Molecular Medicine

, Volume 18, Issue 6, pp 957–970 | Cite as

Expanding the Clinical Indications for α1-Antitrypsin Therapy

  • Eli C Lewis
Review Article


α1-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.



The author thanks Charles A Dinarello and Sabina Janciauskiene for indispensible insights and advice regarding the biology of AAT. The author also thanks Galit Shahaf, Eyal Ozeri, Mark Mizrahi, Hadas Moser, Keren Bellacen, Noa Kalay, Efrat Ashkenazi, Avishag Abecassis and David Ochayon for exceptional assistance in writing this manuscript.


  1. 1.
    Niemann H, Kues WA. (2003) Application of transgenesis in livestock for agriculture and biomedicine. Anim. Reprod. Sci. 79:291–317.PubMedCrossRefGoogle Scholar
  2. 2.
    Stoller JK, Aboussouan LS. (2012) A review of alpha1-antitrypsin deficiency. Am. J. Respir. Crit. Care Med. 185:246–59.PubMedCrossRefGoogle Scholar
  3. 3.
    Jie Z, et al. (2003) Protective effects of alpha 1-antitrypsin on acute lung injury in rabbits induced by endotoxin. Chin. Med. J. 116:1678–82.PubMedGoogle Scholar
  4. 4.
    Pott GB, Chan ED, Dinarello CA, Shapiro L. (2009) Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J. Leukoc. Biol. 85:886–95.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Tilg H, Vannier E, Vachino G, Dinarello CA, Mier JW. (1993) Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells. J. Exp. Med. 178:1629–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Subramanian S, et al. (2011) Sustained expression of circulating human alpha-1 antitrypsin reduces inflammation, increases CD4+FoxP3+ Treg cell population and prevents signs of experimental autoimmune encephalomyelitis in mice. Metab. Brain Dis. 26:107–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Koulmanda M, et al. (2008) Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc. Natl. Acad. Sci. U. S. A. 105:16242–7.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Lewis EC, et al. (2008) Alpha1-antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc. Natl. Acad. Sci. U. S. A. 105:16236–41.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ozeri E, Mizrahi M, Shahaf G, Lewis EC. (2012) α-1 Antitrypsin promotes semimature, IL-10-producing and readily migrating tolerogenic dendritic cells. J. Immunol. 189:146–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis EC, Shapiro L, Bowers OJ, Dinarello CA. (2005) Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc. Natl. Acad. Sci. U. S. A. 102:12153–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Marcondes AM, et al. (2011) Inhibition of IL-32 activation by alpha-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood. 118:5031–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Tawara I, et al. (2012) Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc. Natl. Acad. Sci. U. S. A. 109:564–9.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Arora PK, Miller HC, Aronson LD. (1978) Alpha1-antitrypsin is an effector of immunological stasis. Nature. 274:589–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Wewers MD, et al. (1987) Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N. Engl. J. Med. 316:1055–62.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Gotzsche PC, Johansen HK. (2010) Intravenous alpha-1 antitrypsin augmentation therapy: systematic review. Dan. Med. Bull. 57:A4175.PubMedGoogle Scholar
  16. 16.
    Janciauskiene SM, et al. (2011) The discovery of alpha1-antitrypsin and its role in health and disease. Respir. Med. 105:1129–39.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Larsson A, Palm M, Hansson LO, Basu S, Axelsson O. (2008) Reference values for alpha1-acid glycoprotein, alpha1-antitrypsin, albumin, haptoglobin, C-reactive protein, IgA, IgG and IgM during pregnancy. Acta. Obstet. Gynecol. Scand. 87:1084–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Paczek L, Michalska W, Bartlomiejczyk I. (2008) Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process. Age Ageing. 37:318–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Dhami R, et al. (1999) Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium. J. Mol. Med. (Berl.). 77:377–85.CrossRefGoogle Scholar
  20. 20.
    Tuder RM, Janciauskiene SM, Petrache I. (2010) Lung disease associated with alpha1-antitrypsin deficiency. Proc. Am. Thorac. Soc. 7:381–6.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    de Serres FJ, Blanco I, Fernandez-Bustillo E. (2007) PI S and PI Z alpha-1 antitrypsin deficiency worldwide: a review of existing genetic epidemiological data. Monaldi Arch. Chest Dis. 67:184–208.PubMedGoogle Scholar
  22. 22.
