Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions

Mutation Research - Reviews in Mutation Research

Volumn 773, Issue , 2017, Pages 14-25

  Hazari, Younis Mohammad ^a   Bashir, Arif ^a   Habib, Mudasir ^a   Bashir, Samirul ^a   Habib, Huma ^b   Qasim, M Abul ^c   Shah, Naveed Nazir ^d   Haq, Ehtishamul ^a   Teckman, Jeffrey ^e   Fazili, Khalid Majid ^a  

^a UNIVERSITY OF KASHMIR   (India)

^b Islamia College of Science and Commerce   (India)

^c INDIANA UNIVERSITY PURDUE UNIVERSITY FORT WAYNE   (United States)

^d GOVERNMENT MEDICAL COLLEGE   (India)

^e SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Alpha 1 antitrypsin; COPD; Gain of function; Liver disease; Loss of function; Panniculitis; Serine protease inhibitor; Vasculitis

Indexed keywords

ALPHA 1 ANTITRYPSIN;

ALPHA 1 ANTITRYPSIN DEFICIENCY; BIOCHEMICAL ANALYSIS; CLINICAL FEATURE; DNA POLYMORPHISM; GAIN OF FUNCTION MUTATION; GENE THERAPY; GENETIC ANALYSIS; GENETIC VARIABILITY; GENETIC VARIATION; HUMAN; LOSS OF FUNCTION MUTATION; OXIDATION; PANNICULITIS; PATHOLOGY; PATHOPHYSIOLOGY; POLYMERIZATION; PRIORITY JOURNAL; REVIEW; SECRETION (PROCESS); SMOKING; STEM CELL; STRUCTURE ANALYSIS; ALPHA 1-ANTITRYPSIN DEFICIENCY; ANIMAL; COMPLICATION; DISEASE MODEL; GENETICS; LIVER; LIVER DISEASES; LUNG; METABOLISM; PROTEIN CONFORMATION; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; PULMONARY EMPHYSEMA; SINGLE NUCLEOTIDE POLYMORPHISM;

ALPHA 1-ANTITRYPSIN; ALPHA 1-ANTITRYPSIN DEFICIENCY; ANIMALS; DISEASE MODELS, ANIMAL; HUMANS; LIVER; LIVER DISEASES; LUNG; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN CONFORMATION; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; PULMONARY EMPHYSEMA;

EID: 85017322807     PISSN: 13835742     EISSN: 13882139     Source Type: Journal    
DOI: 10.1016/j.mrrev.2017.03.001     Document Type: Review

References (174)

