- Open Access
Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema
© Blanco et al; licensee BioMed Central Ltd. 2011
Received: 21 September 2010
Accepted: 12 April 2011
Published: 12 April 2011
Up to now alpha 1-antitrypsin (AAT) augmentation therapy has been approved only for commercial use in selected adults with severe AAT deficiency-related pulmonary emphysema (i.e. PI*ZZ genotypes as well as combinations of Z, rare and null alleles expressing AAT serum concentrations <11 μmol/L). However, the compassionate use of augmentation therapy in recent years has proven outstanding efficacy in small cohorts of patients suffering from uncommon AAT deficiency-related diseases other than pulmonary emphysema, such as fibromyalgia, systemic vasculitis, relapsing panniculitis and bronchial asthma. Moreover, a series of preclinical studies provide evidence of the efficacy of AAT augmentation therapy in several infectious diseases, diabetes mellitus and organ transplant rejection. These facts have generated an expanding number of medical applications and patents with claims for other indications of AAT besides pulmonary emphysema. The aim of the present study is to compile and analyze both clinical and histological features of the aforementioned published case studies and reports where AAT augmentation therapy was used for conditions other than pulmonary emphysema. Particularly, our research refers to ten case reports and two clinical trials on AAT augmentation therapy in patients with both AAT deficiency and, at least, one of the following diseases: fibromyalgia, vasculitis, panniculitis and bronchial asthma. In all the cases, AAT was successfully applied whereas previous maximal conventional therapies had failed. In conclusion, laboratory studies in animals and humans as well as larger clinical trials should be, thus, performed in order to determine both the strong clinical efficacy and security of AAT in the treatment of conditions other than pulmonary emphysema.
Alpha1-antitrypsin (AAT) deficiency is an autosomal, codominant genetic disorder, characterized by the polymerization of abnormal, misfolded proteins in the rough endoplasmic reticulum of hepatocytes and, secondarily, a decreased concentration and activity of AAT in blood and tissues. Although several degrees of AAT deficiency are quite common worldwide, severe deficiency (i.e. AAT serum levels below 11 μmol or 50 mg/dL) represents a rare condition affecting 1 per 2,000-5,000 Caucasian individuals of Western European origin, with about a quarter or half of them developing clinically significant diseases [1, 2].
Human alpha-1 antitrypsin (AAT), also called alpha-1 proteinase inhibitor (PI), and SERPINA1 (Serine Protease Inhibitor, clade A, member 1), is a 394-amino acid, circulating glycoprotein with a molecular weigh of 52-kDa. AAT is medium sized and globular in shape (6.7 × 3.2 nm), water soluble and diffusible into different tissues, with an average of 4-5 day life span in circulating blood. AAT is mainly secreted by hepatocytes (~80%) and, to a minor extent, by monocytes, pancreatic islets, lung alveolar cells and colonic enterocytes, reaching high mean concentrations in plasma (1-2 g/L). Eighty percent of plasmatic protein diffuses into different body tissues and approximately 10% reaches most biological fluids .
Extensive data show that the major function of AAT is the inhibition of over-expressed neutrophil elastase and other serine proteinases (i.e. proteinase-3, myeloperoxidase and cathepsin G from neutrophils, tryptase and chymase from mast cells, etc.) in order to maintain the physiological proteinase-antiproteinase balance [4–34]. Moreover, an increasing number of new inhibitory and non-inhibitory properties conferring to ATT outstanding anti-inflammatory, inmunomodulatory and antimicrobial attributes have been discovered in later years, together with the fact that AAT activity is not only limited to lungs but also to most body tissues [35–38].
AAT gene has two alleles. Normal alleles are called M; thus, normal individuals have genotype MM. The most common severe deficiency allele is called Z (Glu342Lys); in clinical practice over 95% of severely deficiency patients have genotype ZZ (expressing 10-20% of serum AAT). The remaining 5% belongs to patients with genotype SZ and about 30 rare deficiency and null phenotypes, expressing 0-30% AAT serum levels. Most common diseases related to severe AAT-deficiency are pulmonary emphysema (found in around 3% of adults with COPD), liver cirrhosis (2.5% of children and 10-20% of PI*Z adult homozygotes), systemic vasculitis (7%) and relapsing panniculitis (0.1%) [3, 39, 40].
In 1987 the Food and Drug Administration (FDA) published the first guidelines on augmentation therapy with intravenous infusions of purified AAT obtained from human serum of adults suffering from moderate pulmonary emphysema (FEV1 30-65%) and severe AAT deficiency (i.e. PI*ZZ genotypes and combinations of Z, rare and null alleles expressing AAT serum concentrations < 11 μmol or 50 mg/dL) . Taking into account scientific evidence and knowledge, the American Thoracic Society, the European Respiratory Society, the American College of Chest Physicians and the American Association for Respiratory Care recommend augmentation therapy for selected patients with lung emphysema. Augmentation therapy not only has been approved in the US but also in Germany, Canada, Italy, Spain, Austria, Ukraine, Argentina and Brazil, with similar criteria of use [3, 42–52].