    Perlmutter DH. (2011) Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu. Rev. Med. 62:333–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang D, et al. (2011) Deletion of Serpina1a, a murine alpha1-antitrypsin ortholog, results in embryonic lethality. Exp. Lung Res. 37:291–300.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee WL, Downey GP. (2001) Leukocyte elastase: physiological functions and role in acute lung injury. Am. J. Respir. Crit. Care Med. 164:896–904.PubMedCrossRefGoogle Scholar
  25. 25.
    Perlmutter DH, et al. (1990) Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor. J. Biol. Chem. 265:16713–6.PubMedGoogle Scholar
  26. 26.
    Joslin G, Fallon RJ, Bullock J, Adams SP, Perlmutter DH. (1991) The SEC receptor recognizes a pentapeptide neodomain of alpha 1-antitrypsin-protease complexes. J. Biol. Chem. 266:11282–8.PubMedGoogle Scholar
  27. 27.
    Janciauskiene S, Zelvyte I, Jansson L, Stevens T. (2004) Divergent effects of alpha1-antitrypsin on neutrophil activation, in vitro. Biochem. Biophys. Res. Commun. 315:288–96.PubMedCrossRefGoogle Scholar
  28. 28.
    Janciauskiene S, Moraga F, Lindgren S. (2001) C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor. Atherosclerosis. 158:41–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Subramaniyam D, et al. (2006) C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways. Int. J. Biochem. Cell Biol. 38:563–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Janciauskiene S, Wright HT, Lindgren S. (1999) Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin. Atherosclerosis. 147:263–75.PubMedCrossRefGoogle Scholar
  31. 31.
    Dichtl W, et al. (2000) The carboxyl-terminal fragment of alpha1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human mono-cytes. Mol. Cell. Biol. Res. Commun. 4:50–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Shpacovitch V, Feld M, Hollenberg MD, Luger TA, Steinhoff M. (2008) Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J. Leukoc. Biol. 83:1309–22.PubMedCrossRefGoogle Scholar
  33. 33.
    Fields RC, et al. (2003) Protease-activated receptor-2 signaling triggers dendritic cell development. Am. J. Pathol. 162:1817–22.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Shah R. (2009) Protease-activated receptors in cardiovascular health and diseases. Am. Heart J. 157:253–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Vergnolle N, et al. (2006) A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J. Clin. Invest. 116:2056.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Noorbakhsh F, et al. (2006) Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med. 203:425–35.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Yoshida K, et al. (2005) Aggrecanase-1 (ADAMTS–4) interacts with alpha1-antitrypsin. Biochim. Biophys. Acta. 1725:152–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu Z, et al. (2000) The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell. 102:647–55.PubMedCrossRefGoogle Scholar
  39. 39.
    Muroski ME, et al. (2008) Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. Curr. Pharm. Biotechnol. 9:34–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Al-Omari M, et al. (2011) Acute-phase protein alpha1-antitrypsin inhibits neutrophil calpain I and induces random migration. Mol. Med. 17:865–74.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Segel GB, Halterman MW, Lichtman MA. (2011) The paradox of the neutrophil’s role in tissue injury. J. Leukoc. Biol. 89:359–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Bergin DA, et al. (2010) Alpha-1 antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J. Clin. Invest. 120:4236–50.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Miyake Y, Yamasaki S. (2012) Sensing necrotic cells. Adv. Exp. Med. Biol. 738:144–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Tsan MF. (2011) Heat shock proteins and high mobility group box 1 protein lack cytokine function. J. Leukoc. Biol. 89:847–53.PubMedCrossRefGoogle Scholar
  45. 45.
    Finotti P, Pagetta A. (2004) A heat shock protein70 fusion protein with alpha1-antitrypsin in plasma of type 1 diabetic subjects. Biochem. Biophys. Res. Commun. 315:297–305.PubMedCrossRefGoogle Scholar
  46. 46.
    Subramaniyam D, et al. (2010) Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1. Int. J. Biochem. Cell Biol. 42:1562–70.PubMedCrossRefGoogle Scholar
  47. 47.