1. [1] Mornex, J.F., et al. Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin-deficient individuals. J. Clin. Invest. 77:6 (1986), 1952–1961.
2. [2] Carlson, J.A., et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83:4 (1989), 1183–1190.
3. [3] Molmenti, E.P., Perlmutter, D.H., Rubin, D.C., Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. J. Clin. Invest. 92:4 (1993), 2022–2034.
4. [4] Cichy, J., Potempa, J., Travis, J., Biosynthesis of alpha1-proteinase inhibitor by human lung-derived epithelial cells. J. Biol. Chem. 272:13 (1997), 8250–8255.
5. [5] Mulgrew, A.T., et al. Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 125:5 (2004), 1952–1957.
6. [6] Habib, H., Fazili, K.M., Plant protease inhibitors: a defence strategy in plants. Biotechnol. Mol. Biol. Rev. 2:3 (2007), 068–085.
7. [7] Russo, A.J., Neville, L., Wroge, C., Low serum alpha-1 antitrypsin (AAT) in family members of individuals with autism correlates with PiMZ genotype. Biomark. Insights 4 (2009), 45–56.
8. [8] Llewellyn-Jones, C.G., et al. The effect of the Z mutation on the ability of alpha 1-antitrypsin to prevent neutrophil mediated tissue damage. Biochim. Biophys. Acta 1227:3 (1994), 155–160.
9. [9] Owen, M.C., et al. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg): a fatal bleeding disorder. N. Engl. J. Med. 309:12 (1983), 694–698.
10. [10] Patschull, A.O., et al. Therapeutic target-site variability in alpha1-antitrypsin characterized at high resolution. Acta Crystallogr. Sect F Struct. Biol. Cryst. Commun. 67:Pt 12 (2011), 1492–1497.
11. [11] Lomas, D.A., Molecular mousetraps: alpha1-antitrypsin deficiency and the serpinopathies. Clin. Med. (Lond.) 5:3 (2005), 249–257.
12. [12] Lomas, D.A., et al. Molecular mousetraps and the serpinopathies. Biochem. Soc. Trans. 33:Pt 2 (2005), 321–330.
13. [13] Silverman, G.A., et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution: mechanism of inhibition, novel functions, and a revised nomenclature. J. Biol. Chem. 276:36 (2001), 33293–33296.
14. [14] Law, R.H., et al. An overview of the serpin superfamily. Genome Biol., 7(5), 2006, 216.
15. [15] Irving, J.A., et al. Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res. 10:12 (2000), 1845–1864.
16. [16] Billingsley, G.D., et al. Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1. Am. J. Hum. Genet. 52:2 (1993), 343–353.
17. [17] Schroeder, W.T., et al. Chromosomal localization of the human alpha 1-antitrypsin gene (PI) to 14q31-32. Am. J. Hum. Genet. 37:5 (1985), 868–872.
18. [18] Perlino, E., Cortese, R., Ciliberto, G., The human alpha 1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes. EMBO J. 6:9 (1987), 2767–2771.
19. [19] Denden, S., et al. Alpha-1 antitrypsin gene polymorphism in chronic obstructive pulmonary disease (COPD). Genet. Mol. Biol. 33:1 (2010), 23–26.
20. [20] Bashir, A., et al. Novel variants of SERPIN1A gene: interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease. Respir. Med. 117 (2016), 139–149.
21. [21] Cox, D.W., Genetic variation of alpha 1-antitrypsin. Am. J. Hum. Genet. 30:6 (1978), 660–662.
22. [22] Topic, A., et al. Alpha-1-antitrypsin deficiency in serbian adults with lung diseases. Genet. Test. Mol. Biomarkers 16:11 (2012), 1282–1286.
23. [23] Hildesheim, J., et al. Genetic diversity from a limited repertoire of mutations on different common allelic backgrounds: alpha 1-antitrypsin deficiency variant Pduarte. Hum. Mutat. 2:3 (1993), 221–228.
24. [24] Nukiwa, T., et al. Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene. J. Biol. Chem. 261:34 (1986), 15989–15994.
25. [25] Dafforn, T.R., et al. A kinetic mechanism for the polymerization of alpha1-antitrypsin. J. Biol. Chem. 274:14 (1999), 9548–9555.
26. [26] Lomas, D.A., et al. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357:6379 (1992), 605–607.
27. [27] Eriksson, S., Carlson, J., Velez, R., Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N. Engl. J. Med. 314:12 (1986), 736–739.
28. [28] Seyama, K., et al. Alpha 1-antitrypsin-deficient variant siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in japan. status of alpha 1-antitrypsin deficiency in Japan. Am. J. Respir. Crit. Care Med. 152:6 Pt 1 (1995), 2119–2126.
