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Background: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure., Methods: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007)., Findings: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer)., Interpretation: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency., Funding: CSL Behring., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A Belgian alpha-1-antitrypsin (AAT) deficiency registry has been established in 2003. Currently 55 patients are included. At the same time, a working group has been set up for publishing national guidelines. In 2014, several Belgian patients founded Alpha-1 Global. We hope that the integrated activities of all the stakeholders involved in AAT deficiency will permit a high quality care for all patients suffering from this disabling disease.

Pre- and post-transplant infusions of donor splenocytes treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI-SPs) induce donor-specific tolerance and prolong rat renal allograft survival. However, proinflammatory cytokine production during peritransplantation negates the effects of ECDI-SPs. Therefore, we reasoned that blocking proinflammatory cytokines would promote long-term ECDI-SP-induced allograft survival. We therefore examined the effects of infusing ECDI-SPs alone or in combination with a short course of α1-Antitrypsin (AAT) on the long-term outcomes of a rat kidney allograft model. The data showed that ECDI-SPs+AAT promote renal allograft survival compared with ECDI-SPs alone. This effect was accompanied by expansion of Foxp3+ Tregs, enhanced alloantigen-specific Treg function, and modulation of expression levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and the anti-inflammatory cytokine IL-10. In conclusion, our strategy of combining ECDI-SPs and AAT provides a promising approach for inducing specific transplant tolerance., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50 mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive the pharmacological and non-pharmacological treatment recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines. The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD., (Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.)

Introduction: Alpha-1 antitrypsin, secreted by the liver, inhibits neutrophil elastase. Its deficiency favours the development of emphysema. Restoring a "protective" serum level in deficient patients should make it possible to inhibit the development of emphysema., State of the Art: Human plasma-derived alpha-1 antitrypsin is a blood-derived drug sold in France under the name Alfalastin(®). The recommended posology is an I.V. administration of 60 mg/kg once a week. Human plasma-derived alpha-1 antitrypsin restores anti-elastase protection in the lower lung and prevents experimental emphysema induced by the elastasis of human neutrophils in hamster. The low number of patients with alpha-1 antitrypsin deficiency is one of the difficulties to perform sufficiently powerful randomised studies. However, randomised studies have reported the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on mortality, FEV1 decline and the frequency of exacerbations. Randomised control trials have demonstrated the efficacy of human plasma-derived alpha-1 antitrypsin perfusions on the loss of lung density assessed by CT scan., Conclusion: Augmentation therapy is simple in its conception and implementation, but it is expensive. However, there are currently no other solutions., (Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Although it is often under-recognised, α1-antitrypsin deficiency (AATD) represents one of the most common genetic respiratory disorders worldwide. Since the publication of studies in the late 1980s, which demonstrated that plasma-derived augmentation therapy with intravenous α1-antitrypsin (AAT) can reverse the biochemical deficiencies in serum and lung fluid that characterise emphysema, augmentation therapy has become the cornerstone of patient management. This article, with a focus on experience gained in clinical practice in Germany, provides an overview of some of the research highlights and clinical experience gained in the use of augmentation therapy for AATD during the past 25 years, and briefly discusses the potential role of AAT augmentation therapy in lung transplant recipients. Additionally, the goals of AAT augmentation therapy will be discussed, namely to delay the progression of emphysema, reduce the frequency of exacerbations and improve health-related quality of life. Beyond pulmonary disease, there is recent growing evidence to indicate that AATD could also play a role in rare disorders such as panniculitis, granulomatosis with polyangiitis and ulcerative colitis., (Copyright ©ERS 2015.)

One would assume that the anti-inflammatory activity of α1-anti-trypsin (AAT) is the result of inhibiting neutrophil enzymes. However, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition or by reduced inflammatory parameters. Targets outside the serine-protease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is over-emphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumour susceptibilities, stunt B lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acute-phase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds interleukin (IL)-8, ADAM metallopeptidase domain 17 (ADAM17) and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity - 'relative AAT deficiency'. Unlike immunosuppression, AAT appears to help the immune system to distinguish between desired responses against authentic threats, and unwanted responses fuelled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force: cell injury., (© 2014 British Society for Immunology.)