    Correale M, Brunetti ND, De Gennaro L, Di Biase M. (2008) Acute phase proteins in atherosclerosis (acute coronary syndrome). Cardiovasc. Hematol. Agents Med. Chem. 6:272–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Mashiba S, et al. (2001) In vivo complex formation of oxidized alpha(1)-antitrypsin and LDL. Arterioscler. Thromb. Vasc. Biol. 21:1801–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Talmud PJ, et al. (2003) Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene. Arterioscler. Thromb. Vasc. Biol. 23:644–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Shapiro L, Pott GB, Ralston AH. (2001) Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J. 15:115–22.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Munch J, et al. (2007) Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell. 129:263–75.PubMedCrossRefGoogle Scholar
  52. 52.
    Bryan CL, et al. (2010) HIV infection is associated with reduced serum alpha-1-antitrypsin concentrations. Clin. Invest. Med. 33:E384–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Congote LF. (2006) The C-terminal 26-residue peptide of serpin A1 is an inhibitor of HIV-1. Biochem. Biophys. Res. Commun. 343:617–22.PubMedCrossRefGoogle Scholar
  54. 54.
    Forssmann WG, et al. (2010) Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci. Transl. Med. 2:63re63.CrossRefGoogle Scholar
  55. 55.
    Petrache I, et al. (2006) A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema. Am. J. Respir. Crit. Care Med. 173:1222–8.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Tuder RM, Yoshida T, Fijalkowka I, Biswal S, Petrache I. (2006) Role of lung maintenance program in the heterogeneity of lung destruction in emphysema. Proc. Am. Thorac. Soc. 3:673–9.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zelvyte I, Stevens T, Westin U, Janciauskiene S. (2004) Alpha1-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro. Cancer Cell Int. 4:7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kurtagic E, Jedrychowski MP, Nugent MA. (2009) Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity. Am. J. Physiol. Lung Cell Mol. Physiol. 296:L534–46.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ikari Y, Fujikawa K, Yee KO, Schwartz SM. (2000) Alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, or alpha(2)-macroglobulin is required for vascular smooth muscle cell spreading in three-dimensional fibrin gel. J. Biol. Chem. 275:12799–805.PubMedCrossRefGoogle Scholar
  60. 60.
    Petrache I, et al. (2006) Alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am. J. Pathol. 169:1155–66.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Tuder RM, et al. (2003) Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am. J. Respir. Cell Mol. Biol. 29:88–97.PubMedCrossRefGoogle Scholar
  62. 62.
    Elias JA, Kang MJ, Crothers K, Homer R, Lee CG. (2006) State of the art: mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice. Proc. Am. Thorac. Soc. 3:494–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Kasahara Y, et al. (2001) Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am. J. Respir. Crit. Care Med. 163:737–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Taraseviciene-Stewart L, et al. (2001) Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15:427–38.PubMedCrossRefGoogle Scholar
  65. 65.
    Wenger RH, Rolfs A, Marti HH, Bauer C, Gassmann M. (1995) Hypoxia, a novel inducer of acute phase gene expression in a human hepatoma cell line. J. Biol. Chem. 270:27865–70.PubMedCrossRefGoogle Scholar
  66. 66.
    Wewers MD. (2004) Alpha1-antitrypsin deficiency: more than a protease imbalance? Chest. 125:1607–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhong X, et al. (2007) Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells. Eur. J. Immunol. 37:2400–4.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lee WW, et al. (2010) Regulating human Th17 cells via differential expression of IL-1 receptor. Blood. 115:530–40.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Pemberton PA, et al. (2006) Inhaled recombinant alpha 1-antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse. COPD. 3:101–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Hadzic R, et al. (2006) Alpha1-antitrypsin inhibits Moraxella catarrhalis MID protein-induced tonsillar B cell proliferation and IL-6 release. Immunol. Lett. 102:141–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Blank CA, Brantly M. (1994) Clinical features and molecular characteristics of alpha 1-antitrypsin deficiency. Ann. Allergy. 72:105–20.PubMedGoogle Scholar
  72. 72.
    Yaghmaei M, et al. (2009) Serum trypsin inhibitory capacity in normal pregnancy and gestational diabetes mellitus. Diabetes Res. Clin. Pract. 84:201–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Ekeowa UI, Marciniak SJ, Lomas DA. (2011) Alpha(1)-antitrypsin deficiency and inflammation. Expert Rev. Clin. Immunol. 7:243–52.PubMedCrossRefGoogle Scholar
  74. 74.