In the last years, preclinical studies in cells, animal models and small cohorts of humans provided initial evidence for the efficacy of AAT in several infectious diseases, diabetes mellitus, organ transplant rejection and other possible inflammatory diseases [38, 53–60]. As a consequence, the number of medical applications and patents for other indications of AAT other than pulmonary emphysema is increasing http://www.omnibiopharma.com/development. In this context, clinical observations describing the remarkable (even impressive) efficacy of the augmentation therapy in AAT deficiency patients with fibromyalgia, systemic vasculitis, panniculitis and bronchial asthma have also been reported [61–70]. According to Jenicek's statement on clinical case reporting, these observations should be taken into account: "Although a case report has the weakest level of Evidence Based Medicine, sometimes an unusual case may become an "index case", and it may lead to the formulation of new hypothesis on diagnostic and therapeutic options". The aim of the present manuscript is to compile published case reports and small trials where augmentation therapy was provided, on a compassionate basis, to humans with disorders other than pulmonary emphysema and to discuss their results in the light of current knowledge on AAT deficiency-related disorders.
Firstly, a research on the MEDLINE database (1966-2010) was made using the generic terms: "alpha-1 antitrypsin", "alpha-1-proteinase inhibitor" and "alpha-1 antitrypsin deficiency" and combining them with one of the following key concepts: "augmentation therapy", "replacement therapy", "treatment". Afterwards, a more specific search was carried out adding to the previous terms one of the following terms: "infectious diseases", "inflammatory diseases", "associated diseases", ("NOT emphysema"), "fibromyalgia", "human immunodeficiency virus", "HIV", panniculitis", "vasculitis", "bronchial asthma", "graft rejection", "diabetes", "influenza", "tuberculosis" and "anthrax". We also consulted EMBASE Excerpta Medica, SciVerse Scopus and the Cochrane Library databases in order to search for abstracts of similar types of papers, as well as bibliographic references of previously retrieved articles, authors' databases and reviews from several experts on this topic.
Only reports related to human beings were selected. Studies on augmentation therapy for pulmonary emphysema have not been included in the present analysis, considering this topic to be out of the scope of the present manuscript.
Ten case reports [61–68] and two clinical trials [69, 70] have been found on intravenous AAT augmentation therapy in 12 patients with both AAT deficiency and one of the following diseases: vasculitis, panniculitis, fibromyalgia and bronchial asthma. Ten of these 12 treated patients had genotype PI*ZZ [61–68] and the remaining 2, PI*MZ.[69, 70].
In the same context, the results of two liver transplants in PI*ZZ patients with end-stage liver cirrhosis and AAT deficiency-related panniculitis will be summarized. In both cases, a rapid and steady control of panniculitis was observed after the replacement of each damaged liver by a new efficient organ, restoring AAT serum levels back to normal. The first case was reported in 1997 by O'Riordan et al. (Northwestern University Medical School, Chicago, IL, USA) . Authors observed evolution in "a 53-year old man...ZZ (AAT: 17 mg/100 ml)...with end-stage liver cirrhosis and relapsing panniculitis... [who] received a liver transplant. His new phenotype was PI*MM... and serum AAT of 153 mg/dL. One month after...a complete resolution of the skin lesions" was noticed.
The second case was reported by Fernandez-Torre et al. from the Hospital Juan Canalejo, La Coruña, Spain, in 2009 . On the contrary, authors noticed alterations in "A 56-year-old MM patient [who] acquired a ZZ phenotype after a liver transplant for alcoholic liver cirrhosis. Subsequently, he developed cirrhosis and panniculitis. Liver transplantation was again performed, with complete resolution of the skin lesions and restoration of AAT serum levels (from 28 to 270 mg/dl)...11 months later he remains asymptomatic".
In the same context, de Oliveira et al. (São Paulo, Brazil) published in 2004 the case of a 23-year-old patient with extensive, ulcerative relapsing panniculitis, and AAT serum levels of 22 mg/dL and phenotype ZZ . The patient was treated with 16 sessions of plasma exchange therapy, with cutaneous lesions clinically controlled after five sessions. AAT increased to 60 mg/dL after the first session, slowly decreasing to initial levels in approximately 15 days until the next plasma infusion (when AAT levels increased again and, thus, relapses were promptly controlled). This case shows many similarities with the first report on the use of plasma exchange therapy in panniculitis, made in 1986 by Viraben et al. , who used fresh plasma every other day for 2 weeks, with dramatic effectiveness. Both authors consider plasma exchange as an effective therapeutic alternative for unresponsive patients to conventional treatments, thus highlighting the necessity of further studies with a larger number of individuals.
At present, the 3 patients continue to be under long-term AAT augmentation therapy with successful results.
4. Bronchial asthma
AAT deficiency is a congenital disorder with a remarkable variability in its clinical presentation : some subjects can develop liver cirrhosis and others pulmonary emphysema; to a minor extent, they can also develop panniculitis, vasculitis, bronchial asthma or fibromyalgia; and more than one third of the remaining carriers can stay symptomless their entire life.
