010).
   PubMedGoogle Scholar
• Greene CM, McElvaney NG. Protein misfolding and obstructive lung disease. Proc. Am. Thorac. Soc.7(6), 346–355 (2010).
   PubMedGoogle Scholar
• Carroll TP, McElvaney NG, Greene CM, Gain-of-function effects of Z α-1 antitrypsin. Antiinflamm. Antiallergy Agents Med. Chem.9, 336–346 (2010).
   Google Scholar
• 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 α 1-antitrypsin deficiency. J. Immunol.172(9), 5722–5726 (2004).
   PubMed Web of Science ®Google Scholar
• Miller SD, Greene CM, McLean C et al. Tauroursodeoxycholic acid inhibits apoptosis induced by Z α-1 antitrypsin via inhibition of Bad. Hepatology46(2), 496–503 (2007).
   PubMed Web of Science ®Google Scholar
• Greene CM, Miller SD, Carroll TP et al. Anti-apoptotic effects of Z α1-antitrypsin in human bronchial epithelial cells. Eur. Respir. J.35(5), 1155–1163 (2010).
   PubMed Web of Science ®Google Scholar
• Carroll T, Greene CM, O’Connor CA, Nolan A, O’Neill SJ, McElvaney NG. Evidence for unfolded protein response (UPR) activation in monocytes from individuals with α-1 antitrypsin deficiency. J. Immunol.184(8), 4538–4546 (2010).
   PubMed Web of Science ®Google Scholar
• Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant α1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFκB, and BAP31 but not the unfolded protein response. J. Biol. Chem.280(47), 39002–39015 (2005).
   PubMed Web of Science ®Google Scholar
• Bergin DA, Reeves EP, Meleady P et al. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J. Clin. Invest.120(12), 4236–4250 (2010).
   PubMed Web of Science ®Google Scholar
• Elliott PR, Bilton D, Lomas DA. Lung polymers in Z α1-antitrypsin deficiency-related emphysema. Am. J. Respir. Cell. Mol. Biol.18(5), 670–674 (1998).
   PubMed Web of Science ®Google Scholar
• Mulgrew AT, Taggart CC, Lawless MW et al. Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest125(5), 1952–1957 (2004).
   PubMed Web of Science ®Google Scholar
• Mahadeva R, Atkinson C, Li Z et al. Polymers of Z α1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am. J. Pathol.166(2), 377–386 (2005).
   PubMed Web of Science ®Google Scholar
• Brodsky JL, McCracken AA. ER protein quality control and proteasome-mediated protein degradation. Semin. Cell Dev. Biol.10(5), 507–513 (1999).
   PubMed Web of Science ®Google Scholar
• Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of α-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology45(5), 1313–1323 (2007).
   PubMed Web of Science ®Google Scholar
• Perlmutter DH. α-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu. Rev. Med.62, 333–345 (2011).
   PubMed Web of Science ®Google Scholar
• Eskelinen EL. New insights into the mechanisms of macroautophagy in mammalian cells. Int. Rev. Cell Mol. Biol.266, 207–247 (2008).
   PubMed Web of Science ®Google Scholar
• Kundu M, Thompson CB. Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol.3, 427–455 (2008).
   PubMed Web of Science ®Google Scholar
• Eskelinen EL, Saftig P. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim. Biophys. Acta1793(4), 664–673 (2009).
   PubMed Web of Science ®Google Scholar
• Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep.9(9), 859–864 (2008).
   PubMed Web of Science ®Google Scholar
• Perlmutter DH. The role of autophagy in α-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy2(4), 258–263 (2006).
   PubMed Web of Science ®Google Scholar
• Perlmutter DH. Liver injury in α1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J. Clin. Invest.110(11), 1579–1583 (2002).
   PubMed Web of Science ®Google Scholar
• Teckman JH, Perlmutter DH. Retention of mutant α(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am. J. Physiol. Gastrointest. Liver Physiol.279(5), G961–G974 (2000).
   PubMed Web of Science ®Google Scholar
• Teckman JH, An JK, Loethen S, Perlmutter DH. Fasting in α1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am. J. Physiol. Gastrointest. Liver Physiol.283(5), G1156–G1165 (2002).
   PubMed Web of Science ®Google Scholar
• Teckman JH, An JK, Blomenkamp K, Schmidt B, Perlmutter D. Mitochondrial autophagy and injury in the liver in α 1-antitrypsin deficiency. Am. J. Physiol. Gastrointest. Liver Physiol.286(5), G851–G862 (2004).
   PubMed Web of Science ®Google Scholar
• Wood AM, Tan SL, Stockley RA. Chronic obstructive pulmonary disease: towards pharmacogenetics. Genome Med.1(11), 112 (2009).
   PubMed Web of Science ®Google Scholar
• Silverman EK. Genetics of chronic obstructive pulmonary disease. Novartis Found. Symp.234(1), 45–58 (2001).
   PubMedGoogle Scholar
• Wood AM, Needham M, Simmonds MJ, Newby PR, Gough SC, Stockley RA. Phenotypic differences in α 1 antitrypsin-deficient sibling pairs may relate to genetic variation. COPD5(6), 353–359 (2008).
   PubMedGoogle Scholar
• Seersholm N. Pi MZ and COPD: will we ever know? Thorax59(10), 823–825 (2004).
   PubMed Web of Science ®Google Scholar
• Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax59(10), 843–849 (2004).
   PubMed Web of Science ®Google Scholar
• Silverman EK, Province MA, Rao DC, Pierce JA, Campbell EJ. A family study of the variability of pulmonary function in α 1-antitrypsin deficiency. Quantitative phenotypes. Am. Rev. Respir. Dis.142(5), 1015–1021 (1990).