29. [29] Yoshida, A., et al. Molecular abnormality of PI S variant of human alpha1-antitrypsin. Am. J. Hum. Genet. 29:3 (1977), 233–239.
30. [30] Elliott, P.R., et al. Inhibitory conformation of the reactive loop of alpha 1-antitrypsin. Nat. Struct. Biol. 3:8 (1996), 676–681.
31. [31] Turino, G.M., et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency: alpha 1-antitrypsin deficiency registry study group. Am. J. Respir. Crit. Care Med. 154:6 Pt 1 (1996), 1718–1725.
32. [32] Mahadeva, R., et al. Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. J. Clin. Invest. 103:7 (1999), 999–1006.
33. [33] Holmes, M., et al. Characterization of the intracellular mechanism causing the alpha-1-antitrypsin Nullgranite falls deficiency state. Am. Rev. Respir. Dis. 140:6 (1989), 1662–1667.
34. [34] Curiel, D., et al. Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin nullmattawa gene: an insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin. J. Clin. Invest. 83:4 (1989), 1144–1152.
35. [35] Satoh, K., et al. Emphysema associated with complete absence of alpha 1- antitrypsin in serum and the homozygous inheritance [corrected] of a stop codon in an alpha 1-antitrypsin-coding exon. Am. J. Hum. Genet. 42:1 (1988), 77–83.
36. [36] Fregonese, L., et al. Alpha-1 antitrypsin Null mutations and severity of emphysema. Respir. Med. 102:6 (2008), 876–884.
37. [37] Cook, L., et al. Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of emphysema. Aust. N. Z. J. Med. 24:3 (1994), 263–269.
38. [38] Takahashi, H., Crystal, R.G., Alpha 1-antitrypsin null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons. Am. J. Hum. Genet. 47:3 (1990), 403–413.
39. [39] Sifers, R.N., et al. A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. J. Biol. Chem. 263:15 (1988), 7330–7335.
40. [40] Topic, A., et al. Alpha-1-antitrypsin phenotypes in adult liver disease patients. Ups. J. Med. Sci. 114:4 (2009), 228–234.
41. [41] Scott, D.A., et al. The influence of vitamin C on systemic markers of endothelial and inflammatory cell activation in smokers and non-smokers. Inflamm. Res. 54:3 (2005), 138–144.
42. [42] Curiel, D.T., et al. Molecular basis of the liver and lung disease associated with the alpha 1-antitrypsin deficiency allele Mmalton. J. Biol. Chem. 264:23 (1989), 13938–13945.
43. [43] Medicina, D., et al. Molecular characterization of the new defective P(brescia) alpha1-antitrypsin allele. Hum. Mut., 2009, 30.
44. [44] Fra, A.M., et al. Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization. PLoS One, 7(6), 2012, e38405.
45. [45] Curiel, D., et al. Characterization of the sequence of the normal alpha-1-antitrypsin M3 allele and function of the M3 protein. Am. J. Respir. Cell Mol. Biol. 1:6 (1989), 471–477.
46. [46] Nukiwa, T., et al. Characterization of the gene and protein of the common alpha 1-antitrypsin normal M2 allele. Am. J. Hum. Genet. 43:3 (1988), 322–330.
47. [47] Klasen, E.C., Bos, A., Simmelink, H.D., PI. (alpha 1-antitrypsin) subtypes: frequency of PI*M4 in several populations. Hum. Genet. 62:2 (1982), 139–141.
48. [48] Poller, W., et al. Molecular characterisation of the defective alpha 1-antitrypsin alleles PI mwurzburg (Pro369Ser): mheerlen (Pro369Leu), and Q0lisbon (Thr68Ile). Eur. J. Hum. Genet. 7:3 (1999), 321–331.
49. [49] Joly, P., et al. Clinical heterogeneity and potential high pathogenicity of the Mmalton alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states. Orphanet J. Rare Dis., 10, 2015, 130.
50. [50] Ferrarotti, I., et al. Prevalence and phenotype of subjects carrying rare variants in the Italian registry for alpha1-antitrypsin deficiency. J. Med. Genet. 42:3 (2005), 282–287.
51. [51] Yuasa, I., et al. Molecular characterization of four alpha-1-antitrypsin variant alleles found in a Japanese population: a mutation hot spot at the codon for amino acid 362. Leg. Med. (Tokyo) 3:4 (2001), 213–219.
52. [52] Ferrarotti, I., et al. Identification and characterisation of eight novel SERPINA1 Null mutations. Orphanet J. Rare Dis. 9:1 (2014), 1–9.
53. [53] Lee, J.H., Brantly, M., Molecular mechanisms of alpha1-antitrypsin null alleles. Respir. Med. 94:Suppl. C (2000), S7–S11.
54. [54] Zorzetto, M., et al. Identification of a novel alpha1-antitrypsin null variant (Q0Cairo). Diagn. Mol. Pathol. 14:2 (2005), 121–124.