    Schmechel DE, Edwards CL. (2012) Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent. Neurotoxicology. 2012 March 10 [Epub ahead of print]Google Scholar
  75. 75.
    Schmechel DE. (2007) Art, alpha-1-antitrypsin polymorphisms and intense creative energy: blessing or curse? Neurotoxicology. 28:899–914.PubMedCrossRefGoogle Scholar
  76. 76.
    Dinarello CA. (2010) Anti-inflammatory agents: present and future. Cell. 140:935–50.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Desouza CV. (2010) An overview of salsalate as a potential antidiabetic therapy. Drugs Today (Barc.). 46:847–53.CrossRefGoogle Scholar
  78. 78.
    Larsen CM, et al. (2007) [Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes]. Ugeskr. Laeger. 169:3868–71.PubMedGoogle Scholar
  79. 79.
    Geiler J, McDermott MF. (2010) Gevokizumab, an anti-IL-1beta mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease. Curr. Opin. Mol. Ther. 12:755–69.PubMedGoogle Scholar
  80. 80.
    Donath MY, Shoelson SE. (2011) Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11:98–107.PubMedCrossRefGoogle Scholar
  81. 81.
    Bendtzen K, et al. (1986) Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science. 232:1545–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Kalis M, Kumar R, Janciauskiene S, Salehi A, Cilio CM. (2010) Alpha 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic beta-cells. Islets. 2:185–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Weir GC, Koulamnda M. (2009) Control of inflammation with alpha1-antitrypsin: a potential treatment for islet transplantation and new-onset type 1 diabetes. Curr. Diab. Rep. 9:100–2.PubMedCrossRefGoogle Scholar
  84. 84.
    Pileggi A, et al. (2008) Alpha-1 antitrypsin treatment of spontaneously diabetic nonobese diabetic mice receiving islet allografts. Transplant Proc. 40:457–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Strom TB. (2005) Saving islets from allograft rejection. Proc. Natl. Acad. Sci. U. S. A. 102:12651–2.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Papaccio G, Pedulla M, Ammendola E, Todaro M. (2002) Cytokine regulatory effects on alpha-1 proteinase inhibitor expression in NOD mouse islet endothelial cells. J. Cell. Biochem. 85:123–30.PubMedCrossRefGoogle Scholar
  87. 87.
    Sandstrom CS, et al. (2008) An association between type 2 diabetes and alpha-antitrypsin deficiency. Diabet. Med. 25:1370–3.PubMedGoogle Scholar
  88. 88.
    Phillips B, Trucco M, Giannoukakis N. (2011) Current state of type 1 diabetes immunotherapy: incremental advances, huge leaps, or more of the same? Clin. Dev. Immunol. 2011:432016.Google Scholar
  89. 89.
    Donath MY, Mandrup-Poulsen T. (2008) The use of interleukin-1-receptor antagonists in the treatment of diabetes mellitus. Nat. Clin. Pract. Endocrinol. Metab. 4:240–1.PubMedCrossRefGoogle Scholar
  90. 90.
    Sumpter KM, Adhikari S, Grishman EK, White PC. (2011) Preliminary studies related to anti-interleukin-1beta therapy in children with newly diagnosed type 1 diabetes. Pediatr. Diabetes. 12:656–67.PubMedCrossRefGoogle Scholar
  91. 91.
    Hashemi M, Naderi M, Rashidi H, Ghavami S. (2007) Impaired activity of serum alpha-1-antitrypsin in diabetes mellitus. Diabetes Res. Clin. Pract. 75:246–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Lisowska-Myjak B, Pachecka J, Kaczynska B, Miszkurka G, Kadziela K. (2006) Serum protease inhibitor concentrations and total antitrypsin activity in diabetic and non-diabetic children during adolescence. Acta Diabetol. 43:88–92.PubMedCrossRefGoogle Scholar
  93. 93.
    Bristow CL, Di Meo F, Arnold RR. (1998) Specific activity of alpha1proteinase inhibitor and alpha2macroglobulin in human serum: application to insulin-dependent diabetes mellitus. Clin. Immunol. Immunopathol. 89:247–59.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Sandler M, Gemperli BM, Hanekom C, Kuhn SH. (1988) Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity. Diabetes Res. Clin. Pract. 5:249–55.PubMedCrossRefGoogle Scholar
  95. 95.