The common Z mutation (Glu342Lys) of α1-antitrypsin (A1AT) results in the polymerization and intracellular retention of A1AT protein. The concomitant deficiency of functional A1AT predisposes PiZZ subjects to early onset emphysema. Clinical studies have implied that, among the biomarkers associated with emphysema, matrix metalloproteinase 9 (MMP-9) is of particular importance. Increased plasma MMP-9 levels are proposed to predict the decline of lung function as well as greater COPD exacerbations in A1AT deficiency-associated emphysema. The aim of the present study was to investigate the effect of A1AT therapy (Prolastin) on plasma MMP-9 and myeloperoxidase (MPO) levels. In total 34 PiZZ emphysema patients were recruited: 12 patients without and 22 with weekly intravenous (60 mg/kg body weight) A1AT therapy. The quantitative analysis of A1AT, MMP-9 and MPO was performed in serum and in supernatants of blood neutrophils isolated from patients before and after therapy. Patients with Prolastin therapy showed significantly lower serum MMP-9 and MPO levels than those without therapy. However, parallel analysis revealed that a rapid infusion of Prolastin is accompanied by a transient elevation of plasma MMP-9 and MPO levels. Experiments with freshly isolated blood neutrophils confirmed that therapy with Prolastin causes transient MMP-9 and MPO release. Prolastin induced the rapid release of MMP-9 and MPO when added directly to neutrophil cultures and this reaction was associated with the presence of IgA in A1AT preparation. Our data support the conclusion that changes in plasma levels of MMP-9 and MPO mirror the effect of Prolastin on blood neutrophils.

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.

Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase restenosis. Two virus-derived anti-inflammatory proteins, M-T7 and Serp-1, reduce inflammation and plaque growth after BA and transplant in animal models through separate pathways. M-T7 is a broad spectrum C, CC and CXC chemokine-binding protein. Serp-1 is a serine protease inhibitor (serpin) inhibiting thrombotic and thrombolytic pathways. Serp-1 also reduces arterial inflammation and improves survival in a mouse herpes virus (MHV68) model of lethal vasculitis. In addition, Serp-1 demonstrated safety and efficacy in patients with unstable coronary disease and stent implant, reducing markers of myocardial damage. We investigate here the effects of Porphyromonas gingivalis, a periodontal pathogen, on restenosis after BA and the effects of blocking chemokine and protease pathways with M-T7 and Serp-1. ApoE-/- mice had aortic BA and oral P. gingivalis infection. Arterial plaque growth was examined at 24 weeks with and without anti-inflammatory protein treatment. Dental plaques from mice infected with P. gingivalis tested positive for infection. Neither Serp-1 nor M-T7 treatment reduced infection, but IgG antibody levels in mice treated with Serp-1 and M-T7 were reduced. P. gingivalis significantly increased monocyte invasion and arterial plaque growth after BA (P<0.025). Monocyte invasion and plaque growth were blocked by M-T7 treatment (P<0.023), whereas Serp-1 produced only a trend toward reductions. Both proteins modified expression of TLR4 and MyD88. In conclusion, aortic plaque growth in ApoE-/- mice increased after angioplasty in mice with chronic oral P. gingivalis infection. Blockade of chemokines, but not serine proteases significantly reduced arterial plaque growth, suggesting a central role for chemokine-mediated inflammation after BA in P. gingivalis infected mice.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by neutrophil-driven lung destruction and early emphysema in a low AAT, and high neutrophil elastase environment in the lungs of affected individuals. In this study, we examined peripheral blood neutrophil apoptosis and showed it to be accelerated in individuals with AATD by a mechanism involving endoplasmic reticulum stress and aberrant TNF-α signaling. We reveal that neutrophil apoptosis in individuals homozygous for the Z allele (PiZZ) is increased nearly 2-fold compared with healthy controls and is associated with activation of the external death pathway. We demonstrate that in AATD, misfolded AAT protein accumulates in the endoplasmic reticulum of neutrophils, leading to endoplasmic reticulum stress and the expression of proapoptotic signals, including TNF-α, resulting in increased apoptosis and defective bacterial killing. In addition, treatment of AATD individuals with AAT augmentation therapy decreased neutrophil ADAM-17 activity and apoptosis in vivo and increased bacterial killing by treated cells. In summary, this study demonstrates that AAT can regulate neutrophil apoptosis by a previously unidentified and novel mechanism and highlights the role of AAT augmentation therapy in ameliorating inflammation in AATD., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Alpha-1 antitrypsin (AAT) deficiency is an under-recognized hereditary disorder associated with the premature onset of chronic obstructive pulmonary disease, liver cirrhosis in children and adults, and less frequently, relapsing panniculitis, systemic vasculitis and other inflammatory, autoimmune and neoplastic diseases. Severe AAT deficiency mainly affects Caucasian individuals and has its highest prevalence (1 : 2000-1 : 5000 individuals) in Northern, Western and Central Europe. In the USA and Canada, the prevalence is 1: 5000-10 000. Prevalence is five times lower in Latin American countries and is rare or nonexistent in African and Asian individuals. The key to successful diagnosis is by measuring serum AAT, followed by the determination of the phenotype or genotype if low concentrations are found. Case detection allows implementation of genetic counselling and, in selected cases, the application of augmentation therapy. Over the past decade, it has been demonstrated that AAT is a broad-spectrum anti-inflammatory, immunomodulatory, anti-infective and tissue-repair molecule. These new capacities are promoting an increasing number of clinical studies, new pharmacological formulations, new patent applications and the search for alternative sources of AAT (including transgenic and recombinant AAT) to meet the expected demand for treating a large number of diseases, inside and outside the context of AAT deficiency., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

