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

Expert Review of Respiratory Medicine

Volumn 5, Issue 3, 2011, Pages 395-411

  Greene, Catherine M ^a   Hassan, Tidi ^a   Molloy, Kevin ^a   McElvaney, Noel G ^a  

^a BEAUMONT HOSPITAL   (Ireland)

Author keywords

augmentation therapy; endoplasmic reticulum stress; serine antiprotease; serine proteases; SERPINA1 heterozygosity; 1 anti trypsin deficiency

Indexed keywords

ALPHA 1 ANTITRYPSIN; CATHEPSIN B; COLLAGEN; CYTOKINE; ELASTIN; FIBRONECTIN; GELATINASE A; GELATINASE B; INTERLEUKIN 8; LAMININ; NEUTROPHIL COLLAGENASE; PROTEINASE; PROTEOGLYCAN; TOLL LIKE RECEPTOR;

ALPHA 1 ANTITRYPSIN DEFICIENCY; ASTHMA; AUTOPHAGY; BRONCHIECTASIS; CHEMOTAXIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL FEATURE; DISEASE ASSOCIATION; DISEASE PREDISPOSITION; DYSPNEA; EMPHYSEMA; ENDOPLASMIC RETICULUM STRESS; ENZYME ACTIVITY; EXTRACELLULAR MATRIX; GAIN OF FUNCTION MUTATION; GENE; HETEROZYGOSITY; HUMAN; LIVER CELL; LIVER DISEASE; LOSS OF FUNCTION MUTATION; LUNG ALVEOLUS EPITHELIUM; LUNG DISEASE; LUNG FIBROSIS; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; REVIEW; RISK FACTOR; SERPINA1 GENE;

EID: 79959756889     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/ers.11.20     Document Type: Review

References (182)