    Hall P, Tryon E, Nikolai TF, Roberts RC. (1986) Functional activities and nonenzymatic glycosylation of plasma proteinase inhibitors in diabetes. Clin. Chim. Acta. 160:55–62.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Lu Y, et al. (2006) Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice. Hum. Gene Ther. 17:625–34.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ma H, et al. (2010) Intradermal alpha1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hypergly-caemia in the NOD mouse model of the disease. Diabetologia. 53:2198–204.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zhang B, et al. (2007) Alpha1-antitrypsin protects beta-cells from apoptosis. Diabetes. 56:1316–23.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lou J, et al. (1999) Expression of alpha-1 proteinase inhibitor in human islet microvascular endothelial cells. Diabetes. 48:1773–8.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Bosco D, et al. (2005) Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells. Diabetologia. 48:1523–33.PubMedCrossRefGoogle Scholar
  101. 101.
    Fujita M, Nakanishi Y. (2007) The pathogenesis of COPD: lessons learned from in vivo animal models. Med. Sci. Monit. 13:RA19–24.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Pizzutto SJ, Upham JW, Yerkovich ST, Chang AB. (2010) Inhaled non-steroid anti-inflammatories for children and adults with bronchiectasis. Cochrane Database Syst. Rev. CD007525.Google Scholar
  103. 103.
    Kerem E, et al. (2009) Safety and efficacy of inhaled human alpha-1 antitrypsin (AAT) in cystic fibrosis (CF): a report of a phase II clinical study [abstract]. Am. J. Respir. Crit. Care Med. 179:A1185.Google Scholar
  104. 104.
    Sly PD, et al. (2009) Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am. J. Respir. Crit. Care Med. 180:146–52.PubMedCrossRefGoogle Scholar
  105. 105.
    Siekmeier R. (2010) Lung deposition of inhaled alpha-1-proteinase inhibitor (alpha 1-PI): problems and experience of alpha1-PI inhalation therapy in patients with hereditary alpha1-PI deficiency and cystic fibrosis. Eur. J. Med. Res. 15 (Suppl. 2):164–74.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Hagen LE, et al. (2011) High alpha-1 antitrypsin clearance predicts severity of gut graft-versus-host disease (GVHD) in children. Pediatr. Transplant. 15:659–63.PubMedGoogle Scholar
  107. 107.
    Dinarello CA. (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 117:3720–32.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Antin JH, et al. (1994) Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease. Blood. 84:1342–8.PubMedGoogle Scholar
  109. 109.
    Antin JH, et al. (2002) Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood. 100:3479–82.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Zeiser R, Penack O, Holler E, Idzko M. (2011) Danger signals activating innate immunity in graft-versus-host disease. J. Mol. Med. (Berl.). 89:833–45.CrossRefGoogle Scholar
  111. 111.
    McInnes IB, O’Dell JR. (2010) State-of-the-art: rheumatoid arthritis. Ann. Rheum. Dis. 69:1898–906.PubMedCrossRefGoogle Scholar
  112. 112.
    Chidwick K, et al. (1994) Relationship between alpha 1-antitrypsin inactivation and tumor necrosis factor alpha concentration in the synovial fluid of patients with rheumatoid arthritis. Arthritis Rheum. 37:1723–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Kakimoto K, Matsukawa A, Yoshinaga M, Nakamura H. (1995) Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. Cell Immunol. 165:26–32.PubMedCrossRefGoogle Scholar
  114. 114.
    Grimstein C, et al. (2011) Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model. J. Transi. Med. 9:21.CrossRefGoogle Scholar
  115. 115.
    Grimstein C, et al. (2010) Combination of alpha-1 antitrypsin and doxycycline suppresses collagen-induced arthritis. J. Gene Med. 12:35–44.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Wee Yong V. (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist. 16:408–20.CrossRefGoogle Scholar
  117. 117.
    Lolin YI, Ward AM. (1995) Alpha-1-antitrypsin phenotypes and associated disease patterns in neurological patients. Acta Neurol. Scand. 91:394–8.PubMedCrossRefGoogle Scholar
  118. 118.
    McCombe PA, et al. (1985) Alpha-1 antitrypsin phenotypes in demyelinating disease: an association between demyelinating disease and the allele PiM3. Ann. Neurol. 18:514–6.PubMedCrossRefGoogle Scholar
  119. 119.