α1 Antitrypsin deficiency (AATD) increases the risk of chronic obstructive pulmonary disease (COPD), liver disease and other conditions. Although it is not a rare disease, it is a condition rarely diagnosed because of unawareness by most healthcare providers who manage subjects at risk. Testing recommendations have been published and strongly suggest testing all subjects with confirmed COPD, cryptogenic liver cirrhosis, subjects with incompletely reversible airflow obstruction and siblings of affected individuals. Testing strategies usually imply a combination of measures of α1 antitrypsin (AAT) levels, phenotyping and genotyping, techniques that have been facilitated for in-office use by development of testing kits using dried blood spots. Early detection of subjects is crucial to apply effective preventive measures and early institution of therapy. The only specific Food and Drug Administration - approved therapy for this condition is lifelong weekly intravenous AAT replacement (augmentation therapy). Observational studies strongly suggest a beneficial effect of augmentation therapy in slowing lung function decline and randomized trials suggest a beneficial effect in slowing the progression of emphysema over time as measured by computed tomography. In addition, augmentation therapy has been shown to modulate systemic inflammatory responses and affect markers of elastin degradation. As new markers of disease progression are discovered, new doses of AAT replacement are tested and sub-phenotypes of disease are described, treatment recommendations are likely to change towards a more individualized therapeutic approach., (© The Author(s), 2014.)

Context: Recent studies have implicated proinflammatory responses in the mechanism of type 1 diabetes (T1D)., Objective: Our objective was to evaluate the safety and effects of therapy with the anti-inflammatory serum protein α1-antitrypsin (AAT) on islet function and innate immunity in recent-onset patients., Design and Setting: This was an open-label phase I trial at the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver., Patients: Twelve recently diagnosed subjects with T1D with detectable C-peptides were included in the study., Intervention: Eight consecutive weekly infusions of 80 mg/kg of AAT were given., Main Outcome Measures: PATIENTS were monitored for adverse effects of AAT therapy, C-peptide responses to a mixed-meal tolerance test, and toll-like receptor (TLR)-induced cellular IL-1β in monocytes and myeloid dendritic cells (mDCs)., Results: No adverse effects were detected. AAT led to increased, unchanged, or moderately reduced levels of C-peptide responses compared with baseline in 5 patients. The total content of TLR4-induced cellular IL-1β in monocytes at 12 months after AAT therapy was 3-fold reduced compared with baseline (P < .05). Furthermore, at baseline, 82% of monocytes produced IL-1β, but at 12 months after therapy, the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1β was observed only 9 and 12 months after treatment but not in untreated diabetics. Improved β-cell function in the 5 AAT-treated individuals correlated with lower frequencies of monocytes and mDCs producing IL-1β compared with subjects without improvement of islet function (P < .04 and P < .02, respectively)., Conclusions: We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1β.

Unlabelled: Acute liver failure remains a critical clinical condition, with high mortality rates, and increased apoptosis of hepatocytes represents a key event in the cause of liver failure. Alpha-1-antitrypsin (AAT) is synthesized and secreted mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AAT deficiency. Because AAT therapy exerts antiinflammatory and immune modulatory activities in various experimental models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute liver failure in mice. Well-established preclinical models of acute liver failure such as the Jo2 FAS/CD95 activating model and models of acetaminophen and α-amanitin poisoning were used. Therapeutic effects of AAT were evaluated by monitoring animal survival, histopathological changes, measurement of caspase activity, and serum cytokine levels. Systemic treatment with AAT significantly decreased Jo2-induced liver cell apoptosis and prolonged survival of mice. Native and oxidized (lacking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver injury and showed direct inhibition of active caspase-3 and -8 in liver homogenates and in a cell-free system in vitro. Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor necrosis factor alpha (TNF-α), which also paralleled the reduced activity of ADAM17 (TACE). Noticeably, the increased survival and a reduction of apoptotic hepatocytes were also observed in the α-amanitin and acetaminophen-induced liver injury mouse models., Conclusion: Our data suggest that systemic administration of AAT can be a promising therapy to treat acute liver failure and clinical studies to explore this treatment in humans should be initiated., (© 2014 by the American Association for the Study of Liver Diseases.)