1. Mason DY, Cramer EM, Masse JM, Crystal R, Bassot JM, Breton-Gorius J. a1-antitrypsin is present within the primary granules of human polymorphonuclear leukocytes. Am. J. Pathol. 139(3), 623-628 (1991
2. 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 (Pubitemid 20218222)
3. Hu C, Perlmutter DH. Cell-specific involvement of HNF-1β in α1-antitrypsin gene expression in human respiratory epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 282(4), L757-L765 (2002 (Pubitemid 34665592)
4. 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 (Pubitemid 19095180)
5. Lomas DA, Mahadeva R. α1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J. Clin. Invest. 110(11), 1585-1590 (2002 (Pubitemid 35424233)
6. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 357(6379), 605-607 (1992
7. Zimmerman MR, Jensen AM, Sheehan GW. Agnaiyaaq: the autopsy of a frozen Thule mummy. Arctic Anthropol. 37(2), 52-59 (2000 (Pubitemid 33621631)
8. 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 (Pubitemid 43092670)
9. de Serres FJ. Worldwide racial and ethnic distribution of α1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 122(5), 1818-1829 (2002
10. Seyama K, Nukiwa T, Souma S, Shimizu K, Kira S. α1-antitrypsin- deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of α1-antitrypsin deficiency in Japan. Am. J. Respir. Crit. Care Med. 152(6 Pt 1), 2119-2126 (1995
11. Luisetti M, Seersholm N. α1-antitrypsin deficiency. 1: epidemiology of α1- antitrypsin deficiency. Thorax 59(2), 164-169 (2004
12. Cox DW, Woo SL, Mansfield T. DNA restriction fragments associated with α1-antitrypsin indicate a single origin for deficiency allele PI Z. Nature 316(6023), 79-81 (1985 (Pubitemid 15013719)
13. Lomas DA. The selective advantage of α1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 173(10), 1072-1077 (2006
14. 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 (Pubitemid 351524193)
15. Campos MA, Wanner A, Zhang G, Sandhaus RA. Trends in the diagnosis of symptomatic patients with α1-antitrypsin deficiency between 1968 and 2003. Chest 128(3), 1179-1186 (2005
16. Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C. Delay in diagnosis of α1-antitrypsin deficiency: a continuing problem. Chest 128(4), 1989-1994 (2005). (Pubitemid 41507532)
17. Silverman EK, Sandhaus RA. Clinical practice. α1-antitrypsin deficiency. N. Engl. J. Med. 360(26), 2749-2757 (2009
18. 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 (Pubitemid 20227005)
19. 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 (Pubitemid 14086066)
20. Smallman LA, Hill SL, Stockley RA. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax 39(9), 663-667 (1984 (Pubitemid 14059514)
21. 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
22. 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
23. Wu MC, Eriksson S. Lung function, smoking and survival in severe α1- antitrypsin deficiency, PiZZ. J. Clin. Epidemiol. 41(12), 1157-1165 (1988 (Pubitemid 19036518)
24. 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 (Pubitemid 39577374)
25. 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 (Pubitemid 47163528)
26. Larsson C. Natural history and life expectancy in severe α1-antitrypsin deficiency, Pi Z. Acta Med. Scand. 204(5), 345-351 (1978 (Pubitemid 9051719)
27. 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. Chest 111(2), 394-403 (1997 (Pubitemid 27096957)
28. Gishen P, Saunders AJ, Tobin MJ, Hutchison DC. α1-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 (Pubitemid 12081354)
29. 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. Thorax 58(12), 1027-1030 (2003 (Pubitemid 37542105)
30. Tobin MJ, Cook PJ, Hutchison DC. a1 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. Chest 77(1), 14-27 (1983 (Pubitemid 13183041)
31. 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
32. 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
33. 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
34. Sapey E, Wood AM, Ahmad A, Stockley RA. Tumor necrosis factor-{a} 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
35. The α-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
36. Dawkins PA, Dowson LJ, Guest PJ, Stockley RA. Predictors of mortality in α1-antitrypsin deficiency. Thorax 58(12), 1020-1026 (2003
37. Schenkein JG, Nahm MH, Dransfield MT. Pneumococcal vaccination for patients with COPD: current practice and future directions. Chest 133(3), 767-774 (2008 (Pubitemid 351367387)
38. O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 55(8), 635-642 (2000 (Pubitemid 30468217)
39. 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 (Pubitemid 350256475)
40. RJ Fallat. Reactive airways disease and α1-antitrypsin deficiency. In: α1-Antitrypsin Deficiency: Biology, Pathogenesis, Clinical Manifestation, Therapy. Crystal R (Ed.Marcel Dekker, NY, USA, 259-279 (1996
41. Cuvelier A, Muir JF, Hellot MF et al. Distribution of a(1)-antitrypsin alleles in patients with bronchiectasis. Chest 117(2), 415-419 (2000 (Pubitemid 30111592)
42. 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 (Pubitemid 47189022)
43. 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. Chest 123(3), 765-771 (2003 (Pubitemid 36315491)
44. Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA. Exercise capacity predicts health status in a(1)-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 163(4), 936-941 (2001 (Pubitemid 32275867)
45. 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 (Pubitemid 27293169)
46. 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 (Pubitemid 30480127)