55. [55] Ko, D.H., et al. Identification of compound heterozygous mutation in a Korean patient with alpha 1-antitrypsin deficiency. Korean J. Lab. Med. 31:4 (2011), 294–297.
56. [56] Hernandez Perez, J.M., et al. Description of alpha-1-antitrypsin deficiency associated with PI*Q0ourem allele in La Palma Island (Spain) and a genotyping assay for its detection. Arch. Bronconeumol. 51:1 (2015), e1–3.
57. [57] Frazier, G.C., et al. A null deficiency allele of alpha 1-antitrypsin: QOludwigshafen, with altered tertiary structure. J. Clin. Invest. 86:6 (1990), 1878–1884.
58. [58] Curiel, D.T., et al. Serum alpha 1-antitrypsin deficiency associated with the common S-type (Glu264—Val) mutation results from intracellular degradation of alpha 1-antitrypsin prior to secretion. J. Biol. Chem. 264:18 (1989), 10477–10486.
59. [59] Lomas, D.A., et al. Alpha 1-antitrypsin siiyama (Ser53– > Phe). further evidence for intracellular loop-sheet polymerization. J. Biol. Chem. 268:21 (1993), 15333–15335.
60. [60] Holmes, M.D., et al. Alpha 1-antitrypsin Wbethesda: molecular basis of an unusual alpha 1-antitrypsin deficiency variant. Biochem. Biophys. Res. Commun. 170:3 (1990), 1013–1020.
61. [61] Brennan, S.O., Carrell, R.W., alpha 1-antitrypsin Christchurch, 363 Glu—Lys: mutation at the P'5 position does not affect inhibitory activity. Biochim. Biophys. Acta 873:1 (1986), 13–19.
62. [62] Ogushi, F., et al. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J. Clin. Invest. 80:5 (1987), 1366–1374.
63. [63] Laurell, C.B., Eriksson, S., The electrophoretic alpha1-globulin pattern of serum in alpha1-antitrypsin deficiency. 1963. Copd 10:Suppl. 1 (2013), 3–8.
64. [64] Piitulainen, E., Eriksson, S., Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ). Eur. Respir. J. 13:2 (1999), 247–251.
65. [65] Whisstock, J.C., et al. Conformational changes in serpins: I: the native and cleaved conformations of alpha(1)-antitrypsin. J. Mol. Biol. 295:3 (2000), 651–665.
66. [66] de Serres, F.J., Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 122:5 (2002), 1818–1829.
67. [67] Tomashefski, J.F. Jr., et al. The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with severe deficiency of alpha-1 Antitrypsin. Hum. Pathol. 35:12 (2004), 1452–1461.
68. [68] Ortiz, P.G., Skov, B.G., Benfeldt, E., Alpha1-antitrypsin deficiency-associated panniculitis: case report and review of treatment options. J. Eur. Acad. Dermatol. Venereol. 19:4 (2005), 487–490.
69. [69] Janciauskiene, S.M., et al. The discovery of alpha1-antitrypsin and its role in health and disease. Respir. Med. 105:8 (2011), 1129–1139.
70. [70] Gordon, P., et al. Successful endovascular treatment of multiple mesenteric arterial aneurysms associated with alpha-1-antitrypsin deficiency. J. Vasc. Surg. 52:2 (2010), 467–470.
71. [71] Bofinger, A., et al. Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia. J. Hum. Hypertens. 14:2 (2000), 91–94.
72. [72] Rabassa, A.A., Schwartz, M.R., Ertan, A., Alpha 1-antitrypsin deficiency and chronic pancreatitis. Dig. Dis. Sci. 40:9 (1995), 1997–2001.
73. [73] Blanco, I., et al. Alpha-1 antitrypsin deficiency PI*Z and PI*S gene frequency distribution using on maps of the world by an inverse distance weighting (IDW) multivariate interpolation method. Hepat. Mon., 12, 2012 (10 hcc): p. e7434.
74. [74] Dimcheff, D.E., et al. Endoplasmic reticulum stress is a determinant of retrovirus-induced spongiform neurodegeneration. J. Virol. 77:23 (2003), 12617–12629.
75. [75] Hersh, C.P., et al. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 59:10 (2004), 843–849.
76. [76] Blanco, I., et al. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur. Respir. J. 27:1 (2006), 77–84.
77. [77] Luisetti, M., Seersholm, N., Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax 59:2 (2004), 164–169.
78. [78] Stoller, J.K., Aboussouan, L.S., A review of alpha1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 185:3 (2012), 246–259.
79. [79] Topic, A., Ljujic, M., Radojkovic, D., Alpha-1-antitrypsin in pathogenesis of hepatocellular carcinoma. Hepat. Mon., 12, 2012 (10 HCC): p. e7042.
80. [80] Kopito, R.R., Ron, D., Conformational disease. Nat. Cell Biol. 2:11 (2000), E207–9.
