scholarly journals Alpha-1 Antitrypsin Augmentation Inhibits Proteolysis of Neutrophil Membrane Voltage-Gated Proton Channel-1 in Alpha-1 Deficient Individuals

Medicina ◽  
2021 ◽  
Vol 57 (8) ◽  
pp. 814
Author(s):  
Padraig Hawkins ◽  
Julian Sya ◽  
Nee Kee Hup ◽  
Mark P. Murphy ◽  
Noel G. McElvaney ◽  
...  
Keyword(s):  
Lung Disease ◽  
Serine Protease ◽  
Resonance Energy ◽  
Membrane Voltage ◽  
Proton Channel ◽  
Augmentation Therapy ◽  
Membrane Expression ◽  
Voltage Gated ◽  
Increased Risk ◽  
Alpha 1 Antitrypsin

Background and Objectives: Alpha-1 antitrypsin is a serine protease inhibitor that demonstrates an array of immunomodulatory functions. Individuals with the genetic condition of alpha-1 antitrypsin deficiency (AATD) are at increased risk of early onset emphysematous lung disease. This lung disease is partly driven by neutrophil mediated lung destruction in an environment of low AAT. As peripheral neutrophil hyper-responsiveness in AATD leads to excessive degranulation and increased migration to the airways, we examined the expression of the membrane voltage-gated proton channel-1 (HVCN1), which is integrally linked to neutrophil function. The objectives of this study were to evaluate altered HVCN1 in AATD neutrophils, serine protease-dependent degradation of HVCN1, and to investigate the ability of serum AAT to control HVCN1 expression. Materials and Methods: Circulating neutrophils were purified from AATD patients (n = 20), AATD patients receiving AAT augmentation therapy (n = 3) and healthy controls (n = 20). HVCN1 neutrophil expression was assessed by flow cytometry and Western blot analysis. Neutrophil membrane bound elastase was measured by fluorescence resonance energy transfer. Results: In this study we demonstrated that HVCN1 protein is under-expressed in AATD neutrophils (p = 0.02), suggesting a link between reduced HVCN1 expression and AAT deficiency. We have demonstrated that HVCN1 undergoes significant proteolytic degradation in activated neutrophils (p < 0.0001), primarily due to neutrophil elastase activity (p = 0.0004). In addition, the treatment of AATD individuals with AAT augmentation therapy increased neutrophil plasma membrane HVCN1 expression (p = 0.01). Conclusions: Our results demonstrate reduced levels of HVCN1 in peripheral blood neutrophils that may influence the neutrophil-dominated immune response in the AATD airways and highlights the role of antiprotease treatment and specifically AAT augmentation therapy in protecting neutrophil membrane expression of HVCN1.

scholarly journals Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know

2021 ◽  
Vol 12_suppl ◽  
pp. 204062232110101
Author(s):  
Igor Barjaktarevic ◽  
Michael Campos
Keyword(s):  
Lung Disease ◽  
Treatment Guidelines ◽  
Management Program ◽  
Lifestyle Changes ◽  
Chronic Obstructive ◽  
Augmentation Therapy ◽  
Lung Function Decline ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

scholarly journals COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

2017 ◽  
Vol 26 (146) ◽  
pp. 170068 ◽  
Author(s):  
Haitham S. Al Ashry ◽  
Charlie Strange
Keyword(s):  
General Population ◽  
Population Based ◽  
Rapid Decline ◽  
Augmentation Therapy ◽  
Ongoing Debate ◽  
Increased Risk ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Study Designs

Since the discovery of severe alpha-1 antitrypsin deficiency as a genetic risk factor for emphysema, there has been ongoing debate over whether individuals with intermediate deficiency with one protease inhibitor Z allele (PiMZ, or MZ) are at some risk for emphysema. This is important, because MZ individuals comprise 2–5% of the general population. In this review we summarise the evidence about the risks of the MZ population to develop emphysema or asthma. We discuss the different study designs that have tried to answer this question. The risk of emphysema is more pronounced in case–control than in population-based studies, perhaps due to inadequate power. Carefully designed family studies show an increased risk of emphysema in MZ smokers. This is supported by the rapid decline in lung function of MZ individuals when compared to the general population after massive environmental exposures. The risk of asthma in MZ subjects is less studied, and more literature is needed before firm conclusions can be made. Augmentation therapy in MZ individuals is not supported by any objective studies. MZ smokers are at increased risk for emphysema that is more pronounced when other environmental challenges are present.