The 12 subjects mentioned in the present paper suffered from less common AAT deficiency-related diseases (i.e. leukocitoclastic vasculitis; relapsing panniculitis, fibromyalgia, and refractory asthma). All these patients have in common AAT deficiency genotypes (10 ZZ, 2 MZ). Also they all experienced a positive response to intravenous AAT augmentation therapy, applied on a compassionate basis as the last resource after the repetitive failure of conventional therapies and the extremely difficult clinical control of AAT deficiency-related diseases (life-threatening in some cases).
The skin samples of the patient with leukocytoclastic vasculitis related to ZZ AAT deficiency showed acute and chronic inflammation. Neither anti-neutrophil cytoplasmic antibodies (ANCA) nor anti-neutrophil enzyme proteinase 3 (PR3-ANCA) antibodies were analyzed. Although the pathophysiological mechanisms of vasculitis have not been determined yet, they seem to be related to inflammatory mechanisms mediated by neutrophil invasion of the small and medium vessels. The excess of proteinase-3, not neutralized by AAT, could also play an important role in AAT deficiency subjects with antineutrophilic cytoplasmatic antibody C-ANCA positive vasculitis. Since AAT is a major inhibitor of PR3, the PR3-AAT imbalance in AAT deficiency-related vasculitis could lead to increased circulating levels of PR3 and trigger the synthesis of PR3-ANCA antibodies . AAT deficiency-related vasculitis would be, therefore, restricted to PR3-ANCA-positive cases and not to less common occurrences of MPO-positive or ANCA-negative cases. On the other hand, patients with both vasculitis and AAT deficiency have been reported to have a reduced ability to bind PR3 released by neutrophils previously activated, thus promoting PR3-mediated proteolytic vessel damage. Actually, several findings show that the disease course of Wegener's granulomatosis (WG) is more severe when it is related to AAT deficiency than when it is not. This supports the hypothesis that AAT deficiency could trigger vasculitis by means of PR3-ANCA autoimmunity . The role of circulating Z polymers, attacking the endothelial walls of blood vessels and promoting vasculitic responses, has not been determined yet nor whether all patients with manifestations of vasculitis and severe AAT deficiency could benefit from AAT augmentation therapy. However, the administration of this glycoprotein seems to be logical for selected cases of AAT deficiency-related refractory vasculitis.
The pathophysiological mechanisms of panniculitis in AAT deficiency subjects have not been determined yet. As some hypotheses suggest an inflammatory process mediated by neutrophils invading the subcutaneous fat layer, the most logical mechanism seems to be the unopposed anti-inflammatory proteolytic damage by neutrophil-serine proteinases in the context of deficient serum levels of AAT . In one of the aforementioned cases of the present study, Z polymers were found in both active lesions and surrounding non-inflamed tissues, suggesting a potential pro-inflammatory role of polymers in the development of panniculitis. The histological features of panniculitis, especially neutrophil invasion, could explain the rapid clinical resolution of inflammation with AAT augmentation therapy. Therefore, its application should be tried in cases which fail to respond to conventional therapeutic approaches.
Fibromyalgia syndrome is characterized by the central amplification of sensory impulses (central sensitization) causing autonomic, hormonal, immune and cytokine interactions and perturbations. Fibromyalgia can result from the disordered expression of inflammatory substances, amplified by genetic factors. Recent evidence indicates that fibromyalgia can be added to the list of AAT deficiency-related diseases. Main evidence elements include: (I) The short and long-term repetitive positive response to AAT augmentation therapy showed by the three aforementioned patients with both AAT deficiency and fibromyalgia [68, 69]. (II) An epidemiological study showing a twofold higher frequency of PI*Z allele in fibromyalgia patients than in general population (4% vs. 2%), with a calculated prevalence of MZ, SZ and ZZ deficiency genotypes being 2-4 times higher in fibromyalgia patients than in general population . Therefore, AAT deficiency should be considered as a predisposing factor for the development of early and severe onset of fibromyalgia in a subgroup of patients with AAT serum levels lower than normal (7% MZ, 0.5% SZ and 0.2% ZZ). (III) A case-control study showing plasma levels of MCP-1, VEGF and TNF-alpha significantly lower in AAT deficiency subjects with fibromyalgia than in controls . (IV) A blinded inmunohistochemical study of skin biopsies performed in 112 subjects (63 fibromyalgia vs. 49 controls) with AAT normal and deficient genotypes. The results showed a significantly increased number of mast cells in the dermis of fibromyalgia patients, with a proportion fibromyalgia/controls of about 5:1 cells per microscopic high power field (p = 0.000) . Mastocytes positively stained with tryptase, AAT and PAR-2 antibodies as well as with a kit receptor marker (CD117) and a cell activation marker (CD63), showing that about 50-80% of these mastocytes were activated. Remarkably, the skin samples of the 3 patients under long-term AAT augmentation therapy did not show any clinical fibromyalgia manifestations but also an increased number of dermal mast cells. Therefore, exogenous AAT could serve as a mast cell stabiliser and, as demonstrated in some laboratory studies, as a neutraliser of certain mast cells mediators (i.e. histamine and serine proteinases, such as tryptase and chymase) [17–19]. AAT augmentation therapy should be considered to treat selected cases of AAT deficiency-related refractory fibromyalgia not responding to conventional therapeutic measures, and larger trials are needed to determine the strong clinical efficacy of AAT in fibromyalgia patients.