Apha-1-antitrypsin deficiency is an autosomal recessive genetic disorder seen in all races. The molecular defect is a specific mutation of the SERPINA1 gene leading to synthesis of an abnormal protein (alpha-1-antitrypsin Z) that cannot be secreted and polymerizes in the endoplasmic reticulum of hepatocytes. The inter-individual variability in the responses to intracellular stress induced by the accumulation of abnormal polymers and the mechanisms allowing their degradation is, without doubt, responsible for the different clinical manifestations of the disease. The disease affects the liver where the abnormal protein is synthesized and the lung, which is its place of action. Liver involvement is well recognized in homozygous infants of the phenotype ZZ. In this situation the disease may present a varying picture from neonatal cholestasis (about 15% of neonatal defects) to cirrhosis. However, evolution towards cirrhosis affects less than 3% of infants with the ZZ phenotype and it is preceded in 80% of cases by neonatal cholestasis. In adolescents or adults the manifestations associated with alpha-1-antitrypsin deficiency are usually limited to biochemical abnormalities but may lead to cirrhosis or hepatocellular carcinoma. The hepatic disorder and its complications are treated symptomatically though the pulmonary involvement may benefit from substitution treatment. More specific treatments targeting the molecular and cellular abnormalities are the subject of research., (Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Alpha-1 antitrypsin deficiency is a frequent genetic disorder associated with pulmonary emphysema in smokers and with liver cirrhosis. Aside from lung or liver transplantation, only replacement therapy can currently slow the progression of emphysema. Progress in the pathogenesis of this disorder (protein misfolding, RER aggregation) is opening the way to new strategies such as proteostasis control. Alpha-1 antitrypsin deficiency remains poorly known and underdiagnosed.

Background: Pulmonary ischemia-reperfusion (IR)-induced lung injury is a severe complication that increases the likelihood of primary graft dysfunction and early death after lung transplantation. Inflammatory cytokine release and cell death play a critical role in the development of IR-induced lung injury. α1-Antitrypsin (A1AT) is a protease inhibitor clinically used for the treatment of A1AT-deficiency emphysema. On the basis of a literature review, we hypothesize that A1AT may have the potential to reduce IR-induced lung injury through its anti-inflammatory and anti-apoptotic effects., Methods: A human pulmonary cell culture model was used to simulate IR processes in lung transplantation. Effects of A1AT on cell death and cytokine production were examined. A rat pulmonary IR model, in which the left pulmonary hilum was clamped for 90 minutes, followed by reperfusion for 2 hours, was used to determine the effects of A1AT on acute lung injury, function, cell death, and inflammatory response., Results: A1AT significantly inhibited cell death and inflammatory cytokine release dose-dependently in vitro and significantly improved lung oxygenation and lung mechanics and reduced pulmonary edema in vivo. Moreover, A1AT inhibited neutrophil infiltration in the lung and reduced cell death and significantly reduced IR-induced inflammatory mediators in plasma, including interleukin (IL)-1α, IL-4, IL-12p70, monocyte chemotactic protein 1, and tumor necrosis factor-α., Conclusions: Considering its current clinical use, our findings indicate that administration of A1AT may be an effective and safe therapy for the treatment of IR injury in human lung transplantation., (© 2013 International Society for Heart and Lung Transplantation Published by International Society for the Heart and Lung Transplantation All rights reserved.)