47. Dycaico MJ, Grant SG, Felts K et al. Neonatal hepatitis induced by α1-antitrypsin: a transgenic mouse model. Science 242(4884), 1409-1412 (1988 (Pubitemid 19008065)
48. Carlson JA, Rogers BB, Sifers RN et al. Accumulation of PiZ α1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83(4), 1183-1190 (1989 (Pubitemid 19113030)
49. Jeppsson JO, Larsson C, Eriksson S. Characterization of α1-antitrypsin in the inclusion bodies from the liver in α1-antitrypsin deficiency. N. Engl. J. Med. 293(12), 576-579 (1975
50. Sveger T. Liver disease in α1-antitrypsin deficiency detected by screening of 200,000 infants. N. Engl. J. Med. 294(24), 1316-1321 (1976).
51. Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in α1-antitrypsin deficiency. N. Engl. J. Med. 314(12), 736-739 (1986 (Pubitemid 16124387)
52. 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
53. Sveger T, Eriksson S. The liver in adolescents with α1-antitrypsin deficiency. Hepatology 22(2), 514-517 (1995
54. 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 (Pubitemid 17099492)
55. Piitulainen E, Carlson J, Ohlsson K, Sveger T. α1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest 128(4), 2076-2081 (2005 (Pubitemid 41507543)
56. Bernspang E, Carlson J, Piitulainen E. The liver in 30-year-old individuals with a(1)-antitrypsin deficiency. Scand. J. Gastroenterol. 44(11), 1349-1355 (2009
57. Kok KF, Wahab PJ, Houwen RH et al. Heterozygous a-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth. J. Med. 65(5), 160-166 (2007 (Pubitemid 47161617)
58. 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
59. 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
60. 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. Hepatology 50(1), 275-281 (2009
61. Bartlett JR, Friedman KJ, Ling SC et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 302(10), 1076-1083 (2009
62. 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
63. Fortin PR, Fraser RS, Watts CS, Esdaile JM. a-1 antitrypsin deficiency and systemic necrotizing vasculitis. J. Rheumatol. 18(10), 1613-1616 (1991
64. Barnett VT, Sekosan M, Khurshid A. Wegener's granulomatosis and α1- antitrypsin-deficiency emphysema: proteinase-related diseases. Chest 116(1), 253-255 (1999 (Pubitemid 29340293)
65. 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 (Pubitemid 26278036)
66. Yang P, Bamlet WR, Sun Z et al. α1- antitrypsin and neutrophil elastase imbalance and lung cancer risk. Chest 128(1), 445-452 (2005 (Pubitemid 40994509)
67. 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
68. 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 (Pubitemid 24346985)
69. Novis BH, Young GO, Bank S, Marks IN. Chronic pancreatitis and a-1 antitrypsin. Lancet 2(7938), 748-749 (1975
70. Schmechel DE, Browndyke J, Ghio A. Strategies for dissecting genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology 27(5), 637-657 (2006 (Pubitemid 44232993)
71. Russo AJ, Neville L, Wroge C. Low Serum a-1 Antitrypsin (AAT) in Family Members of Individuals with Autism Correlates with PiMZ Genotype. Biomark. Insights 4(1), 45-56 (2009
72. Schmechel DE. Art, α-1-antitrypsin polymorphisms and intense creative energy: blessing or curse? Neurotoxicology 28(5), 899-914 (2007 (Pubitemid 47519798)
73. 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 (Pubitemid 37064057)
74. Beyer J, Kuchibhatla M, Gersing K, Krishnan KR. Medical comorbidity in a bipolar outpatient clinical population. Neuropsychopharmacology 30(2), 401-404 (2005 (Pubitemid 40129491)
75. Baugh RJ, Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry 15(4), 836-841 (1976
76. 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 (Pubitemid 32881931)
77. 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. Biochemistry 40(51), 15762-15770 (2001 (Pubitemid 34015205)
78. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 69(3), 562-573 (2006 (Pubitemid 43139720)
79. 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
80. 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 (Pubitemid 351947962)
81. 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 (Pubitemid 19247604)
82. 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
83. 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
84. Hirche TO, Benabid R, Deslee G et al. Neutrophil elastase mediates innate host protection against Pseudomonas aeruginosa. J. Immunol. 181(7), 4945-4954 (2008
85. 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 (Pubitemid 28237363)
86. Rogan MP, Taggart CC, Greene CM, Murphy PG, O'Neill SJ, McElvaney NG. Loss of microbicidal activity and increased formation of biofilm due to decreasedlactoferrin activity in patients with cystic fibrosis. J. Infect. Dis. 190(7), 1245-1253 (2004 (Pubitemid 39287750)
87. 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 (Pubitemid 350224252)
88. 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
89. 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
90. 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. Thorax 63(7), 621-626 (2008 (Pubitemid 351969256)
91. 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-a and leaves RANTES and MCP-2 intact. Blood 96(8), 2673-2681 (2000
92. 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 a(1)- antitrypsin deficiency. Chest 117(5 Suppl. 1), 250S-251S (2000 (Pubitemid 30326977)
93. 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 (Pubitemid 36628048)
94. 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 (Pubitemid 46674384)
95. Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br. J. Pharmacol. 153(Suppl. 1), S263-S282 (2008 (Pubitemid 351340983)