   PubMed Web of Science ®Google Scholar
• Sorheim IC, Bakke P, Gulsvik A et al. α-1 Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest138(5), 1125–1132 (2010).
   PubMed Web of Science ®Google Scholar
• Malerba M, Ricciardolo F, Radaeli A et al. Neutrophilic inflammation and IL-8 levels in induced sputum of α-1-antitrypsin PiMZ subjects. Thorax61(2), 129–133 (2006).
   PubMed Web of Science ®Google Scholar
• Larsson C, Dirksen H, Sundstrom G, Eriksson S. Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of α1-antitrypsin. Scand. J. Respir. Dis.57(6), 267–280 (1976).
   PubMedGoogle Scholar
• Turino GM, Barker AF, Brantly ML et al. Clinical features of individuals with PI*SZ phenotype of α 1-antitrypsin deficiency. α 1-Antitrypsin Deficiency Registry Study Group. Am. J. Respir. Crit. Care Med.154(6 Pt 1), 1718–1725 (1996).
   PubMed Web of Science ®Google Scholar
• Holme J, Stockley RA. CT scan appearance, densitometry, and health status in protease inhibitor SZ α1-antitrypsin deficiency. Chest136(5), 1284–1290 (2009).
   PubMed Web of Science ®Google Scholar
• Dahl M, Hersh CP, Ly NP, Berkey CS, Silverman EK, Nordestgaard BG. The protease inhibitor PI*S allele and COPD: a meta-analysis. Eur. Respir. J.26(1), 67–76 (2005).
   PubMed Web of Science ®Google Scholar
• Sandhaus RA, Turino G, Stocks J et al. A1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note. Chest134(4), 831–834 (2008).
   PubMed Web of Science ®Google Scholar
• Senn O, Russi EW, Imboden M, Probst-Hensch NM. α1-Antitrypsin deficiency and lung disease: risk modification by occupational and environmental inhalants. Eur. Respir. J.26(5), 909–917 (2005).
   PubMed Web of Science ®Google Scholar
• American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with α-1 antitrypsin deficiency. Am. J. Respir. Crit. Care Med.168(7), 818–900 (2003).
   PubMed Web of Science ®Google Scholar
• Spencer LT, Humphries JE, Brantly ML.Transgenic Human α 1-Antitrypsin Study Group. Antibody response to aerosolized transgenic human α1-antitrypsin. N. Engl. J. Med.352(19), 2030–2031 (2005).
   PubMed Web of Science ®Google Scholar
• McLean C, Greene CM, McElvaney NG. Gene targeted therapeutics for liver disease in α-1 antitrypsin deficiency. Biologics3, 63–75 (2009).
   PubMedGoogle Scholar
• McNab GL, Ahmad A, Mistry D, Stockley RA. Modification of gene expression and increase in α1-antitrypsin (α1-AT) secretion after homologous recombination in α1-AT-deficient monocytes. Hum. Gene Ther.18(11), 1171–1177 (2007).
   PubMed Web of Science ®Google Scholar
• Argyros O, Wong SP, Niceta M et al. Persistent episomal transgene expression in liver following delivery of a scaffold/matrix attachment region containing non-viral vector. Gene Ther.15(24), 1593–1605 (2008).
   PubMed Web of Science ®Google Scholar
• Chulay JD, Knop DR, Ye GJ et al. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human α-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum. Gene Ther.22(2), 155–165 (2010).
   PubMed Web of Science ®Google Scholar
• Brantly ML, Chulay JD, Wang L et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc. Natl Acad. Sci. USA106(38), 16363–16368 (2009).
   PubMed Web of Science ®Google Scholar
• Liqun Wang R, McLaughlin T, Cossette T et al. Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of α-1-antitrypsin using invasive and noninvasive delivery. Mol. Ther.17(1), 81–87 (2009).
   PubMed Web of Science ®Google Scholar
• Flotte TR, Conlon TJ, Poirier A, Campbell-Thompson M, Byrne BJ. Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites. Hum. Gene Ther.18(3), 245–256 (2007).
   PubMed Web of Science ®Google Scholar
• Brantly ML, Spencer LT, Humphries M et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 αl-antitrypsin (AAT) vector in AAT-deficient adults. Hum. Gene Ther.17(12), 1177–1186 (2006).
   PubMed Web of Science ®Google Scholar
• Ghaedi M, Lotfi AS, Soleimani M. Establishment of lentiviral-vector-mediated model of human α-1 antitrypsin delivery into hepatocyte-like cells differentiated from mesenchymal stem cells. Tissue Cell42(3), 181–189 (2010).
   PubMed Web of Science ®Google Scholar
• Sifers RN. Medicine. Clearing conformational disease. Science329(5988), 154–155 (2010).
   PubMed Web of Science ®Google Scholar
• Hidvegi T, Ewing M, Hale P et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science329(5988), 229–232 (2010).
   PubMed Web of Science ®Google Scholar
• Kelly E, Greene CM, Carroll TP, McElvaney NG, O’Neill SJ. Selenoprotein S/Seps1 modifies endoplasmic reticulum stress in z variant α1-antitrypsin deficiency. J. Biol. Chem.284(25), 16891–16897 (2009).
   PubMed Web of Science ®Google Scholar
• Somers A, Jean JC, Sommer CA et al. Generation of transgene-free lung disease specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells28(10), 1728–1740 (2010).
   PubMed Web of Science ®Google Scholar
• Pillai SG, Ge D, Zhu G et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet.5(3), e1000421 (2009).
   PubMed Web of Science ®Google Scholar