a1-antitrypsin therapy for non-deficient individuals: integrating and mitigating cross-pathology inflammatory and immune responses to the injured cell

Eli C Lewis


Human a1-antitrypsin (AAT) is an endogenous circulating anti-inflammatory glycoprotein presently infused to patients with genetic AAT deficiency. It represents a regimen of remarkable safety for life-long weekly slow drip intravenous infusion sessions. Based on its anti-inflammatory properties, it has been suggested that it may be of benefit in medical conditions outside genetic AAT deficiency. In the past five years, reports on the testing of AAT therapy for various unmet medical needs had surfaced, and a novel clinical parameter appears to have become critically relevant: AAT insufficiency. The molecule is programmed to rise during inflammatory flares, as well as during the 3rd trimester of pregnancy and with age; yet in some instances, one meets conditions in which it might fail to rise. The review focuses on advances in the utilization of AAT therapy outside AAT deficiency in the past years, depicting well-coordinated preclinical and clinical studies, leaps in basic research in as far as the mechanism of AAT is concerned and novel binding partners of AAT, including lipids. The collective data places endogenous and exogenous AAT as centering on the critical junction between the immune system, inflammation and the injured cell. Thus, clinical trials span conditions as sparse as type 1 autoimmune diabetes, acute myocardial infarction, lung transplantation and cystic fibrosis. The phenomenon of immune cell repopulation appears to bridge several pathologies and expose a window of opportunities for tissue preconditioning using AAT therapy, whether in the case of bone marrow transplantation or cell/organ grafting. The safety of AAT is by now demonstrated to embrace broader patient populations both in as far as age and underlying clinical condition. Together with the growing interest in drug repurposing, and the capacity to formulate novel AAT-based agents, we may expect further extension of this primordial molecule for the bettering of our health.    


inflammation, cell injury, acute phase response

Full Text:

 Subscribers Only



Chotirmall SH, Al-Alawi M, McEnery T, McElvaney NG. Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes. Ther Clin Risk Manag. 2015;11:143-51.

Stoller JK, Fallat R, Schluchter MD, O'Brien RG, Connor JT, Gross N, et al. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events. Chest. 2003;123(5):1425-34.

Chapman KR, Burdon JG, Piitulainen E, Sandhaus RA, Seersholm N, Stocks JM, et al. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-8.

Lewis EC. Expanding the clinical indications for alpha(1)-antitrypsin therapy. Molecular medicine. 2012;18:957-70.

de Serres F, Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014;276(4):311-35.

Wick MR. Panniculitis: A summary. Semin Diagn Pathol. 2016.

Nylander-Lundqvist E, Egelrud T. Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro. Acta Derm Venereol. 1997;77(3):203-6.

Rider P, Carmi Y, Yossef R, Guttman O, Eini H, Azam T, et al. IL-1 Receptor Antagonist Chimeric Protein: Context-Specific and Inflammation-Restricted Activation. Journal of immunology. 2015;195(4):1705-12.

Ochayon DE, Mizrahi M, Shahaf G, Baranovski BM, Lewis EC. Human alpha1-Antitrypsin Binds to Heat-Shock Protein gp96 and Protects from Endogenous gp96-Mediated Injury In vivo. Front Immunol. 2013;4:320.

Finotti P, Pagetta A. A heat shock protein70 fusion protein with alpha1-antitrypsin in plasma of type 1 diabetic subjects. Biochem Biophys Res Commun. 2004;315(2):297-305.

Guttman O, Baranovski BM, Schuster R, Kaner Z, Freixo-Lima GS, Bahar N, et al. Acute-phase protein alpha1-anti-trypsin: diverting injurious innate and adaptive immune responses from non-authentic threats. Clinical and experimental immunology. 2015;179(2):161-72.

Bergin DA, Reeves EP, Meleady P, Henry M, McElvaney OJ, Carroll TP, et al. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. The Journal of clinical investigation. 2010;120(12):4236.

Jonigk D, Al-Omari M, Maegel L, Muller M, Izykowski N, Hong J, et al. Anti-inflammatory and immunomodulatory properties of alpha1-antitrypsin without inhibition of elastase. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(37):15007-12.

Crystal RG. Compelling evidence for the efficacy of alpha1-antitrypsin augmentation treatment for alpha1-antitrypsin deficiency. Lancet Respir Med. 2017;5(1):7-8.

Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, et al. A novel antiapoptotic role for α1-antitrypsin in the prevention of pulmonary emphysema. American journal of respiratory and critical care medicine. 2006;173(11):1222-8.

Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, et al. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol. 2006;169(4):1155-66.

Serban KA, Petrache I. Alpha-1 Antitrypsin and Lung Cell Apoptosis. Ann Am Thorac Soc. 2016;13 Suppl 2:S146-9.

Iskender I, Sakamoto J, Nakajima D, Lin H, Chen M, Kim H, et al. Human alpha1-antitrypsin improves early post-transplant lung function: Pre-clinical studies in a pig lung transplant model. J Heart Lung Transplant. 2016;35(7):913-21.

Feng Y, Hu L, Xu Q, Yuan H, Ba L, He Y, et al. Cytoprotective Role of Alpha-1 Antitrypsin in Vascular Endothelial Cell Under Hypoxia/Reoxygenation Condition. J Cardiovasc Pharmacol. 2015;66(1):96-107.

Hunt JM, Tuder R. Alpha 1 anti-trypsin: one protein, many functions. Curr Mol Med. 2012;12(7):827-35.

Ganrot PO, Bjerre B. Alpha-1-antitrypsin and alpha-2-macroglobulin concentration in serum during pregnancy. Acta Obstet Gynecol Scand. 1967;46(2):126-37.

Larsson A, Palm M, Hansson LO, Basu S, Axelsson O. Reference values for alpha1-acid glycoprotein, alpha1-antitrypsin, albumin, haptoglobin, C-reactive protein, IgA, IgG and IgM during pregnancy. Acta Obstet Gynecol Scand. 2008;87(10):1084-8.

Senn O, Russi EW, Schindler C, Imboden M, von Eckardstein A, Brandli O, et al. Circulating alpha1-antitrypsin in the general population: determinants and association with lung function. Respir Res. 2008;9:35.

Paczek L, Michalska W, Bartlomiejczyk I. Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process. Age Ageing. 2008;37(3):318-23.

Henry CJ, Casas-Selves M, Kim J, Zaberezhnyy V, Aghili L, Daniel AE, et al. Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. J Clin Invest. 2015;125(12):4666-80.

Greulich T, Nell C, Hohmann D, Grebe M, Janciauskiene S, Koczulla AR, et al. The prevalence of diagnosed alpha1-antitrypsin deficiency and its comorbidities: results from a large population-based database. Eur Respir J. 2017;49(1).

Madar T, Shahaf G, Sheiner E, Brazg J, Levinson J, Yaniv Salem S, et al. Low levels of circulating alpha-1 antitrypsin are associated with spontaneous abortions. J Matern Fetal Neonatal Med. 2013;26(18):1782-7.

Salem SY, Shahaf G, Sheiner E, Levinson J, Baron J, Madar T, et al. Diminished activity of circulating alpha1-antitrypsin is associated with pre-gestational isolated obesity. J Matern Fetal Neonatal Med. 2015;28(5):500-3.

Twina G, Sheiner E, Shahaf G, Yaniv Salem S, Madar T, Baron J, et al. Lower circulation levels and activity of alpha-1 antitrypsin in pregnant women with severe preeclampsia. J Matern Fetal Neonatal Med. 2012;25(12):2667-70.

Baron J, Sheiner E, Abecassis A, Ashkenazi E, Shahaf G, Salem SY, et al. alpha1-antitrypsin insufficiency is a possible contributor to preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2012;25(7):934-7.

Lockett AD, Van Demark M, Gu Y, Schweitzer KS, Sigua N, Kamocki K, et al. Effect of cigarette smoke exposure and structural modifications on the alpha-1 Antitrypsin interaction with caspases. Molecular medicine. 2012;18:445-54.

Fleixo-Lima G, Ventura H, Medini M, Bar L, Strauss P, Lewis EC. Mechanistic evidence in support of alpha1-antitrypsin as a therapeutic approach for type 1 diabetes. J Diabetes Sci Technol. 2014;8(6):1193-203.

Gottlieb PA, Alkanani AK, Michels AW, Lewis EC, Shapiro L, Dinarello CA, et al. alpha1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J Clin Endocrinol Metab. 2014;99(8):E1418-26.

Lewis EC, Mizrahi M, Toledano M, Defelice N, Wright JL, Churg A, et al. alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(42):16236-41.

Sinden NJ, Stockley RA. Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD. Eur Respir J. 2013;41(5):1042-50.