81. [81] Ekeowa, U.I., et al. alpha1-antitrypsin deficiency: chronic obstructive pulmonary disease and the serpinopathies. Clin. Sci. (Lond.) 116:12 (2009), 837–850.
82. [82] Lomas, D.A., The selective advantage of alpha1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 173:10 (2006), 1072–1077.
83. [83] Lieberman, J., Winter, B., Sastre, A., Alpha 1-antitrypsin pi-types in 965 COPD patients. Chest 89:3 (1986), 370–373.
84. [84] Long, O.S., et al. A C. elegans model of human alpha1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum. Mol. Genet. 23:19 (2014), 5109–5122.
85. [85] O'Reilly, L.P., et al. A genome-wide RNAi screen identifies potential drug targets in a C: elegans model of alpha1-antitrypsin deficiency. Hum. Mol. Genet. 23:19 (2014), 5123–5132.
86. [86] Wang, Y., Perlmutter, D.H., Targeting intracellular degradation pathways for treatment of liver disease caused by alpha1-antitrypsin deficiency. Pediatr. Res. 75:1–2 (2014), 133–139.
87. [87] Greene, C.M., et al. Alpha-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations. J. Inherit. Metab. Dis. 31:1 (2008), 21–34.
88. [88] Hazari, Y.M., et al. Emerging tale of UPR and cancer: an essentiality for malignancy. Tumour Biol., 14, 2016, 14.
89. [89] Hidvegi, T., et al. 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. 280:47 (2005), 39002–39015.
90. [90] Sveger, T., Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N. Engl. J. Med. 294:24 (1976), 1316–1321.
91. [91] Kok, K.F., et al. Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth. J. Med. 65:5 (2007), 160–166.
92. [92] Sokol, R.J., et al. Vitamin E deficiency in adults with chronic liver disease. Am. J. Clin. Nutr. 41:1 (1985), 66–72.
93. [93] El Hazmi, M.A., Alpha-1-antitrypsin deficiency: an overview of recent advances. Saudi J. Gastroenterol. 2:3 (1996), 113–119.
94. [94] Massi, G., Pathogenesis and pathology of liver disease associated with alpha 1-antitrypsin deficiency. Chest 110:Suppl. 6 (1996), 251S–255S.
95. [95] Stolk, J., Seersholm, N., Kalsheker, N., Alpha(1)-antitrypsin deficiency: current perspective on research, diagnosis, and management. Int. J. Chron. Obstruct. Pulmon. Dis. 1:2 (2006), 151–160.
96. [96] Bowlus, C.L., et al. Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin. Gastroenterol. Hepatol. 3:4 (2005), 390–396.
97. [97] Lindblad, D., Blomenkamp, K., Teckman, J., Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 46:4 (2007), 1228–1235.
98. [98] Stein, P.D., et al. Pathophysiology of the pulmonary circulation in emphysema associated with alpha antitrypsin deficiency. Circulation 43:2 (1971), 227–239.
99. [99] Kramps, J.A., Bakker, W., Dijkman, J.H., A matched-pair study of the leukocyte elastase-like activity in normal persons and in emphysematous patients with and without alpha 1-antitrypsin deficiency. Am. Rev. Respir. Dis. 121:2 (1980), 253–261.
100. [100] Janciauskiene, S.M., Nita, I.M., Stevens, T., Alpha1-antitrypsin: old dog, new tricks: alpha1-antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevating cAMP. J. Biol. Chem. 282:12 (2007), 8573–8582.
101. [101] Dowson, L.J., Guest, P.J., Stockley, R.A., Longitudinal changes in physiological, radiological, and health status measurements in alpha(1)-antitrypsin deficiency and factors associated with decline. Am. J. Respir. Crit. Care Med. 164:10 Pt 1 (2001), 1805–1809.
102. [102] Stoller, J.K., Aboussouan, L.S., Alpha1-antitrypsin deficiency. Lancet 365:9478 (2005), 2225–2236.
103. [103] Needham, M., Stockley, R., α(1)-Antitrypsin deficiency • 3: clinical manifestations and natural history. Thorax 59:5 (2004), 441–445.
104. [104] Wall, M., et al. Long-term follow-up of a cohort of children with alpha-1-antitrypsin deficiency. J. Pediatr. 116:2 (1990), 248–251.
105. [105] Janus, E.D., Phillips, N.T., Carrell, R.W., Smoking: lung function, and alpha 1-antitrypsin deficiency. Lancet 1:8421 (1985), 152–154.
106. [106] Mahadeva, R., et al. Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am. J. Pathol. 166:2 (2005), 377–386.
107. [107] Stockley, R.A., Mannino, D., Barnes, P.J., Burden and pathogenesis of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 6:6 (2009), 524–526.
108. [108] Hu, C., Perlmutter, D.H., Cell-specific involvement of HNF-1beta in alpha(1)-antitrypsin gene expression in human respiratory epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 282:4 (2002), L757–65.