Alpha1-antitrypsin (AAT) deficiency was first described in 1963 together with its associations with severe early-onset basal panacinar emphysema. The genetic defects leading to deficiency have been elucidated and the pathophysiologic processes, clinical variation in phenotype, and the role of genetic modifiers have been recognized. Strategies to increase plasma (and hence tissue) concentrations of AAT have been developed. The only recognized specific therapeutic strategy is regular infusions of the purified plasma protein, and evidence confirms its efficacy in protecting the lung (at least partially). Early detection and modification of lifestyle remains crucial to the management of AAT deficiency., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Maintaining serum levels of alpha-1-proteinase inhibitor (A1PI) >11 μM by augmentation with plasma-derived human A1PI is currently the only specific therapy available to treat patients with the genetic deficiency of A1PI. In this study, a new, high-purity (≥90% A1PI in monomeric form), ready-to-use, liquid formulation of A1PI-GLASSIA (Kamada, Ness Ziona, Israel) was compared to PROLASTINÆ (Talecris, Research Triangle Park, NC, now Grifols), both commercially available, FDA-approved products. This multicenter, double-blind, randomized controlled trial with partial cross-over was designed to test the non-inferiority and safety of GLASSIA compared to PROLASTIN, assessing both antigenic and functional A1PI trough levels in subject serum. Non-inferiority of GLASSIA to PROLASTIN was demonstrated by remaining within the lower bounds of the confidence intervals (≤3 μM) for both antigenic and functional A1PI. The study concluded that GLASSIA, a new liquid, ready to use, formulation of A1PI, was not inferior to PROLASTIN and it was well tolerated with a safety profile comparable to PROLASTIN.

Alpha 1 antitrypsin deficiency (AATD) is a rare cause of chronic obstructive pulmonary disease. The lung disease is thought to be caused primarily by a lack of effective protection against the harmful effects of neutrophil elastase due to the low AAT levels in the lung. Patients may also develop liver disease due to polymerisation of AAT within hepatocytes. Consequently there has been much research over the years into AAT augmentation therapy in patients with lung disease, initially intravenously, and more recently in inhaled forms. This review article will discuss the role of augmentation therapy in AATD and the current status of recombinant AAT. The potential for other therapeutic strategies, such as blocking polymer formation, enhancing autophagy, gene therapy and stem cell-based treatment, will also be discussed more briefly.

Background: Pseudomonas aeruginosa (PA) infection is involved in various lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. However, treatment of PA infection is not very effective in part due to antibiotic resistance. α1-antitrypsin (A1AT) has been shown to reduce PA infection in humans and animals, but the underlying mechanisms remain unclear. The goal of our study is to test whether a novel endogenous host defense protein, short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is involved in the therapeutic effect of A1AT during lung PA infection., Method: SPLUNC1 knockout (KO) and littermate wild-type (WT) mice on the C57BL/6 background were intranasally infected with PA to determine the therapeutic effects of A1AT. A1AT was aerosolized to mice 2 hrs after the PA infection, and mice were sacrificed 24 hrs later. PA load and inflammation were quantified in the lung, and SPLUNC1 protein in bronchoalveolar lavage (BAL) fluid was examined by Western blot., Results: In WT mice, PA infection significantly increased neutrophil elastase (NE) activity, but reduced SPLUNC1 protein in BAL fluid. Notably, PA-infected mice treated with A1AT versus bovine serum albumin (BSA) demonstrated higher levels of SPLUNC1 protein expression, which are accompanied by lower levels of NE activity, lung bacterial load, and pro-inflammatory cytokine production. To determine whether A1AT therapeutic effects are dependent on SPLUNC1, lung PA load in A1AT- or BSA-treated SPLUNC1 KO mice was examined. Unlike the WT mice, A1AT treatment in SPLUNC1 KO mice had no significant impact on lung PA load and pro-inflammatory cytokine production., Conclusion: A1AT reduces lung bacterial infection in mice in part by preventing NE-mediated SPLUNC1 degradation.

Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

Background: Fecal alpha-1-antitrypsin (AAT) clearance has been a marker of clinical disease severity in inflammatory bowel diseases (IBDs) for many years. Although AAT deficiency is more often associated with lung and liver pathologies, AAT-deficient patients with concomitant IBD have been shown to develop more aggressive disease and rapid progression to surgery. Although recent studies have highlighted the pleiotropic anti-inflammatory functions of AAT, including reducing proinflammatory cytokine production and suppressing immune cell activation, its potential therapeutic role in IBD has not been described., Methods: The therapeutic potential of human AAT administration was assessed in murine models of IBD including new-onset and established chemically induced colitis and spontaneous chronic murine ileitis. Histological assessment of inflammation, cytokine secretion profiling, and flow cytometric evaluation of inflammatory infiltrate were performed in each model. The effect of AAT on intestinal barrier function was also examined both in vitro and in vivo., Results: AAT attenuated inflammation in small and large intestinal IBD models through reduced secretion of proinflammatory cytokines, inflammatory cell infiltration, and reduced tissue injury. AAT also increased intestinal restitution after chemically induced colitis. AAT significantly decreased intestinal permeability in vitro and in vivo as part of a protective mechanism for both acute and chronic models of IBD., Conclusions: Our findings describe a beneficial role for AAT in IBD models through suppression of cytokine production and enhanced intestinal barrier function. This raises the possibility that AAT supplementation, which has a long history of proven safety, may have a therapeutic effect in human IBD.