Wang Y, Xiao Y, Zhong L, Ye D, Zhang J, Tu Y, et al. Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with beta-cell autoimmunity in patients with type 1 diabetes. Diabetes. 2014;63(12):4239-48.

Rachmiel M, Strauss P, Dror N, Benzaquen H, Horesh O, Tov N, et al. Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus. Pediatr Diabetes. 2016;17(5):351-9.

Baranovski BM, Ozeri E, Shahaf G, Ochayon DE, Schuster R, Bahar N, et al. Exploration of alpha1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration. J Pharmacol Exp Ther. 2016.

Koulmanda M, Sampathkumar RS, Bhasin M, Qipo A, Fan Z, Singh G, et al. Prevention of nonimmunologic loss of transplanted islets in monkeys. Am J Transplant. 2014;14(7):1543-51.

Koulmanda M, Bhasin M, Fan Z, Hanidziar D, Goel N, Putheti P, et al. Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(38):15443-8.

Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, et al. Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(42):16242-7.

Gilutz H, Siegel Y, Paran E, Cristal N, Quastel MR. Alpha 1-antitrypsin in acute myocardial infarction. Br Heart J. 1983;49(1):26-9.

Toldo S, Mauro AG, Marchetti C, Rose SW, Mezzaroma E, Van Tassell BW, et al. Recombinant Human Alpha-1 Antitrypsin-Fc Fusion Protein Reduces Mouse Myocardial Inflammatory Injury After Ischemia-Reperfusion Independent of Elastase Inhibition. J Cardiovasc Pharmacol. 2016;68(1):27-32.

Toldo S, Seropian IM, Mezzaroma E, Van Tassell BW, Salloum FN, Lewis EC, et al. Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. Journal of molecular and cellular cardiology. 2011;51(2):244-51.

Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 2010;106(3):360-8.

Maicas N, van der Vlag J, Bublitz J, Florquin S, Bakker-van Bebber M, Dinarello CA, et al. Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury. PLoS One. 2017;12(2):e0168981.

Gao W, Zhao J, Kim H, Xu S, Chen M, Bai X, et al. alpha1-Antitrypsin inhibits ischemia reperfusion-induced lung injury by reducing inflammatory response and cell death. J Heart Lung Transplant. 2014;33(3):309-15.

Daemen MA, Heemskerk VH, van't Veer C, Denecker G, Wolfs TG, Vandenabeele P, et al. Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation. Circulation. 2000;102(12):1420-6.

Abbate A, Van Tassell BW, Christopher S, Abouzaki NA, Sonnino C, Oddi C, et al. Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study). Am J Cardiol. 2015;115(1):8-12.

Marcondes AM, Karoopongse E, Lesnikova M, Margineantu D, Welte T, Dinarello CA, et al. alpha-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics. Blood. 2014;124(18):2881-91.

Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E, et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(2):564-9.

Marcondes AM, Li X, Tabellini L, Bartenstein M, Kabacka J, Sale GE, et al. Inhibition of IL-32 activation by alpha-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model. Blood. 2011;118(18):5031-9.

Marcondes AM, Hockenbery D, Lesnikova M, Dinarello CA, Woolfrey A, Gernsheimer T, et al. Response of Steroid-Refractory Acute GVHD to alpha1-Antitrypsin. Biol Blood Marrow Transplant. 2016;22(9):1596-601.

Gerner RR, Feistritzer C, Moschen AR, Kircher B, Moser P, Tilg H, et al. Treatment With alpha-1-Antitrypsin for Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease: A Report of 2 Cases. Transplantation. 2016;100(12):e158-e9.

Cathomas M, Schuller A, Candinas D, Inglin R. Severe postoperative wound healing disturbance in a patient with alpha-1-antitrypsin deficiency: the impact of augmentation therapy. International wound journal. 2015;12(5):601-4.

Frochaux V, Hildebrand D, Talke A, Linscheid MW, Schluter H. Alpha-1-antitrypsin: a novel human high temperature requirement protease A1 (HTRA1) substrate in human placental tissue. PLoS One. 2014;9(10):e109483.

Parmar T, Gadkar-Sable S, Savardekar L, Katkam R, Dharma S, Meherji P, et al. Protein profiling of human endometrial tissues in the midsecretory and proliferative phases of the menstrual cycle. Fertil Steril. 2009;92(3):1091-103.