109. [109] Seersholm, N., Kok-Jensen, A., Dirksen, A., Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases. Thorax 49:7 (1994), 695–698.
110. [110] Wewers, M.D., et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N. Engl. J. Med. 316:17 (1987), 1055–1062.
111. [111] Beatty, K., Bieth, J., Travis, J., Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J. Biol. Chem. 255:9 (1980), 3931–3934.
112. [112] Elliott, P.R., Bilton, D., Lomas, D.A., Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. Am. J. Respir. Cell Mol. Biol. 18:5 (1998), 670–674.
113. [113] Lomas, D.A., Mahadeva, R., Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J. Clin. Invest. 110:11 (2002), 1585–1590.
114. [114] Hubbard, R.C., et al. Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency: Spontaneous release of leukotriene B4 by alveolar macrophages. J. Clin. Invest. 88:3 (1991), 891–897.
115. [115] Parmar, J.S., et al. Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am. J. Respir. Cell Mol. Biol. 26:6 (2002), 723–730.
116. [116] Banda, M.J., et al. The inhibitory complex of human alpha 1-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant. J. Exp. Med. 167:5 (1988), 1608–1615.
117. [117] Senior, R.M., Griffin, G.L., Mecham, R.P., Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 66:4 (1980), 859–862.
118. [118] Randle, S.M., et al. Panniculitis: a report of four cases and literature review. Arch. Dis. Child. 66:9 (1991), 1057–1060.
119. [119] Warter, J., et al. Weber-Christian syndrome associated with an alpha-1 antitrypsin deficiency: Familial investigation. Ann. Med. Interne (Paris) 123:10 (1972), 877–882.
120. [120] Laureano, A., et al. Alpha-1-antitrypsin deficiency-associated panniculitis: a case report. Dermatol. Online J., 20(1), 2014, 21245.
121. [121] Stoller, J.K., On the evidence that augmentation therapy helps asthma: are storks really responsible for new babies?. Monaldi Arch. Chest Dis. 69:4 (2008), 155–156.
122. [122] Gross, B., et al. New findings in PiZZ α(1)-antitrypsin deficiency-related panniculitis: demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. Dermatology (Basel, Switzerland) 218:4 (2009), 370–375.
123. [123] Blanco, I., Lara, B., de Serres, F., Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Orphanet J. Rare Dis., 6, 2011, 14.
124. [124] O'Donoghue, D.J., et al. Alpha-1-proteinase inhibitor and pulmonary haemorrhage in systemic vasculitis. Adv. Exp. Med. Biol. 336 (1993), 331–335.
125. [125] Esnault, V.L., et al. Alpha 1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis. Kidney Int. 43:6 (1993), 1329–1332.
126. [126] Segelmark, M., et al. The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis. Kidney Int. 48:3 (1995), 844–850.
127. [127] Griffith, M.E., et al. C-antineutrophil cytoplasmic antibody positivity in vasculitis patients is associated with the Z allele of alpha-1-antitrypsin: and P-antineutrophil cytoplasmic antibody positivity with the S allele. Nephrol. Dial. Transplant. 11:3 (1996), 438–443.
128. [128] Esnault, V.L., Audrain, M.A., Sesboue, R., Alpha-1-antitrypsin phenotyping in ANCA-associated diseases: one of several arguments for protease/antiprotease imbalance in systemic vasculitis. Exp. Clin. Immunogenet. 14:3 (1997), 206–213.
129. [129] Rahman, I., Oxidative stress and gene transcription in asthma and chronic obstructive pulmonary disease: antioxidant therapeutic targets. Curr. Drug Targets Inflamm. Allergy 1:3 (2002), 291–315.
130. [130] Janoff, A., et al. Cigarette smoke inhalation decreases alpha 1-antitrypsin activity in rat lung. Science 206:4424 (1979), 1313–1314.
131. [131] Pryor, W.A., Stone, K., Oxidants in cigarette smoke radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. N. Y. Acad. Sci. 686 (1993), 12–27 discussion 27-8.
132. [132] Sharafkhaneh, A., Hanania, N.A., Kim, V., Pathogenesis of emphysema: from the bench to the bedside. Proc. Am. Thorac. Soc. 5:4 (2008), 475–477.
133. [133] Deslee, G., et al. Cigarette smoke induces nucleic-acid oxidation in lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 43:5 (2010), 576–584.
134. [134] Hackett, T.L., Knight, D.A., Sin, D.D., Potential role of stem cells in management of COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 5 (2010), 81–88.