SERPINA1, α-antitrypsin (AAT) is an acute phase protein, a member of the serpin (serine protease inhibitor) super family and one of the most abundant protease inhibitors in the circulation. The clinical importance of AAT is emphasized in persons with inherited AAT deficiency who exhibit high risk of developing early onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, which may appear at any age, and in rare cases panniculitis and vasculitis. The most common and severe AAT deficiency is associated with the Z (Glu342 to Lys) mutation. It is also well established that Z AAT deficiency results from the polymerization and accumulation of the misfolded AAT protein. Consequently, low levels of circulating Z AAT are assumed to be inadequate to neutralize elastolytic activity and to prevent lung tissue damage. Novel studies, however, are expanding the link between AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, vasculitis, panniculitis and other diseases. Given the importance of the protease/antiprotease imbalance in causing emphysema, augmentation of circulating AAT is used as a specific therapy for patients with AAT deficiency-related emphysema but not for those with liver diseases. According to the novel findings, therapy with AAT possesses antiinflammatory and immuno-modulatory effects across a broad spectrum of experimental models of systemic and local inflammation. Hence, in this article we will discuss putative new directions for the clinical use of therapy with AAT.

Background: Intravenous alpha-1 antitrypsin protein (AAT) augmentation is a prescribed therapy for severe, genetically determined, alpha-1 antitrypsin deficiency (AATD), a genetic basis for pulmonary emphysema. AAT, a predominant systemic inhibitor of neutrophil elastase thus far has not been shown to decrease elastin degradation in a significant number of patients on this therapy. The objective of this study was to compare levels of biomarkers of elastin degradation in plasma, bronchoalveolar lavage (BALF) fluid and urine before and after beginning AAT augmentation therapy in patients with AATD., Methods: Desmosine and isodesmosine (DI), which occur only in elastin, are amino acid cross-links in mature elastin. Levels of DI in body fluids measure degradation of elastin and can be measured more specifically by mass spectrometry. This method was used to measure DI levels in plasma, bronchoalveolar lavage fluid and urine in cohorts of severe AATD patients on augmentation, not on augmentation and before and after the initiation of augmentation therapy., Results: Statistically significant reductions in plasma DI and in BALF DI were demonstrated in AATD patients receiving intravenous (IV) augmentation therapy as compared with those not receiving it. Administration by aerosol also produced statistically significant reductions in levels of DI in BALF., Conclusions: Results indicate that the currently prescribed doses of AAT augmentation inhibit neutrophil elastase adequately to reduce elastin degradation, both systemically and in the lung per se. The currently prescribed doses did not reduce elastin degradation to control levels, which may be possible with higher doses.

α-1-antitrypsin deficiency (A1ATD) is an under-recognized hereditary disorder associated with the premature onset of chronic obstructive pulmonary disease. There is considerable heterogeneity in the phenotypic expression of lung disease in A1ATD and the pathophysiology is complex, involving the interaction of multiple pathways. Other genetic factors that may contribute to emphysema risk in A1AT-deficient individuals are beginning to be identified. Methods of monitoring disease progression have evolved, including the use of computed tomography densitometry and biomarkers of disease activity. Progress in the development of novel treatment strategies continues, including the hope for a potential cure through the use of gene therapies. In this article, the authors review the recent advances in this field and outline potential future directions of research in A1ATD.

α1-Antitrypsin (AAT) is a member of the serine proteinase inhibitor family that impedes the enzymatic activity of serine proteinases, including human neutrophil elastase, cathepsin G and neutrophil proteinase 3. Here, we expressed recombinant AAT by fusing the intact AAT gene to the constant region of IgG1 to generate soluble recombinant AAT-Fc protein. The recombinant AAT-Fc protein was produced in Chinese hamster ovary (CHO) cells and purified using mini-protein A affinity chromatography. Recombinant AAT-Fc protein was tested for antiinflammatory function and AAT-Fc sufficiently suppressed tumor necrosis factor (TNF)-α-induced interleukin (IL)-6 in human peripheral blood mononuclear cells (PBMCs) and inhibited cytokine-induced TNFα by different cytokines in mouse macrophage Raw 264.7 cells. However, AAT-Fc failed to suppress lipopolysaccharide-induced cytokine production in both PBMCs and macrophages. In addition, our data showed that AAT-Fc blocks the development of hyperglycemia in a streptozotocin-induced mouse model of diabetes. Interestingly, we also found that plasma-derived AAT specifically inhibited the enzymatic activity of elastase but that AAT-Fc had no inhibitory effect on elastase activity.