Dube V, Grigull J, DeSouza LV, Ghanny S, Colgan TJ, Romaschin AD, et al. Verification of endometrial tissue biomarkers previously discovered using mass spectrometry-based proteomics by means of immunohistochemistry in a tissue microarray format. J Proteome Res. 2007;6(7):2648-55.

Guttman O, Freixo-Lima GS, Kaner Z, Lior Y, Rider P, Lewis EC. Context-Specific and Immune Cell-Dependent Antitumor Activities of alpha1-Antitrypsin. Front Immunol. 2016;7:559.

Guttman O, Yossef R, Freixo-Lima G, Rider P, Porgador A, Lewis EC. alpha1-Antitrypsin modifies general NK cell interactions with dendritic cells and specific interactions with islet beta-cells in favor of protection from autoimmune diabetes. Immunology. 2014.

Faas MM, de Vos P. Uterine NK cells and macrophages in pregnancy. Placenta. 2017.

O'Meara A, Kapel N, Xhaard A, Sicre de Fontbrune F, Manene D, Dhedin N, et al. Fecal calprotectin and alpha1-antitrypsin dynamics in gastrointestinal GvHD. Bone Marrow Transplant. 2015;50(8):1105-9.

Rodriguez-Otero P, Porcher R, Peffault de Latour R, Contreras M, Bouhnik Y, Xhaard A, et al. Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease. Blood. 2012;119(24):5909-17.

Hagen LE, Schechter T, Luk Y, Brodovitch A, Gassas A, Doyle JJ. High alpha-1 antitrypsin clearance predicts severity of gut graft-versus-host disease (GVHD) in children. Pediatr Transplant. 2011;15(6):659-63.

Siddiqui I, Majid H, Abid S. Update on clinical and research application of fecal biomarkers for gastrointestinal diseases. World J Gastrointest Pharmacol Ther. 2017;8(1):39-46.

Molmenti EP, Perlmutter DH, Rubin DC. Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. J Clin Invest. 1993;92(4):2022-34.

Collins CB, Aherne CM, Ehrentraut SF, Gerich ME, McNamee EN, McManus MC, et al. Alpha-1-antitrypsin therapy ameliorates acute colitis and chronic murine ileitis. Inflamm Bowel Dis. 2013;19(9):1964-73.

Matalon S, Elad H, Brazowski E, Santo E, Tulchinsky H, Dotan I. Serum alpha-1 antitrypsin: a noninvasive marker of pouchitis. Inflamm Bowel Dis. 2015;21(3):589-95.

Nielsen K. Coeliac disease: alpha-1-antitrypsin contents in jejunal mucosa before and after gluten-free diet. Histopathology. 1984;8(5):759-64.

Roche M, Kusumanjali G, Reddy GC, Kanagasabhapathy AS, Rao P. Serum alpha-2-macroglobulin, antitrypsin and antichymotrypsin activities in patients receiving treatment with cyclosporine. Indian J Clin Biochem. 2006;21(2):63-6.

Cichy J, Potempa J, Travis J. Effect of dexamethasone on alpha 1-proteinase inhibitor synthesis in human cells of monocytic origin. Biochem Biophys Res Commun. 1995;208(1):216-22.

Cichy J, Potempa J, Travis J. Biosynthesis of alpha1-proteinase inhibitor by human lung-derived epithelial cells. The Journal of biological chemistry. 1997;272(13):8250-5.

Mitchell GB, Clark ME, Caswell JL. Alterations in the bovine bronchoalveolar lavage proteome induced by dexamethasone. Vet Immunol Immunopathol. 2007;118(3-4):283-93.

Perez V, Lopez D, Boixadera E, Ibernon M, Espinal A, Bonet J, et al. Comparative differential proteomic analysis of minimal change disease and focal segmental glomerulosclerosis. BMC Nephrol. 2017;18(1):49.

Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, et al. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol. 2007;18(3):913-22.

Vaziri ND, Gonzales EC, Shayestehfar B, Barton CH. Plasma levels and urinary excretion of fibrinolytic and protease inhibitory proteins in nephrotic syndrome. J Lab Clin Med. 1994;124(1):118-24.

Ovrehus MA, Zurbig P, Vikse BE, Hallan SI. Urinary proteomics in chronic kidney disease: diagnosis and risk of progression beyond albuminuria. Clin Proteomics. 2015;12(1):21.

Candiano G, Musante L, Bruschi M, Petretto A, Santucci L, Del Boccio P, et al. Repetitive fragmentation products of albumin and alpha1-antitrypsin in glomerular diseases associated with nephrotic syndrome. J Am Soc Nephrol. 2006;17(11):3139-48.