135. [135] Griffiths, S.W., King, J., Cooney, C.L., The reactivity and oxidation pathway of cysteine 232 in recombinant human alpha 1-antitrypsin. J. Biol. Chem. 277:28 (2002), 25486–25492.
136. [136] Taggart, C., et al. Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity. J. Biol. Chem. 275:35 (2000), 27258–27265.
137. [137] Alam, S., et al. Oxidation of Z alpha1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema. Am. J. Respir. Cell Mol. Biol. 45:2 (2011), 261–269.
138. [138] Petrache, I., et al. alpha-1 antitrypsin inhibits caspase-3 activity: preventing lung endothelial cell apoptosis. Am. J. Pathol. 169:4 (2006), 1155–1166.
139. [139] Campbell, E.J., Alpha1-antitrypsin deficiency: incidence and detection program. Respir. Med. 94:Suppl. C (2000), S18–S21.
140. [140] Fairbanks, K.D., Tavill, A.S., Liver disease in alpha 1-antitrypsin deficiency: a review. Am. J. Gastroenterol. 103:8 (2008), 2136–2141.
141. [141] Borawski, J., Naumnik, B., Mysliwiec, M., Serum alpha1-antitrypsin but not complement C3 and C4 predicts chronic inflammation in hemodialysis patients. Ren. Fail. 25:4 (2003), 589–593.
142. [142] Rachelefsky, G., Hogarth, D.K., Issues in the diagnosis of alpha 1-antitrypsin deficiency. J. Allergy Clin. Immunol. 121:4 (2008), 833–838.
143. [143] Chu, A.S., Perlmutter, D.H., Wang, Y., Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases. BioMed Res. Int., 2014, 2014, 459823.
144. [144] Ghouse, R., et al. Mysteries of alpha1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease. Dis. Model Mech. 7:4 (2014), 411–419.
145. [145] Gadek, J.E., et al. Replacement therapy of alpha 1-antitrypsin deficiency: reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J. Clin. Invest. 68:5 (1981), 1158–1165.
146. [146] Chapman, K.R., Burdon, J.G., Piitulainen, E., Sandhaus, R.A., Seersholm, N., Stocks, J.M., Stoel, B.C., Huang, L., Yao, Z., Edelman, J.M., McElvaney, N.G., Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 386 (2015), 360–368.
147. [147] Hubbard, R.C., Crystal, R.G., Strategies for aerosol therapy of alpha 1-antitrypsin deficiency by the aerosol route. Lung 168:Suppl (1990), 565–578.
148. [148] Karnaukhova, E., Ophir, Y., Golding, B., Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use. Amino Acids 30 (2006), 317–332.
149. [149] Cantin, A.M., Hanrahan, J.W., Bilodeau, G., Ellis, L., Dupuis, A., Liao, J., Zielenski, J., Durie, P., Cystic fibrosis transmembrane conductance regulator function is suppressed in cigarette smokers. Am. J. Respir. Crit. Care Med. 173 (2006), 1139–1144.
150. [150] Carver, A., Wright, G., Cottom, D., Cooper, J., Dalrymple, M., Temperley, S., Udell, M., Reeves, D., Percy, J., Scott, A., et al. Expression of human alpha 1 antitrypsin in transgenic sheep. Cytotechnology 9 (1992), 77–84.
151. [151] Carver, A.S., Dalrymple, M.A., Wright, G., Cottom, D.S., Reeves, D.B., Gibson, Y.H., Keenan, J.L., Barrass, J.D., Scott, A.R., Colman, A., et al. Transgenic livestock as bioreactors: stable expression of human alpha-1-antitrypsin by a flock of sheep. Biotechnology (Nature Publishing Company) 11 (1993), 1263–1270.
152. [152] Wright, G., Carver, A., Cottom, D., Reeves, D., Scott, A., Simons, P., Wilmut, I., Garner, I., Colman, A., High level expression of active human alpha-1-antitrypsin in the milk of transgenic sheep. Biotechnology (Nature Publishing Company) 9 (1991), 830–834.
153. [153] Spencer, L.T., Humphries, J.E., Brantly, M.L., Antibody response to aerosolized transgenic human alpha1-antitrypsin. New Engl. J. Med. 352 (2005), 2030–2031.
154. [154] Petrache, I., Hajjar, J., Campos, M., Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics 3 (2009), 193–204.
155. [155] Yu, M.H., Lee, K.N., Kim, J., The Z type variation of human alpha 1-antitrypsin causes a protein folding defect. Nat. Struct. Biol. 2 (1995), 363–367.
156. [156] Hazari, Y.M., Habib, M., Bashir, S., Bashir, A., Hilal, N., Irfan, S., Haq, E.U., Fazili, K.M., Natural osmolytes alleviate GRP78 and ATF-4 levels: corroboration for potential modulators of unfolded protein response. Life Sci. 146 (2016), 148–153.
157. [157] Burrows, J.A., Willis, L.K., Perlmutter, D.H., 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. U. S. A. 97 (2000), 1796–1801.