Histological samples from airways were not collected in the case of the patient with bronchial asthma. However, it is worth noting that severe asthma is considered as an inflammatory airway disease related to sub-acute and chronic inflammation maintained by eosinophils, mastocytes, dendritic, epithelial and endothelial cells, basophiles, T lymphocytes, macrophages and neutrophils. Therefore, AAT could also play a determining anti-inflammatory role in counteracting the effects of released oxidants, cytokines, proteinases and other inflammation mediators. Precisely, the imbalance between elastase and AAT in asthmatic subjects has been already described as well as the relation of airway inflammation to abnormal high levels of active elastase, detected in patients' samples of induced sputum . Neutrophil elastase has not only proteolytic properties but also acts as a powerful secretagogue. Particularly, recent evidence indicates the persistence of neutrophilic and eosinophilic inflammation in patients' airways with severe asthma, and the activation by neutrophil proteinases (i.e. elastase, cathepsin G and proteinase-3) of peripheral blood leukocytes in order to produce superoxide and proinflammatory cytokines, which can further aggravate airway inflammation . On the other hand, it is worth mentioning that the airway smooth muscle (ASM) not only has contractile properties but also is involved in the pathogenesis of asthma, producing inflammatory mediators. Human neutrophil elastase is a mitogen which activates ASM cells through extracellular signal-regulated kinase (ERK) signaling pathway . Other interesting study shows that the allergic stimulation of airways provokes the release of elastase, tissue kallikrein (TK) and reactive oxygen species (ROS), reducing AAT activity and contributing to airway hyperreactivity (AHR) . Moreover, the bronchoconstriction caused by elastase, high-molecular-weight kininogen and ROS and AHR induced by both ROS and antigen was stopped thanks to the application of 10 mg of recombinant AAT, suggesting the key role of AAT in regulating airway responsiveness . In conclusion, the positive effects of AAT augmentation therapy observed in this case support the hypothesis of a proteinase-antiproteinase imbalance in the pathogenesis of asthma, reaffirming the need for further studies on the mechanisms of this bronchial disease and the efficacy of AAT augmentation therapy in selected AAT deficiency subjects with refractory asthma.
In summary, all these 12 cases should promote further laboratory studies in animals and humans as well as larger clinical trials in order to determine the strong efficacy of AAT augmentation therapy in diseases other than pulmonary emphysema, especially as a powerful anti-inflammatory agent in processes such as fibromyalgia, vasculitis, panniculitis and bronchial asthma.
The authors would like to acknowledge the expert editorial assistance of Ms Jimena Blanco Fueyo (BA, MA Université de Genève, Switzerland; Pg. D. United Nations Institute for Training and Research).
The authors are also indebted to Ms Sue Edelstein for her invaluable collaboration in the graphic design of this manuscript (Department of Arts and Photography of the National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, U.S.).
- Blanco I, de Serres FJ, Fernandez-Bustillo E, Lara B, Miravitlles M: Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J. 2006, 27 (1): 77-84. 10.1183/09031936.06.00062305.PubMedGoogle Scholar
- de Serres FJ, Blanco I, Fernández-Bustillo E: PI S and PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis. 2007, 67 (4): 184-208.PubMedGoogle Scholar
- American Thoracic Society/European Respiratory Society Statement: standards for the diagnosis and management of individuals with alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2003, 168 (7): 818-900. 10.1164/rccm.168.7.818.Google Scholar
- Janciauskiene S, Stevens T, Blanco I: New insights into the biology of alpha1-antitrypsin and its role in chronic obstructive pulmonary disease. Current Respiratory Medicine Reviews. 2007, 3: 147-158. 10.2174/157339807780599153.Google Scholar
- Janoff A: Inhibition of human granulocyte elastase by serum alpha-1-antitrypsin. Am Rev Respir Dis. 1972, 105 (1): 121-2.PubMedGoogle Scholar
- Lieberman J, Kaneshiro W: Inhibition of leukocytic elastase from purulent sputum by alpha 1-antitrypsin. J Lab Clin Med. 1972, 80 (1): 88-101.PubMedGoogle Scholar