Gonzalez-Calero L, Martin-Lorenzo M, de la Cuesta F, Maroto AS, Baldan-Martin M, Ruiz-Hurtado G, et al. Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression. Cardiovasc Diabetol. 2016;15:8.

Eming SA, Koch M, Krieger A, Brachvogel B, Kreft S, Bruckner-Tuderman L, et al. Differential proteomic analysis distinguishes tissue repair biomarker signatures in wound exudates obtained from normal healing and chronic wounds. J Proteome Res. 2010;9(9):4758-66.

Lisowska-Myjak B, Pachecka J, Kaczynska B, Miszkurka G, Kadziela K. Serum protease inhibitor concentrations and total antitrypsin activity in diabetic and non-diabetic children during adolescence. Acta Diabetol. 2006;43(4):88-92.

Chen H, Davids JA, Zheng D, Bryant M, Bot I, van Berckel TJ, et al. The serpin solution; targeting thrombotic and thrombolytic serine proteases in inflammation. Cardiovasc Hematol Disord Drug Targets. 2013;13(2):99-110.

Dhami R, Zay K, Gilks B, Porter S, Wright JL, Churg A. Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium. J Mol Med (Berl). 1999;77(4):377-85.

Shahaf G, Moser H, Ozeri E, Mizrahi M, Abecassis A, Lewis EC. alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection. Molecular medicine. 2011;17(9-10):1000-11.

Subramanian S, Shahaf G, Ozeri E, Miller LM, Vandenbark AA, Lewis EC, et al. 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. 2011;26(2):107-13.

Mizrahi M, Cal P, Rosenthal M, Ochayon D, Shahaf G, Kaner Z, et al. Human alpha1-antitrypsin modifies B-lymphocyte responses during allograft transplantation. Immunology. 2013;140(3):362-73.

Kaner Z, Ochayon DE, Shahaf G, Baranovski BM, Bahar N, Mizrahi M, et al. Acute phase protein alpha1-antitrypsin reduces the bacterial burden in mice by selective modulation of innate cell responses. The Journal of infectious diseases. 2015;211(9):1489-98.

Hurley K, Lacey N, O'Dwyer CA, Bergin DA, McElvaney OJ, O'Brien ME, et al. Alpha-1 antitrypsin augmentation therapy corrects accelerated neutrophil apoptosis in deficient individuals. Journal of immunology. 2014;193(8):3978-91.

Miyamoto Y, Akaike T, Alam MS, Inoue K, Hamamoto T, Ikebe N, et al. Novel functions of human alpha(1)-protease inhibitor after S-nitrosylation: inhibition of cysteine protease and antibacterial activity. Biochem Biophys Res Commun. 2000;267(3):918-23.

Pott GB, Beard KS, Bryan CL, Merrick DT, Shapiro L. Alpha-1 antitrypsin reduces severity of pseudomonas pneumonia in mice and inhibits epithelial barrier disruption and pseudomonas invasion of respiratory epithelial cells. Front Public Health. 2013;1:19.

Nichols DP, Jiang D, Happoldt C, Berman R, Chu HW. Therapeutic Effects of alpha1-Antitrypsin on Psedumonas aeruginosa Infection in ENaC Transgenic Mice. PLoS One. 2015;10(10):e0141232.

Jiang D, Persinger R, Wu Q, Gross A, Chu HW. alpha1-Antitrypsin promotes SPLUNC1-mediated lung defense against Pseudomonas aeruginosa infection in mice. Respir Res. 2013;14:122.

Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, et al. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J. 2007;29(2):240-50.

Rosenlocher J, Sandig G, Kannicht C, Blanchard V, Reinke SO, Hinderlich S. Recombinant glycoproteins: The impact of cell lines and culture conditions on the generation of protein species. J Proteomics. 2016;134:85-92.

McCarthy C, Saldova R, Wormald MR, Rudd PM, McElvaney NG, Reeves EP. The role and importance of glycosylation of acute phase proteins with focus on alpha-1 antitrypsin in acute and chronic inflammatory conditions. J Proteome Res. 2014;13(7):3131-43.

Heegaard PM. Changes in serum glycoprotein glycosylation during experimental inflammation in mice are general, unrelated to protein type, and opposite changes in man and rat: studies on mouse serum alpha 1-acid glycoprotein, alpha 1-esterase, and alpha 1-protease inhibitor. Inflammation. 1992;16(6):631-44.