96. 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 (Pubitemid 350159405)
97. Kuwahara I, Lillehoj EP, Lu W et al. Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{k}B activation via EGFR transactivation in a lung epithelial cell line. Am. J. Physiol. Lung Cell. Mol. Physiol. 291(3), L407-L416 (2006 (Pubitemid 44343717)
98. Shao MX, Nadel JA. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc. Natl Acad. Sci. USA 102(3), 767-772 (2005 (Pubitemid 40282740)
99. 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
100. 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-a-converting enzyme. J. Immunol. 175(6), 4009-4016 (2005 (Pubitemid 41292063)
101. 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 (Pubitemid 46231973)
102. Gadek JE, Klein HG, Holland PV, Crystal RG. Replacement therapy of a1 antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J. Clin. Invest. 68(5), 1158-1165 (1981 (Pubitemid 12235015)
103. Abboud RT, Ford GT, Chapman KR. α1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Can. Respir. J. 8, 81-88 (2001 (Pubitemid 32496355)
104. Wewers MD, Casolaro MA, Sellers SE et al. Replacement therapy for a-1 antitrypsin deficiency associated with emphysema. N. Engl. J. Med. 316, 1055-1062 (1987 (Pubitemid 17047294)
105. Russi EW. a-1 antitrypsin: now available, but do we need it? Swiss Med. Wkly. 138, 191-196 (2008 (Pubitemid 351533227)
106. 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
107. Dirksen A, Dijkman JH, Madsen F et al. A randomized clinical trial of a(1)- antitrypsin augmentation therapy. Am. J. Respir. Crit. Care Med. 160, 1468-1472 (1999
108. 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
109. Tonelli AR, Rouhani F, Li N et al. α-1-antitrypsin augmentation therapy in deficient individuals enrolled in the a-1 Foundation DNA and Tissue Bank. Int. J. Chron. Obstruct. Pulmon. Dis. 4, 443-452 (2009
110. 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 α1-antitrypsin deficiency. Respir. Res. 10, 75 (2009
111. Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of a-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)
112. Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ. Augmentation therapy for a1 antitrypsin deficiency: a meta-analysis. COPD 6(3), 177-184 (2009
113. McCarthy C, Dimitrov BD. Augmentation therapy for a-1 antitrypsin deficiency - not enough evidence to support its use yet! COPD 7(3), 234 (2010
114. Hubbard RC, McElvaney NG, Sellers SE, Healy JT, Czerski DB, Crystal RG. Recombinant DNA-produced α1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with α1-antitrypsin deficiency. J. Clin. Invest. 84(4), 1349-1354 (1989). (Pubitemid 19247611)
115. McElvaney NG, Hubbard RC, Birrer P et al. Aerosol α1-antitrypsin treatment for cystic fibrosis. Lancet 337(8738), 392-394 (1991
116. 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 (Pubitemid 46231900)
117. Henriksen PA, Hitt M, Xing Z et al. Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-k B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. J. Immunol. 172(7), 4535-4544 (2004 (Pubitemid 38375271)
118. 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 (Pubitemid 29301766)
119. Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infect. Immun. 73(3), 1271-1274 (2005 (Pubitemid 40470711)
120. 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
121. 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 (Pubitemid 27123626)
122. 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. Acta 1745(3), 310-317 (2005 (Pubitemid 41330785)
123. 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
124. 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
125. 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
126. 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
127. 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 (Pubitemid 34170055)
128. Greene CM, Miller SD, Carroll T et al. a-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations. J. Inherit. Metab. Dis. 31(1), 21-34 (2008
129. Greene CM, McElvaney NG. Z a-1 antitrypsin deficiency and the endoplasmic reticulum stress response. World J. Gastrointest. Pharmacol. Ther. 1(5), 94-101 (2010
130. Greene CM, McElvaney NG. Protein misfolding and obstructive lung disease. Proc. Am. Thorac. Soc. 7(6), 346-355 (2010
131. Carroll TP, McElvaney NG, Greene CM, Gain-of-function effects of Z α-1antitrypsin. Antiinflamm. Antiallergy Agents Med. Chem. 9, 336-346 (2010
132. 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 α1-antitrypsin deficiency. J. Immunol. 172(9), 5722-5726 (2004 (Pubitemid 38542077)
133. Miller SD, Greene CM, McLean C et al. Tauroursodeoxycholic acid inhibits apoptosis induced by Z α-1antitrypsin via inhibition of Bad. Hepatology 46(2), 496-503 (2007 (Pubitemid 47344785)
134. 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
135. 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-1antitrypsin deficiency. J. Immunol. 184(8), 4538-4546 (2010
136. Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant α1- antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkB, and BAP31 but not the unfolded protein response. J. Biol. Chem. 280(47), 39002-39015 (2005 (Pubitemid 41713850)
137. Bergin DA, Reeves EP, Meleady P et al. α-1Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J. Clin. Invest. 120(12), 4236-4250 (2010
138. 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 (Pubitemid 128354139)
139. Mulgrew AT, Taggart CC, Lawless MW et al. Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 125(5), 1952-1957 (2004