    Pearl GS, Mullins RE. (1985) Alpha 1-antitrypsin in cerebrospinal fluid of patients with neurologic diseases. Arch. Neurol. 42:775–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Folwaczny C, et al. (1998) Alpha1-antitrypsin alleles and phenotypes in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 33:78–81.PubMedCrossRefGoogle Scholar
  121. 121.
    Kotlowski R, Bernstein CN, Silverberg MS, Krause DO. (2008) Population-based case-control study of alpha 1-antitrypsin and SLC11A1 in Crohn’s disease and ulcerative colitis. Inflamm. Bowel Dis. 14:1112–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Molmenti EP, Perlmutter DH, Rubin DC. (1993) Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. J. Clin. Invest. 92:2022–34.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Turer AT, Hill JA. (2010) Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am. J. Cardiol. 106:360–8.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Jiang B, Liao R. (2010) The paradoxical role of inflammation in cardiac repair and regeneration. J. Cardiovasc. Transl. Res. 3:410–6.PubMedCrossRefGoogle Scholar
  125. 125.
    Toldo S, et al. (2011) Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. J. Mol. Cell. Cardiol. 51:244–51.PubMedCrossRefGoogle Scholar
  126. 126.
    Daemen MA, et al. (2000) Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation. Circulation. 102:1420–6.PubMedCrossRefGoogle Scholar
  127. 127.
    Kanayama N, Kamijo H, Terao T, Horiuchi K, Fujimoto D. (1986) The relationship between trypsin activity in amniotic fluid and premature rupture of membranes. Am. J. Obstet. Gynecol. 155:1043–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Izumi-Yoneda N, et al. (2009) Alpha 1 antitrypsin activity is decreased in human amnion in premature rupture of the fetal membranes. Mol. Hum. Reprod. 15:49–57.PubMedCrossRefGoogle Scholar
  129. 129.
    Aboussouan LS, Stoller JK. (2009) Detection of alpha-1 antitrypsin deficiency: a review. Respir. Med. 103:335–41.PubMedCrossRefGoogle Scholar
  130. 130.
    Churg A, Wang RD, Xie C, Wright JL. (2003) Alpha-1-antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse. Am. J. Respir. Crit. Care Med. 168:199–207.PubMedCrossRefGoogle Scholar
  131. 131.
    Lieberman J. (2000) Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data. Chest. 118:1480–5.PubMedCrossRefGoogle Scholar
  132. 132.
    Huang H, et al. (2004) Alpha1-antitrypsin inhibits angiogenesis and tumor growth. Int. J. Cancer. 112:1042–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Yavelow J, Tuccillo A, Kadner SS, Katz J, Finlay TH. (1997) Alpha 1-antitrypsin blocks the release of transforming growth factor-alpha from MCF-7 human breast cancer cells. J. Clin. Endocrinol. Metab. 82:745–52.PubMedGoogle Scholar
  134. 134.
    Sallenave JM. (2002) Antimicrobial activity of antiproteinases. Biochem. Soc. Trans. 30:111–5.PubMedCrossRefGoogle Scholar
  135. 135.
    Forney JR, Yang S, Healey MC. (1997) Synergistic anticryptosporidial potential of the combination alpha-1-antitrypsin and paromomycin. Antimicrob. Agents Chemother. 41:2006–8.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Miyamoto Y, et al. (2000) Novel functions of human alpha(1)-protease inhibitor after S-nitrosylation: inhibition of cysteine protease and antibacterial activity. Biochem. Biophys. Res. Commun. 267:918–23.PubMedCrossRefGoogle Scholar
  137. 137.
    Porat R, Clark BD, Wolff SM, Dinarello CA. (1991) Enhancement of growth of virulent strains of Escherichia coli by interleukin-1. Science. 254:430–2.PubMedCrossRefGoogle Scholar
  138. 138.
    Riveau GR, Novitsky TJ, Roslansky PF, Dinarello CA, Warren HS. (1987) Role of interleukin-1 in augmenting serum neutralization of bacterial lipopolysaccharide. J. Clin. Microbiol. 25:889–92.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Chan ED, et al. (2007) Alpha-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. 39:690–6.PubMedCrossRefGoogle Scholar
  140. 140.
    Wencker M, Fuhrmann B, Banik N, Konietzko N. (2001) Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest. 119:737–44.PubMedCrossRefGoogle Scholar
  141. 141.