Wang Z, Hilder TL, van der Drift K, Sloan J, Wee K. Structural characterization of recombinant alpha-1-antitrypsin expressed in a human cell line. Anal Biochem. 2013;437(1):20-8.

Jaberie H, Naghibalhossaini F. Recombinant production of native human alpha-1-antitrypsin protein in the liver HepG2 cells. Biotechnol Lett. 2016;38(10):1683-90.

Wu SR, Reddy P. Tissue Tolerance: a distinct concept to control acute GVHD severity. Blood. 2017.

McElvaney NG. Alpha-1 Antitrypsin Therapy in Cystic Fibrosis and the Lung Disease Associated with Alpha-1 Antitrypsin Deficiency. Ann Am Thorac Soc. 2016;13 Suppl 2:S191-6.

Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H, et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood. 2008;112(4):1461-71.

Al-Omari M, Korenbaum E, Ballmaier M, Lehmann U, Jonigk D, Manstein DJ, et al. Acute-phase protein alpha1-antitrypsin inhibits neutrophil calpain I and induces random migration. Molecular medicine. 2011;17(9-10):865-74.

Surmiak M, Sanak M. Different forms of alpha-1 antitrypsin and neutrophil activation mediated by human anti-PR3 IgG antibodies. Pharmacol Rep. 2016;68(6):1276-84.

O'Dwyer CA, O'Brien ME, Wormald MR, White MM, Banville N, Hurley K, et al. The BLT1 Inhibitory Function of alpha-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling. Journal of immunology. 2015;195(8):3628-41.

Shaul ME, Levy L, Sun J, Mishalian I, Singhal S, Kapoor V, et al. Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology. 2016;5(11):e1232221.

Ozeri E, Mizrahi M, Shahaf G, Lewis EC. alpha-1 antitrypsin promotes semimature, IL-10-producing and readily migrating tolerogenic dendritic cells. Journal of immunology. 2012;189(1):146-53.

Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J, et al. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature. 2008;452(7187):654-8.

Hsieh CC, Chou HS, Yang HR, Lin F, Bhatt S, Qin J, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood. 2013;121(10):1760-8.

Toapanta FR, Ross TM. Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity. Immunol Res. 2006;36(1-3):197-210.

Abecassis A, Schuster R, Shahaf G, Ozeri E, Green R, Ochayon DE, et al. alpha1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation. Cellular & molecular immunology. 2014;11(4):377-86.

Chan ED, Pott GB, Silkoff PE, Ralston AH, Bryan CL, Shapiro L. Alpha-1-antitrypsin inhibits nitric oxide production. J Leukoc Biol. 2012;92(6):1251-60.

Gold M, Dolga AM, Koepke J, Mengel D, Culmsee C, Dodel R, et al. alpha1-antitrypsin modulates microglial-mediated neuroinflammation and protects microglial cells from amyloid-beta-induced toxicity. J Neuroinflammation. 2014;11:165.

van 't Wout EF, van Schadewijk A, Savage ND, Stolk J, Hiemstra PS. alpha1-antitrypsin production by proinflammatory and antiinflammatory macrophages and dendritic cells. Am J Respir Cell Mol Biol. 2012;46(5):607-13.

Gupta VK, Gowda LR. Alpha-1-proteinase inhibitor is a heparin binding serpin: molecular interactions with the Lys rich cluster of helix-F domain. Biochimie. 2008;90(5):749-61.

Rein CM, Desai UR, Church FC. Serpin-glycosaminoglycan interactions. Methods Enzymol. 2011;501:105-37.

Karnaukhova E, Krupnikova SS, Rajabi M, Alayash AI. Heme binding to human alpha-1 proteinase inhibitor. Biochim Biophys Acta. 2012;1820(12):2020-9.

Baker MA, Schneider EK, J XH, Cooper MA, Li J, Velkov T. The Plasma Protein Binding Proteome of Ertapenem: A Novel Compound-Centric Proteomic Approach for Elucidating Drug-Plasma Protein Binding Interactions. ACS Chem Biol. 2016;11(12):3353-64.

Frenzel E, Wrenger S, Brugger B, Salipalli S, Immenschuh S, Aggarwal N, et al. alpha1-Antitrypsin Combines with Plasma Fatty Acids and Induces Angiopoietin-like Protein 4 Expression. Journal of immunology. 2015;195(8):3605-16.