140. 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 (Pubitemid 40192574)
141. Brodsky JL, McCracken AA. ER protein quality control and proteasome-mediated protein degradation. Semin. Cell Dev. Biol. 10(5), 507-513 (1999 (Pubitemid 129513236)
142. Perlmutter DH, Brodsky JL, Balistreri WF, Trapnell BC. Molecular pathogenesis of α-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology 45(5), 1313-1323 (2007 (Pubitemid 46775796)
143. 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
144. Eskelinen EL. New insights into the mechanisms of macroautophagy in mammalian cells. Int. Rev. Cell Mol. Biol. 266, 207-247 (2008
145. Kundu M, Thompson CB. Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol. 3, 427-455 (2008 (Pubitemid 351488288)
146. Eskelinen EL, Saftig P. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim. Biophys. Acta 1793(4), 664-673 (2009).
147. 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
148. Perlmutter DH. The role of autophagy in α-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy 2(4), 258-263 (2006 (Pubitemid 44342367)
149. Perlmutter DH. Liver injury in α1- antitrypsin deficiency: an aggregated protein induces mitochondrial injury. J. Clin. Invest. 110(11), 1579-1583 (2002 (Pubitemid 35424232)
150. Teckman JH, Perlmutter DH. Retention of mutant a(1)-antitrypsin Z in
151. 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 (Pubitemid 35192853)
152. Teckman JH, An JK, Blomenkamp K, Schmidt B, Perlmutter D. Mitochondrial autophagy and injury in the liver in α1-antitrypsin deficiency. Am. J. Physiol. Gastrointest. Liver Physiol. 286(5), G851-G862 (2004 (Pubitemid 38506818)
153. Wood AM, Tan SL, Stockley RA. Chronic obstructive pulmonary disease: towards pharmacogenetics. Genome Med. 1(11), 112 (2009
154. Silverman EK. Genetics of chronic obstructive pulmonary disease. Novartis Found. Symp. 234(1), 45-58 (2001
155. Wood AM, Needham M, Simmonds MJ, Newby PR, Gough SC, Stockley RA. Phenotypic differences in a 1 antitrypsin-deficient sibling pairs may relate to genetic variation. COPD 5(6), 353-359 (2008
156. Seersholm N. Pi MZ and COPD: will we ever know? Thorax 59(10), 823-825 (2004
157. 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. Thorax 59(10), 843-849 (2004 (Pubitemid 39389623)
158. Silverman EK, Province MA, Rao DC, Pierce JA, Campbell EJ. A family study of the variability of pulmonary function in α1-antitrypsin deficiency. Quantitative phenotypes. Am. Rev. Respir. Dis. 142(5), 1015-1021 (1990 (Pubitemid 20384352)
159. Sorheim IC, Bakke P, Gulsvik A et al. α-1Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest 138(5), 1125-1132 (2010
160. Malerba M, Ricciardolo F, Radaeli A et al. Neutrophilic inflammation and IL-8 levels in induced sputum of α-1-antitrypsin PiMZ subjects. Thorax 61(2), 129-133 (2006 (Pubitemid 43235429)
161. 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 (Pubitemid 8017015)
162. Turino GM, Barker AF, Brantly ML et al. Clinical features of individuals with PI. *SZ phenotype of α1-antitrypsin deficiency. α1-Antitrypsin Deficiency Registry Study Group. Am. J. Respir. Crit. Care Med. 154(6 Pt 1), 1718-1725 (1996 (Pubitemid 26424941)
163. Holme J, Stockley RA. CT scan appearance, densitometry, and health status in protease inhibitor SZ α1-antitrypsin deficiency. Chest 136(5), 1284-1290 (2009
164. 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 (Pubitemid 40945933)
165. Sandhaus RA, Turino G, Stocks J et al. α1-Antitrypsin augmentation therapy for PI. *MZ heterozygotes: a cautionary note. Chest 134(4), 831-834 (2008
166. 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 (Pubitemid 41632051)
167. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with α-1antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 168(7), 818-900 (2003
168. Spencer LT, Humphries JE, Brantly ML. Transgenic Human α1-Antitrypsin Study Group. Antibody response to aerosolized transgenic human α1-antitrypsin. N. Engl. J. Med. 352(19), 2030-2031 (2005
169. McLean C, Greene CM, McElvaney NG. Gene targeted therapeutics for liver disease in α-1antitrypsin deficiency. Biologics 3, 63-75 (2009
170. 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 (Pubitemid 350114689)
171. 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
172. Chulay JD, Knop DR, Ye GJ et al. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human α-1antitrypsin made using a recombinant herpes simplex virus production method. Hum. Gene Ther. 22(2), 155-165 (2010
173. 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. USA 106(38), 16363-16368 (2009
174. 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
175. 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 (Pubitemid 46626463)
176. Brantly ML, Spencer LT, Humphries M et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 al-antitrypsin (AAT) vector in AAT-deficient adults. Hum. Gene Ther. 17(12), 1177-1186 (2006). (Pubitemid 44975135)
177. Ghaedi M, Lotfi AS, Soleimani M. Establishment of lentiviral-vector- mediated model of human α-1antitrypsin delivery into hepatocyte-like cells differentiated from mesenchymal stem cells. Tissue Cell 42(3), 181-189 (2010
178. Sifers RN. Medicine. Clearing conformational disease. Science 329(5988), 154-155 (2010
179. Hidvegi T, Ewing M, Hale P et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 329(5988), 229-232 (2010
180. 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
181. 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 Cells 28(10), 1728-1740 (2010
182. 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).