- Travis J, Salvesen GS: Human plasma proteinase inhibitors. Annu Rev Biochem. 1983, 52: 655-709. 10.1146/annurev.bi.52.070183.003255.PubMedGoogle Scholar
- Potempa J, Korzus E, Travis J: The serpin superfamily of proteinase inhibitors: structure, function and regulation. J Biol Chem. 1994, 269 (23): 15957-60.PubMedGoogle Scholar
- Stockley RA, Burnett D: Alpha,-antitrypsin and leukocyte elastase in infected and noninfected sputum. Am Rev Respir Dis. 1979, 120 (5): 1081-6.PubMedGoogle Scholar
- Korkmaz B, Attucci S, Jourdan ML, Juliano L, Gauthier F: Inhibition of neutrophil elastase by alpha1-protease inhibitor at the surface of human polymorphonuclear neutrophils. J Immunol. 2005, 175 (5): 3329-3338.PubMedGoogle Scholar
- Duranton J, Bieth JG: Inhibition of proteinase 3 by [alpha]1-antitrypsin in vitro predicts very fast inhibition in vivo. Am J Respir Cell Mol Biol. 2003, 29 (1): 57-61. 10.1165/rcmb.2002-0258OC.PubMedGoogle Scholar
- Rao NV, Wehner NG, Marshall BC, Gray WR, Gray BH, Hoidal JR, Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase: Structural and functional properties. J Biol Chem. 1991, 266 (15): 9540-8.PubMedGoogle Scholar
- Borregaard N, Jensen HS, Bjerrum OW: Prevention of tissue damage: inhibition of myeloperoxidase mediated inactivation of alpha 1-proteinase inhibitor by N-acetyl cysteine, glutathione, and methionine. Agents Actions. 1987, 22 (3-4): 255-60. 10.1007/BF02009054.PubMedGoogle Scholar
- Campbell EJ, Senior RM, McDonald JA, Cox DL: Proteolysis by neutrophils. Relative importance of cell-substrate contact and oxidative inactivation of proteinase inhibitors in vitro. J Clin Invest. 1982, 70 (4): 845-52. 10.1172/JCI110681.PubMed CentralPubMedGoogle Scholar
- Duranton J, Adam C, Bieth JG: Kinetic mechanism of the inhibition of cathepsin G by alpha 1-antichymotrypsin and alpha 1-proteinase inhibitor. Biochemistry. 1998, 37 (32): 11239-45. 10.1021/bi980223q.PubMedGoogle Scholar
- Rowley PT, Sevilla ML, Schwartz H: Serum alpha-antitrypsin types: elastase inhibition versus trypsin inhibition. Hum Hered. 1974, 24 (5-6): 472-81. 10.1159/000152685.PubMedGoogle Scholar
- He SH, Chen HQ, Zheng J: Inhibition of tryptase and chymase induced nucleated cell infiltration by proteinase inhibitors. Acta Pharmacol Sin. 2004, 25 (12): 1677-84.PubMedGoogle Scholar
- He SH, Xie H, Zhang XJ, Wang XJ: Inhibition of histamine release from human mast cells by natural chymase inhibitors. Acta Pharmacol Sin. 2004, 25 (6): 822-6.PubMedGoogle Scholar
- He SH, Xie H: Inhibition of tryptase release from human colon mast cells by protease inhibitors. World J Gastroenterol. 2004, 10 (3): 332-6.PubMedGoogle Scholar
- Pemberton AD, Belham CM, Huntley JF, Plevin R, Miller HR: Sheep mast cell proteinase-1, a serine proteinase with both tryptase- and chymase-like properties, is inhibited by plasma proteinase inhibitors and is mitogenic for bovine pulmonary artery fibroblasts. Biochem J. 1997, 323 (Pt 3): 719-25.PubMed CentralPubMedGoogle Scholar
- 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. 1980, 255 (9): 3931-4.PubMedGoogle Scholar
- Cohen AB: The interaction of alpha-1-antitrypsin with chymotrypsin, trypsin and elastase. Biochim Biophys Acta. 1975, 391 (1): 193-200.PubMedGoogle Scholar
- Patston PA, Roodi N, Schifferli JA, Bischoff R, Courtney M, Schapira M: Reactivity of alpha 1-antitrypsin mutants against proteolytic enzymes of the kallikrein-kinin, complement, and fibrinolytic systems. J Biol Chem. 1990, 265 (18): 10786-91.PubMedGoogle Scholar
- Luo LY, Jiang W: Inhibition profiles of human tissue kallikreins by serine protease inhibitors. Biol Chem. 2006, 387 (6): 813-6. 10.1515/BC.2006.103.PubMedGoogle Scholar
- Obiezu CV, Michael IP, Levesque MA, Diamandis EP: Human kallikrein 4: enzymatic activity, inhibition, and degradation of extracellular matrix proteins. Biol Chem. 2006, 387 (6): 749-59. 10.1515/BC.2006.094.PubMedGoogle Scholar
- Patston PA, Roodi N, Schifferli JA, Bischoff R, Courtney M, Schapira M, Clemmensen I, Christensen F: Inhibition of urokinase by complex formation with human alpha1-antitrypsin. Biochim Biophys Acta. 1976, 429 (2): 591-9.Google Scholar
- Mast AE, Enghild JJ, Pizzo SV, Salvesen G: Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry. 1991, 30 (6): 1723-30. 10.1021/bi00220a039.PubMedGoogle Scholar