Ortiz-Munoz G, Houard X, Martin-Ventura JL, Ishida BY, Loyau S, Rossignol P, et al. HDL antielastase activity prevents smooth muscle cell anoikis, a potential new antiatherogenic property. FASEB J. 2009;23(9):3129-39.

Miyazaki Y, Katanasaka Y, Sunagawa Y, Hirano-Sunagawa S, Funamoto M, Morimoto E, et al. Effect of statins on atherogenic serum amyloid A and alpha1-antitrypsin low-density lipoprotein complexes. Int J Cardiol. 2016;225:332-6.

Komiyama M, Wada H, Ura S, Yamakage H, Satoh-Asahara N, Shimada S, et al. The effects of weight gain after smoking cessation on atherogenic alpha1-antitrypsin-low-density lipoprotein. Heart Vessels. 2015;30(6):734-9.

Karlsson H, Mortstedt H, Lindqvist H, Tagesson C, Lindahl M. Protein profiling of low-density lipoprotein from obese subjects. Proteomics Clin Appl. 2009;3(6):663-71.

Diffenderfer MR, Schaefer EJ. The composition and metabolism of large and small LDL. Curr Opin Lipidol. 2014;25(3):221-6.

Bristow CL, Modarresi R, Babayeva MA, LaBrunda M, Mukhtarzad R, Trucy M, et al. A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection. Discov Med. 2013;16(89):201-18.

Kotani K, Yamada T, Taniguchi N. The association between adiponectin, HDL-cholesterol and alpha1-antitrypsin-LDL in female subjects without metabolic syndrome. Lipids Health Dis. 2010;9:147.

Moreno JA, Ortega-Gomez A, Rubio-Navarro A, Louedec L, Ho-Tin-Noe B, Caligiuri G, et al. High-density lipoproteins potentiate alpha1-antitrypsin therapy in elastase-induced pulmonary emphysema. Am J Respir Cell Mol Biol. 2014;51(4):536-49.

Shephard EG, de Beer FC, de Beer MC, Jeenah MS, Coetzee GA, van der Westhuyzen DR. Neutrophil association and degradation of normal and acute-phase high-density lipoprotein 3. Biochem J. 1987;248(3):919-26.

Subramaniyam D, Zhou H, Liang M, Welte T, Mahadeva R, Janciauskiene S. Cholesterol rich lipid raft microdomains are gateway for acute phase protein, SERPINA1. Int J Biochem Cell Biol. 2010;42(9):1562-70.

Lockett AD, Petrusca DN, Justice MJ, Poirier C, Serban KA, Rush NI, et al. Scavenger receptor class B, type I-mediated uptake of A1AT by pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2015;309(4):L425-34.

Yang H, Geiger M. Cell penetrating SERPINA5 (ProteinC inhibitor, PCI): More questions than answers. Semin Cell Dev Biol. 2017;62:187-93.

Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1(1):31-9.

Matko J, Szollosi J. Landing of immune receptors and signal proteins on lipid rafts: a safe way to be spatio-temporally coordinated? Immunol Lett. 2002;82(1-2):3-15.

Murray RZ, Stow JL. Cytokine Secretion in Macrophages: SNAREs, Rabs, and Membrane Trafficking. Front Immunol. 2014;5:538.

Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4(6):469-78.

Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.

Breit SN, Penny R. The role of alpha 1 protease inhibitor (alpha 1 antitrypsin) in the regulation of immunologic and inflammatory reactions. Aust N Z J Med. 1980;10(4):449-53.

Arora PK, Miller HC, Aronson LD. alpha1-Antitrypsin is an effector of immunological stasis. Nature. 1978;274(5671):589-90.

Lipsky JJ, Berninger RW, Hyman LR, Talamo RC. Presence of alpha-1-antitrypsin on mitogen-stimulated human lymphocytes. Journal of immunology. 1979;122(1):24-6.

Ehlers MR. Immune-modulating effects of alpha-1 antitrypsin. Biol Chem. 2014;395(10):1187-93.

Karnaukhova E, Ophir Y, Golding B. Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use. Amino Acids. 2006;30(4):317-32.

Spencer LT, Humphries JE, Brantly ML, Transgenic Human Alpha 1-Antitrypsin Study G. Antibody response to aerosolized transgenic human alpha1-antitrypsin. N Engl J Med. 2005;352(19):2030-1.