158. [158] Devlin, G.L., Parfrey, H., Tew, D.J., Lomas, D.A., Bottomley, S.P., Prevention of polymerization of M and Z alpha1-Antitrypsin (alpha1-AT) with trimethylamine N-oxide. Implications for the treatment of alpha1-at deficiency. Am. J. Respir. Cell Mol. Biol. 24 (2001), 727–732.
159. [159] Morral, N., Parks, R.J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., Graham, F.L., Kochanek, S., Beaudet, A.L., High doses of a helper-dependent adenoviral vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum. Gene Therapy 9 (1998), 2709–2716.
160. [160] Jaffe, H.A., Danel, C., Longenecker, G., Metzger, M., Setoguchi, Y., Rosenfeld, M.A., Gant, T.W., Thorgeirsson, S.S., Stratford-Perricaudet, L.D., Perricaudet, M., et al. Adenovirus-mediated in vivo gene transfer and expression in normal rat liver. Nat. Genet. 1 (1992), 372–378.
161. [161] Kay, M.A., Baley, P., Rothenberg, S., Leland, F., Fleming, L., Ponder, K.P., Liu, T., Finegold, M., Darlington, G., Pokorny, W., et al. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc. Natl. Acad. Sci. U. S. A. 89 (1992), 89–93.
162. [162] Kay, M.A., Graham, F., Leland, F., Woo, S.L., Therapeutic serum concentrations of human alpha-1-antitrypsin after adenoviral-mediated gene transfer into mouse hepatocytes. Hepatology 21 (1995), 815–819.
163. [163] Rosenfeld, M.A., Siegfried, W., Yoshimura, K., Yoneyama, K., Fukayama, M., Stier, L.E., Paakko, P.K., Gilardi, P., Stratford-Perricaudet, L.D., Perricaudet, M., et al. Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science 252 (1991), 431–434.
164. [164] Lu, Y., Choi, Y.K., Campbell-Thompson, M., Li, C., Tang, Q., Crawford, J.M., Flotte, T.R., Song, S., Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J. Gene Med. 8 (2006), 730–735.
165. [165] Song, S., Embury, J., Laipis, P.J., Berns, K.I., Crawford, J.M., Flotte, T.R., Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther. 8 (2001), 1299–1306.
166. [166] Song, S., Morgan, M., Ellis, T., Poirier, A., Chesnut, K., Wang, J., Brantly, M., Muzyczka, N., Byrne, B.J., Atkinson, M., Flotte, T.R., Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), 14384–14388.
167. [167] Alino, S.F., Crespo, J., Bobadilla, M., Lejarreta, M., Blaya, C., Crespo, A., Expression of human alpha 1-antitrypsin in mouse after in vivo gene transfer to hepatocytes by small liposomes. Biochem. Biophys. Res. Commun. 204 (1994), 1023–1030.
168. [168] Canonico, A.E., Conary, J.T., Meyrick, B.O., Brigham, K.L., Aerosol and intravenous transfection of human alpha 1-antitrypsin gene to lungs of rabbits. Am. J. Respir. Cell Mol. Biol. 10 (1994), 24–29.
169. [169] Wozniak, J., Wandtke, T., Kopinski, P., Chorostowska-Wynimko, J., Challenges and prospects for alpha-1 antitrypsin deficiency gene therapy. Hum. Gene Ther. 26 (2015), 709–718.
170. [170] Flotte, T.R., Trapnell, B.C., Humphries, M., Carey, B., Calcedo, R., Rouhani, F., Campbell-Thompson, M., Yachnis, A.T., Sandhaus, R.A., McElvaney, N.G., Mueller, C., Messina, L.M., Wilson, J.M., Brantly, M., Knop, D.R., Ye, G.J., Chulay, J.D., Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum. Gene Ther. 22 (2011), 1239–1247.
171. [171] Mueller, C., Chulay, J.D., Trapnell, B.C., Humphries, M., Carey, B., Sandhaus, R.A., McElvaney, N.G., Messina, L., Tang, Q., Rouhani, F.N., Campbell-Thompson, M., Fu, A.D., Yachnis, A., Knop, D.R., Ye, G.J., Brantly, M., Calcedo, R., Somanathan, S., Richman, L.P., Vonderheide, R.H., Hulme, M.A., Brusko, T.M., Wilson, J.M., Flotte, T.R., Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J. Clin. Invest. 123 (2013), 5310–5318.
172. [172] Saito, K., Yoshikawa, M., Ouji, Y., Moriya, K., Nishiofuku, M., Ueda, S., Hayashi, N., Ishizaka, S., Fukui, H., Promoted differentiation of cynomolgus monkey ES cells into hepatocyte-like cells by co-culture with mouse fetal liver-derived cells. World J. Gastroenterol. 12 (2006), 6818–6827.
173. [173] Zhou, Q.J., Xiang, L.X., Shao, J.Z., Hu, R.Z., Lu, Y.L., Yao, H., Dai, L.C., In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate. J. Cell. Biochem. 100 (2007), 29–42.
174. [174] Wang, D., Haviland, D.L., Burns, A.R., Zsigmond, E., Wetsel, R.A., A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 4449–4454.