- Gallimore MJ: Serum inhibitors in fibrinolysis. Br J Haematol. 1975, 31 (2): 217-31. 10.1111/j.1365-2141.1975.tb00852.x.PubMedGoogle Scholar
- Stefansson S, Yepes M, Gorlatova N, Day DE, Moore EG, Zabaleta A, McMahon GA, Lawrence DA: Mutants of plasminogen activator inhibitor-1 designed to inhibit neutrophil elastase and cathepsin G are more effective in vivo than their endogenous inhibitors. J Biol Chem. 2004, 279 (29): 29981-7. 10.1074/jbc.M401913200.PubMedGoogle Scholar
- Spencer LT, Paone G, Krein PM, Rouhani FN, Rivera-Nieves J, Brantly ML: Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency. Am J Physiol Lung Cell Mol Physiol. 2004, 286 (3): L514-20. 10.1152/ajplung.00099.2003.PubMedGoogle Scholar
- Wencker M, Brantly ML: Cytotoxic concentrations of alpha-defensins in the lungs of individuals with alpha(1)-antitrypsin deficiency and moderate to severe lung disease. Cytokine. 2005, 32 (1): 1-6. 10.1016/j.cyto.2005.06.003.PubMedGoogle Scholar
- Mahrus S, Kisiel W, Craik CS: Granzyme M is a regulatory protease that inactivates proteinase inhibitor 9, an endogenous inhibitor of granzyme B. J Biol Chem. 2004, 279 (52): 54275-82. 10.1074/jbc.M411482200.PubMedGoogle Scholar
- Janciauskiene S, Nita I, Subramaniyam D, Li Q, Lancaster JR, Matalon S: Alpha1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro. Am J Respir Cell Mol Biol. 2008, 39 (6): 631-7. 10.1165/rcmb.2008-0015RC.PubMed CentralPubMedGoogle Scholar
- Lazrak A, Nita I, Subramaniyam D, Wei S, Song W, Ji HL, Janciauskiene S, Matalon S: Alpha(1)-antitrypsin inhibits epithelial Na+ transport in vitro and in vivo. Am J Respir Cell Mol Biol. 2009, 41 (3): 261-70. 10.1165/rcmb.2008-0384OC.PubMed CentralPubMedGoogle Scholar
- Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Shapiro L, Zhang B, Song S, Hicklin D, Voelkel NF, Flotte T, Tuder RM: A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary Emphysema. Am J Respir Crit Care Med. 2006, 173 (11): 1222-8. 10.1164/rccm.200512-1842OC.PubMed CentralPubMedGoogle Scholar
- Janciauskiene SM, Nita IM, 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. 2007, 282 (12): 8573-82. 10.1074/jbc.M607976200.PubMedGoogle Scholar
- Subramaniyam D, Virtala R, Pawłowski K, Clausen IG, Warkentin S, Stevens T, Janciauskiene S: TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha1-antitrypsin. Int J Biochem Cell Biol. 2008, 40 (2): 258-71. 10.1016/j.biocel.2007.07.016.PubMedGoogle Scholar
- Kalis M, Kumar R, Janciauskiene S, Salehi A, Cilio CM: α 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic β-cells. Islets. 2010, 2 (3): 185-9. 10.4161/isl.2.3.11654.PubMedGoogle Scholar
- Stoller JK, Aboussouan LS: Alpha1-antitrypsin deficiency. Lancet. 2005, 365 (9478): 2225-36. 10.1016/S0140-6736(05)66781-5.PubMedGoogle Scholar
- Mahr AD, Edberg JC, Stone JH, Hoffman GS, St Clair EW, Specks U, Dellaripa PF, Seo P, Spiera RF, Rouhani FN, Brantly ML, Merkel PA: Alpha(1) -antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. Arthritis Rheum. 2010, 62 (12): 3760-7. 10.1002/art.27742.PubMed CentralPubMedGoogle Scholar
- Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Crystal RG: Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med. 1987, 316 (17): 1055-62. 10.1056/NEJM198704233161704.PubMedGoogle Scholar
- Gadek JE, Klein HG, Holland PV, Crystal RG: Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest. 1981, 68 (5): 1158-65. 10.1172/JCI110360.PubMed CentralPubMedGoogle Scholar
- Seersholm N, Wencker M, Banik N, Viskum K, Dirksen A, Kok-Jensen A, Konietzko N: Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J. 1997, 10 (10): 2260-3. 10.1183/09031936.97.10102260.PubMedGoogle Scholar
- No authors listed: Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1998, 158 (1): 49-59.Google Scholar
- Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DC, Ulrik CS, Skovgaard LT, Kok-Jensen A, Rudolphus A, Seersholm N, Vrooman HA, Reiber JH, Hansen NC, Heckscher T, Viskum K, Stolk J: A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med. 1999, 160 (5 Pt 1): 1468-72.PubMedGoogle Scholar
- Wencker M, Fuhrmann B, Banik N, Konietzko N, Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen: Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest. 2001, 119 (3): 737-44. 10.1378/chest.119.3.737.PubMedGoogle Scholar
- Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, Stockley RA: Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha-1 antitrypsin deficiency. Eur Respir J. 2009, 33 (6): 1345-53. 10.1183/09031936.00159408.PubMedGoogle Scholar