Balbi B, Ferrarotti I, Miravitlles M. Efficacy of augmentation therapy for emphysema associated with alpha1-antitrypsin deficiency: enough is enough. Eur Respir J. 2016;47(1):35-8.

Chiuchiolo MJ, Crystal RG. Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease. Ann Am Thorac Soc. 2016;13 Suppl 4:S352-69.

Sondhi D, Stiles KM, De BP, Crystal RG. Genetic Modification of the Lung Directed Toward Treatment of Human Disease. Hum Gene Ther. 2017;28(1):3-84.

Gruntman AM, Flotte TR. Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency. Hum Gene Ther Methods. 2015;26(3):77-81.

Loring HS, Flotte TR. Current status of gene therapy for alpha-1 antitrypsin deficiency. Expert Opin Biol Ther. 2015;15(3):329-36.

Calcedo R, Somanathan S, Qin Q, Betts MR, Rech AJ, Vonderheide RH, et al. Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for alpha-1-antitrypsin deficiency. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(7):1655-9.

Schnepp BC, Chulay JD, Ye GJ, Flotte TR, Trapnell BC, Johnson PR. Recombinant Adeno-Associated Virus Vector Genomes Take the Form of Long-Lived, Transcriptionally Competent Episomes in Human Muscle. Hum Gene Ther. 2016;27(1):32-42.

Lu Y, Tang M, Wasserfall C, Kou Z, Campbell-Thompson M, Gardemann T, et al. Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice. Hum Gene Ther. 2006;17(6):625-34.

Song S, Goudy K, Campbell-Thompson M, Wasserfall C, Scott-Jorgensen M, Wang J, et al. Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice. Gene Ther. 2004;11(2):181-6.

Yokoo T, Kamimura K, Abe H, Kobayashi Y, Kanefuji T, Ogawa K, et al. Liver-targeted hydrodynamic gene therapy: Recent advances in the technique. World J Gastroenterol. 2016;22(40):8862-8.

Khorsandi SE, Bachellier P, Weber JC, Greget M, Jaeck D, Zacharoulis D, et al. Minimally invasive and selective hydrodynamic gene therapy of liver segments in the pig and human. Cancer Gene Ther. 2008;15(4):225-30.

Dul M, Stefanidou M, Porta P, Serve J, O'Mahony C, Malissen B, et al. Hydrodynamic gene delivery in human skin using a hollow microneedle device. J Control Release. 2017.

Sclar DA, Evans MA, Robison LM, Skaer TL. alpha1-Proteinase inhibitor (human) in the treatment of hereditary emphysema secondary to alpha1-antitrypsin deficiency: number and costs of years of life gained. Clin Drug Investig. 2012;32(5):353-60.

Alkins SA, O'Malley P. Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis. Chest. 2000;117(3):875-80.

Ashkenazi E, Baranovski BM, Shahaf G, Lewis EC. Pancreatic islet xenograft survival in mice is extended by a combination of alpha-1-antitrypsin and single-dose anti-CD4/CD8 therapy. PLoS One. 2013;8(5):e63625.

Iwase H, Liu H, Li T, Zhang Z, Gao B, Hara H, et al. Therapeutic regulation of systemic inflammation in xenograft recipients. Xenotransplantation. 2017.

Leveque D. Off-label use of targeted therapies in oncology. World J Clin Oncol. 2016;7(2):253-7.

Blanco-Reina E, Medina-Claros AF, Vega-Jimenez MA, Ocana-Riola R, Marquez-Romero EI, Ruiz-Extremera A. Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit. Med Intensiva. 2016;40(1):1-8.

Maltz LA, Klugman D, Spaeder MC, Wessel DL. Off-label drug use in a single-center pediatric cardiac intensive care unit. World J Pediatr Congenit Heart Surg. 2013;4(3):262-6.

Henry V. Off-label prescribing. Legal implications. J Leg Med. 1999;20(3):365-83.

Akers KG. New journals for publishing medical case reports. J Med Libr Assoc. 2016;104(2):146-9.

Lotfi Shahreza M, Ghadiri N, Mousavi SR, Varshosaz J, Green JR. A review of network-based approaches to drug repositioning. Brief Bioinform. 2017.

Amantea D, Bagetta G. Drug repurposing for immune modulation in acute ischemic stroke. Curr Opin Pharmacol. 2016;26:124-30.

Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med. 1987;316(17):1055-62.

DOI: http://dx.doi.org/10.18103/imr.v3i5.451


  • There are currently no refbacks.
Copyright 2016. All rights reserved.