α1 -Antitrypsin (AT), a serine protease inhibitor that specifically targets hydrolytic enzymes, plays a significant role in the termination of tissue inflammation and can therefore represent a key factor in chronic incidences as chronic obstructive pulmonary disease (COPD) or chronic hepatitis. A local and low-dose therapy for the treatment of acquired chronic inflammatory processes which are characterized by insufficient AT amounts but also of genetically conditioned AT deficiencies is supposed to be more effective and less cost-intensive compared to current therapies. In this study, a noncovalent complex formation between the cell-penetrating peptide carrier hCT(18-32)-k7 and AT was performed. The complex was applied to HEK293T/17 cells, as proof-of-principle, and polymorphonuclear leukocytes (PMN), which are responsible for tissue destruction and the perpetuation of inflammation in chronic processes. Both cell species show a successful uptake and subsequently both, an intracellular dot-shaped and homogeneous distribution of the complex demonstrating phagolysosomal as well as cytoplasmic availability. Furthermore, a decreased human leukocytic elastase (HLE) activity was observed after the direct complex administration to PMN. Since the application did not cause an enhanced vitality loss, the complex could facilitate an improvement in direct, local and low-dose treatment of chronically proceeding processes in order to attenuate protease-mediated tissue destruction., (Copyright © 2013 International Society for Advancement of Cytometry.)

Elastases of both the neutrophil and macrophage have been implicated in lung disease initiation and progression. Although it is unlikely that these proteases evolved for the purpose of injuring lung tissue, the elastin-rich connective tissue framework of the lungs appears to be particularly susceptible to the action of elastolytic proteases. Assuming that neutrophil elastase most likely plays a role in the migration of neutrophils toward a site of inflammation and degradation of proteins from invading organisms or other products of the inflammatory response, it is the role of inhibitors of this protease to protect normal tissues from its effects. In alpha-1 antitrypsin deficiency we find an experiment of nature that disrupts this protease-anti-protease balance, resulting in an increased risk of destructive lung disease.

Best-in-class systems have evolved among alpha-1 antitrypsin (AAT) producers, specialty pharmacies and the Alpha-1 Foundation and AlphaNet patient groups. The Genetic Alliance, NORD and other independent parties have recognized the benefits regarding public policy, patient advocacy, medical research, medication adherence, patient identification and health outcomes. Driving the next quantum leap in disease state management for Alpha-1 patients will require strong leadership from both industry and patient groups. Six initiatives are suggested that will sustain best-in-class approaches to identify, treat and even cure Alpha-1 patients.

The therapy of alpha-1 antitrypsin deficiency (AATD) is an example of a medical triumph over a common hereditary disease. Based on the understanding of the pathogens of the disease as a deficiency in liver production of alpha-1 antitrypsin (AAT) resulting from inherited genetic variation in both parental AAT genes, the knowledge that A1AT functions primarily to inhibit neutrophil elastase (NE), and the observation that NE instilled into the lung of experimental animals resulted in emphysema, the concept evolved that the pulmonary manifestations of the disease could be halted by intermittent intravenous infusions of AAT purified from pooled human plasma. Following preliminary clinical studies in the academic community, and then pharmaceutical company development of large scale purification of human AAT, the FDA approved the use of weekly AAT augmentation therapy for AATD following a clinical trial which demonstrated that weekly infusions would raise to normal plasma and lung epithelial fluid levels of AAT in AAT-deficient individuals. The therapy is now used worldwide to treat AATD, the only pulmonary genetic disease with effective therapy for all affected individuals.

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration., (Copyright © 2013 S. Karger AG, Basel.)

α(1)-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.