- [No authors listed]: Current status of alpha-1-antitrypsin replacement therapy: recommendations for the management of patients with severe hereditary deficiency. Ad Hoc Committee on Alpha-1-Antitrypsin Replacement Therapy of the Standards Committee, Canadian Thoracic Society. CMAJ. 1992, 146 (6): 841-4.Google Scholar
- Vidal R, Blanco I, Casas F, Jardí R, Miravitlles M, Committee on the National Registry of Individuals with Alpha-1 Antitrypsin Deficiency: [Guidelines for the diagnosis and management of alpha-1 antitrypsin deficiency]. Arch Bronconeumol. 2006, 42 (12): 645-59.PubMedGoogle Scholar
- Gøtzsche PC, Johansen HK: Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2010, 7:CD007851.PubMedGoogle Scholar
- Tonelli AR, Brantly ML: Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010, 4 (5): 289-312. 10.1177/1753465810373911.PubMedGoogle Scholar
- Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A: Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res. 2010, 11:136. 10.1186/1465-9921-11-136.PubMed CentralPubMedGoogle Scholar
- Shapiro L, Pott GB, Ralston AH: Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J. 2001, 15 (1): 115-122. 10.1096/fj.00-0311com.PubMedGoogle Scholar
- Hadzic R, Nita I, Tassidis H, Riesbeck K, Wingren AG, Janciauskiene S: Alpha1-antitrypsin inhibits Moraxella catarrhalis MID protein-induced tonsillar B cell proliferation and IL-6 release. Immunol Lett. 2006, 102 (2): 141-7. 10.1016/j.imlet.2005.08.006.PubMedGoogle Scholar
- Knappstein S, Ide T, Schmidt MA, Heusipp G: Alpha 1-antitrypsin binds to and interferes with functionality of EspB from atypical and typical enteropathogenic Escherichia coli strains. Infect Immun. 2004, 72 (8): 4344-50. 10.1128/IAI.72.8.4344-4350.2004.PubMed CentralPubMedGoogle Scholar
- Cantin AM, Woods DE: Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med. 1999, 160 (4): 1130-5.PubMedGoogle Scholar
- Chan ED, Kaminska AM, Gill W, Chmura K, Feldman NE, Bai X, Floyd CM, Fulton KE, Huitt GA, Strand MJ, Iseman MD, Shapiro L: 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. 2007, 39 (8): 690-6. 10.1080/00365540701225744.PubMedGoogle Scholar
- Lushbaugh WB, Kairalla AB, Hofbauer AF, Arnaud P, Cantey JR, Pittman FE: Inhibition of Entamoeba histolytica cytotoxin by alpha 1 antiprotease and alpha 2 macroglobulin. Am J Trop Med Hyg. 1981, 30 (3): 575-85.PubMedGoogle Scholar
- Forney JR, Yang S, Healey MC: Antagonistic effect of human alpha-1-antitrypsin on excystation of Cryptosporidium parvum oocysts. J Parasitol. 1997, 83 (4): 771-4. 10.2307/3284264.PubMedGoogle Scholar
- Daemen MA, Heemskerk VH, van't Veer C, Denecker G, Wolfs TG, Vandenabeele P, Buurman WA: 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.PubMedGoogle Scholar
- Dowd SK, Rodgers GC, Callen JP: Effective treatment with alpha 1-protease inhibitor of chronic cutaneous vasculitis associated with alpha 1-antitrypsin deficiency. J Am Acad Dermatol. 1995, 33 (5 Pt 2): 913-6. 10.1016/0190-9622(95)90436-0.PubMedGoogle Scholar
- Smith KC, Pittelkow MR, Su WP: Panniculitis associated with severe alpha 1-antitrypsin deficiency. Treatment and review of the literature. Arch Dermatol. 1987, 123 (12): 1655-61. 10.1001/archderm.123.12.1655.PubMedGoogle Scholar
- Furey NL, Golden RS, Potts SR: Treatment of alpha-1-antitrypsin deficiency, massive edema, and panniculitis with alpha-1 protease inhibitor. Ann Intern Med. 1996, 125 (8): 699.PubMedGoogle Scholar
- O'Riordan K, Blei A, Rao MS, Abecassis M: alpha 1-antitrypsin deficiency-associated panniculitis: resolution with intravenous alpha 1-antitrypsin administration and liver transplantation. Transplantation. 1997, 63 (3): 480-2.PubMedGoogle Scholar
- Chowdhury MM, Williams EJ, Morris JS, Ferguson BJ, McGregor AD, Hedges AR, Stamatakis JD, Pope FM: Severe panniculitis caused by homozygous ZZ alpha1-antitrypsin deficiency treated successfully with human purified enzyme (Prolastin). Br J Dermatol. 2002, 147 (6): 1258-61. 10.1046/j.1365-2133.2002.05095.x.PubMedGoogle Scholar
- Kjus T, Lützow-Holm C, Christensen OB: Treatment of panniculitis associated with alpha-1-antitrypsin deficiency with alpha-1-protease inhibitor. Br J Dermatol. 2002, 147 (6): 1258-61. 10.1046/j.1365-2133.2002.05095.x.Google Scholar