    Blanco I, et al. (2008) Long-term augmentation therapy with alpha-1 antitrypsin in an MZ-AAT severe persistent asthma. Monaldi Arch. Chest Dis. 69:178–82.PubMedGoogle Scholar
  142. 142.
    Mordwinkin NM, Louie SG. (2007) Aralast: an alpha 1-protease inhibitor for the treatment of alpha-antitrypsin deficiency. Expert Opin. Pharmacother. 8:2609–14.PubMedCrossRefGoogle Scholar
  143. 143.
    Petrache I, Hajjar J, Campos M. (2009) Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 3:193–204.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Griese M, et al. (2007) Alpha1-antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur. Respir. J. 29:240–50.PubMedCrossRefGoogle Scholar
  145. 145.
    Janciauskiene SM, Nita IM, Stevens T. (2007) Alpha1-antitrypsin, old dog, new tricks: alpha1-antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevating cAMP. J. Biol. Chem. 282:8573–82.PubMedCrossRefGoogle Scholar
  146. 146.
    Wouters D, Wagenaar-Bos I, van Ham M, Zeerleder S. (2008) C1 inhibitor: just a serine protease inhibitor? New and old considerations on therapeutic applications of C1 inhibitor. Expert Opin. Biol. Ther. 8:1225–40.PubMedCrossRefGoogle Scholar
  147. 147.
    Wiedermann Ch J, Romisch J. (2002) The anti-inflammatory actions of antithrombin: a review. Acta Med. Austriaca. 29:89–92.PubMedCrossRefGoogle Scholar
  148. 148.
    Shahaf G, et al. (2011) Alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection. Mol. Med. 17:1000–11.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Stockley RA. (2010) Emerging drugs for alpha-1-antitrypsin deficiency. Expert Opin. Emerg. Drugs. 15:685–94.PubMedCrossRefGoogle Scholar
  150. 150.
    Flotte TR, Mueller C. (2011) Gene therapy for alpha-1 antitrypsin deficiency. Hum. Mol. Genet. 20:R87–92.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Stoll SM, et al. (2001) Epstein-Barr virus/human vector provides high-level, long-term expression of alpha1-antitrypsin in mice. Mol. Ther. 4:122–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Karnaukhova E, Ophir Y, Golding B. (2006) Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use. Amino Acids. 30:317–32.PubMedCrossRefGoogle Scholar
  153. 153.
    Cantin AM, Woods DE, Cloutier D, Dufour EK, Leduc R. (2002) Polyethylene glycol conjugation at Cys232 prolongs the half-life of alpha1 proteinase inhibitor. Am. J. Respir. Cell Mol. Biol. 27:659–65.PubMedCrossRefGoogle Scholar
  154. 154.
    Zbikowska HM, et al. (2002) Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine. Biochem. J. 365:7–11.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Hedin SG. (1906) Trypsin and antitrypsin. Biochem. J. 1:474–83.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Blanco I, Lara B, de Serres F. (2011) Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Orphanet J. Rare Dis. 6:14.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Chen GY, Nunez G. (2010) Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10:826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Eltzschig HK, Carmeliet P. (2011) Hypoxia and inflammation. N. Engl. J. Med. 364:656–65.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Song S, et al. (2004) Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice. Gene Ther. 11:181–6.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Loganathan G, et al. (2010) Culture of impure human islet fractions in the presence of alpha-1 antitrypsin prevents insulin cleavage and improves islet recovery. Transplant. Proc. 42:2055–7.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Congote LF, Temmel N, Sadvakassova G, Dobocan MC. (2008) Comparison of the effects of serpin A1, a recombinant serpin A1-IGF chimera and serpin A1 C-terminal peptide on wound healing. Peptides. 29:39–46.PubMedCrossRefGoogle Scholar
  162. 162.
    Nita I, Hollander C, Westin U, Janciauskiene SM. (2005) Prolastin, a pharmaceutical preparation of purified human alpha1-antitrypsin, blocks endotoxin-mediated cytokine release. Respir. Res. 6:12.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Blanchard V, et al. (2011) N-glycosylation and biological activity of recombinant human alpha1-antitrypsin expressed in a novel human neuronal cell line. Biotechnol. Bioeng. 108:2118–28.PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  1. 1.Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael

Personalised recommendations