Objective: To assess clinical effect of a human plasma-derived alpha-1 antitrypsin (AAT) concentrate in reducing pain severity of patients with fibromyalgia (FM)., Methods: Thirteen subjects with FM completed a randomized, double-blind, placebo-controlled, crossover study which consisted of 9 weeks trial of AAT or placebo with a washout period of 6 weeks. Primary efficacy endpoint was change on pain severity score, assessed by a daily visual analogue scale (VAS) for pain. Other outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire, (FIQ), the Medical Outcomes Study Short Form 36 (SF-36), the Health Assessment Questionnaire Disability Index (HAQ-DI), the Hospital Anxiety and Depression Scale (HADS) and tiredness score evaluated by VAS., Results: No statistically significant differences were observed in either pain severity or other secondary outcome measures in either of the treatment groups, or between treatment groups in either of the treatment periods. No carryover or order of intervention effect was observed from one treatment to the other. Both investigational interventions were generally well tolerated, and vital signs during the drug infusions were within the respective normal ranges., Conclusion: Treatment with a human plasma-derived AAT concentrate did not demonstrate significant improvement over placebo on reducing pain severity and other symptoms of FM. Further research should examine other FM subpopulations and drug doses., (Copyright © 2011 John Wiley & Sons, Ltd.)

Recognizing the clinical heterogeneity of COPD suggests a specific therapeutic approach directed by the so-called clinical phenotypes of the disease. The Spanish COPD Guidelines (GesEPOC) is an initiative of SEPAR, which, together with the scientific societies involved in COPD patient care, and the Spanish Patient Forum, has developed these new clinical practice guidelines. This present article describes the severity classification and the pharmacological treatment of stable COPD. GesEPOC identifies four clinical phenotypes with differential treatment: non-exacerbator, mixed COPD-asthma, exacerbator with emphysema and exacerbator with chronic bronchitis. Pharmacological treatment of COPD is based on bronchodilation in addition to other drugs depending on the clinical phenotype and severity. Severity is established by the BODE/BODEx multidimensional scales. Severity can also be approximated by assessing airflow obstruction, dyspnea, level of physical activity and history of exacerbations. GesEPOC is a new, more individualized approach to COPD treatment according to the clinical characteristics of the patients., (Copyright © 2012 SEPAR. Published by Elsevier Espana. All rights reserved.)

Since the end of the 1980s augmentation therapy with alpha-1 antitrypsin (AAT) from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has demonstrated to be safe and weekly infusions of AAT have demonstrated to result in plasma AAT concentration above those considered protective for the lungs. Randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy. This is the first example of an antiprotease effective in restoring the protease/antiprotease imbalance in the lungs and changing the natural history of congenital emphysema. On the basis of the results obtained with the long-term infusion of AAT, there is growing interest in the possible use of antiprotease treatment in patients with smokers COPD. However, no drugs are yet available to increase antiprotease protection of the lower airways of smokers., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

Objective: Severe exacerbations in alpha-1-antitrypsin (AAT)-deficient patients with chronic obstructive pulmonary disease (COPD) and/or emphysema are a major cause of hospitalization. A multicentre, observational, retrospective study was undertaken to evaluate the effect of continuous AAT augmentation therapy in reducing the incidence of exacerbations in these patients., Methods: Patients treated with Trypsone® or Prolastin® for at least 18 months were recruited if their medical records for 18 months before starting augmentation therapy were available. The number of mild and severe exacerbations in the two periods was compared and hospitalization-related costs were analysed., Results: A total of 127 patients were recruited; 75 of them experienced at least one exacerbation in the period prior to augmentation. In the treatment period, the mean number of exacerbations per patient was reduced in both the total population and the population with exacerbations (mean ± SD: 1.2 ± 1.6 versus 1.0 ± 2.2 and 2.0 ± 1.6 versus 1.4 ± 2.7, respectively; p < 0.01). The percentage of patients experiencing exacerbations was reduced in the total population (59.1% versus 44.1%; p < 0.05). In the patient subgroup of the total population who experienced a change in their number of exacerbations between the two periods, 43.7% had a reduction and 21.4% had an increase (p < 0.01). The number of severe exacerbations diminished in 42.9% of this subgroup and increased in 12.0% (p < 0.001). Most adverse events were nonserious or not related to treatment. Hospitalization costs savings per patient associated with treatment ranged from approximately € 400 to € 900 (p < 0.05)., Conclusions: Augmentation therapy with AAT concentrates was associated with a reduction in the incidence and severity of exacerbations in AAT-deficient patients, which resulted in lower hospitalization expenditures.

Alpha-1 antitrypsin (A1AT) functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted) attributable to emphysema and documented A1AT deficiency (level ≤11 µmol⁄L) who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation) because of benefits in computed tomography scan lung density and mortality.