- Gross B, Grebe M, Wencker M, Stoller JK, Bjursten LM, Janciauskiene S: New Findings in PiZZ alpha(1)-Antitrypsin Deficiency-Related Panniculitis. Demonstration of Skin Polymers and High Dosing Requirements of Intravenous Augmentation Therapy. Dermatology. 2009, 218 (4): 370-5. 10.1159/000202982.PubMed CentralPubMedGoogle Scholar
- Blanco I, Canto H, de Serres FJ, Bustillo EF, Rodríguez MC: Alpha-1-antitrypsin replacement therapy efficiently controls fibromyalgia symptoms in two PI ZZ alpha-1-antitrypsin deficiency patients. J Rheumatol. 2004, 31 (10): 2082-5.PubMedGoogle Scholar
- Blanco I, Astudillo A, Domínguez F, Janciauskiene S, Cárcaba V, Gallo C, Canto H, de Serres FJ, Bustillo EF: Intravenous Infusions of Purified Alpha 1-Antitrypsin Effectively Controls Symptoms and Reverts Muscle Biopsy Changes in an MZ-Alpha-1 Antitripsyn Deficiency and Fibromyalgia Syndrome Patient. J Musculoske Pain. 2010, 18 (2): 167-72. 10.3109/10582452.2010.483962.Google Scholar
- Blanco I, Canto H, Flóres J, Camblor C, Cárcaba V, de Serres FJ, Janciauskiene S, Bustillo EF: Long-term augmentation therapy with alpha-1 antitrypsin in an MZ-AAT severe persistent asthma. Monaldi Arch Chest Dis. 2008, 69 (4): 178-82.PubMedGoogle Scholar
- Jenicek M: Clinical case reporting in Evidence-based Medicine. Oxford University Press Inc, 18 Madison Avenue, NY10016;, 2 2001.Google Scholar
- Fernández-Torres R, García-Silva J, Robles O, Otero A, Vázquez MA, Fonseca E: Alfa-1-antitrypsin deficiency panniculitis acquired after liver transplant and successfully treated with retransplant. J Am Acad Dermatol. 2009, 60 (4): 715-6.PubMedGoogle Scholar
- de Oliveira P, Paz-Melgar L, Takahashi MD, Nico MM, Rivitti EA, Mendrone A, Tatsui NH: Alpha-1-antitrypsin deficiency associated with panniculitis treated with plasma exchange therapy. Int J Dermatol. 2004, 43 (9): 693-7. 10.1111/j.1365-4632.2004.02054.x.PubMedGoogle Scholar
- Viraben R, Massip P, Dicostanzo B, Mathieu C: Necrotic panniculitis with alpha-1-antitrypsin deficiency. J Am Acad Dermatol. 1986, 14 (4): 684-687. 10.1016/S0190-9622(86)80466-2.PubMedGoogle Scholar
- Blanco I, Arbesú D, Al Kassam D, De Serres F, Fernández-Bustillo E, Rodríguez Menéndez C: Alpha1-antitrypsin polymorphism in fibromyalgia patients from the Asturias Province in Northern Spain: A significantly higher prevalence of the PI*Z deficiency allele in patients than in the general population. J Musculoskel Pain. 2006, 14 (3): 5-12. 10.1300/J094v14n03_02.Google Scholar
- Blanco I, Janciauskiene S, Nita I, Fernández-Bustillo E, Cárcaba V, Gallo C, Alvarez-Rico M, de Serres F, Béridze N: Low plasma levels of Monocyte Chemoattractant Protein-1 (MCP-1), Tumor Necrosis Factor-alpha (TNFα), and Vascular Endothelial Growth Factor (VEGF) in patients with Alpha1-Antitrypsin Deficiency-related Fibromyalgia. Clin Rheumatol. 2010, 29 (2): 189-97. 10.1007/s10067-009-1318-5.PubMedGoogle Scholar
- Blanco I, Béritze N, Argüelles M, Cárcaba V, Fernández F, Janciauskiene S, Oikonomopoulou K, de Serres FJ, Fernández-Bustillo E, Hollenberg MD: Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients. Clin Rheumatol. 2010, 29 (12): 1403-12. 10.1007/s10067-010-1474-7.PubMedGoogle Scholar
- Vignola AM, Bonanno A, Mirabella A, Riccobono L, Mirabella F, Profita M, Bellia V, Bousquet J, Bonsignore G: Increased levels of elastase and alpha1-antitrypsin in sputum of asthmatic patients. Am J Respir Crit Care Med. 1998, 157 (2): 505-11.PubMedGoogle Scholar
- Hiraguchi Y, Nagao M, Hosoki K, Tokuda R, Fujisawa T: Neutrophil Proteases Activate Eosinophil Function in vitro. Int Arch Allergy Immunol. 2008, 146 (Suppl 1): 16-21. 10.1159/000126055.PubMedGoogle Scholar
- Huang CD, Chen HH, Wang CH, Chou CL, Lin SM, Lin HC, Kuo HP: Human neutrophil-derived elastase induces airway smooth muscle cell proliferation. Life Sci. 2004, 74 (20): 2479-2492. 10.1016/j.lfs.2003.07.059.PubMedGoogle Scholar
- Forteza R, Botvinnikova Y, Ahmed A, Cortes A, Gundel RH, Wanner A, Abraham WM: The interaction of alpha 1-proteinase inhibitor and tissue kallikrein in controlling allergic ovine airway hyperresponsiveness. Am J Respir Crit Care Med. 1996, 154 (1): 36-42.PubMedGoogle Scholar
- Scuri M, Botvinnikova Y, Lauredo IT, Abraham WM: Recombinant alpha 1-proteinase inhibitor blocks antigen-and mediator-induced airway responses in sheep. J Appl Physiol. 2002, 93 (6): 1900-06.PubMedGoogle Scholar
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