scholarly journals Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Igor Barjaktarevic ◽  
Marc Miravitlles
Keyword(s):  
Lung Disease ◽  
Therapeutic Strategy ◽  
Specific Treatment ◽  
Augmentation Therapy ◽  
Limited Data ◽  
Severe Deficiency ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Current Guidelines

AbstractAlpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed.

scholarly journals Diagnosing alpha-1 antitrypsin deficiency: the first step in precision medicine

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2049 ◽  
Author(s):  
Craig P. Hersh
Keyword(s):  
Precision Medicine ◽  
Granulomatosis With Polyangiitis ◽  
Genetic Diseases ◽  
Augmentation Therapy ◽  
Delay In Diagnosis ◽  
Increased Risk ◽  
Genetic Subtype ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Severe alpha-1 antitrypsin (AAT) deficiency is one of the most common serious genetic diseases in adults of European descent. Individuals with AAT deficiency have a greatly increased risk for emphysema and liver disease. Other manifestations include bronchiectasis, necrotizing panniculitis and granulomatosis with polyangiitis. Despite the frequency and potential severity, AAT deficiency remains under-recognized, and there is often a delay in diagnosis. This review will focus on three recent updates that should serve to encourage testing and diagnosis of AAT deficiency: first, the publication of a randomized clinical trial demonstrating the efficacy of intravenous augmentation therapy in slowing the progression of emphysema in AAT deficiency; second, the mounting evidence showing an increased risk of lung disease in heterozygous PI MZ genotype carriers; last, the recent publication of a clinical practice guideline, outlining diagnosis and management. Though it has been recognized for more than fifty years, AAT deficiency exemplifies the modern paradigm of precision medicine, with a diagnostic test that identifies a genetic subtype of a heterogeneous disease, leading to a targeted treatment.

scholarly journals FRI0072 DISCONTINUATION OF DMARD USE IN RHEUMATOID ARTHRITIS PATIENTS WITH LUNG DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 612.1-613
Author(s):  
S. Pedro ◽  
T. Mikuls ◽  
J. Zhuo ◽  
K. Michaud
Keyword(s):  
Rheumatoid Arthritis ◽  
Lung Disease ◽  
Pulmonary Disease ◽  
Treatment Patterns ◽  
Dmard Treatment ◽  
Increased Risk ◽  
Pulmonary Manifestations ◽  
Clinical Models ◽  
Comorbidity Index ◽  
Time Varying Covariates

Background:Pulmonary manifestations such as interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are frequent extra-articular features that carry a poor prognosis in Rheumatoid Arthritis (RA). Little data is available on how RA patients (pts) with pulmonary disease are managed in real-world settings.Objectives:To assess treatment patterns and DMARD discontinuation in RA patients with comorbid lung disease in comparison with other RA patients.Methods:The study included RA Patients enrolled in the Forward Databank with ≥1 year observation after 2000 initiating a DMARD. Forward is a large longitudinal rheumatic disease registry in the US. RA patients’ diagnoses were rheumatologist-confirmed, and every 6 months participants completed comprehensive questionnaires regarding symptoms, disease outcomes, medications, and clinical events. Lung disease (LD+) was defined as at least one of the following: emphysema, asthma, bronchitis, COPD, pleural effusion, fibrosis of the lung, “RA lung”, or ILD, the later classified by ICD9 codes (England 2019). DMARDs were categorized hierarchically into four groups: csDMARDs, TNFi and NTNFi (bDMARDs), and tsDMARDs. Percentage of patients who initiated different DMARDs were reported for pts with LD+/LD-. Discontinuation was analyzed by Kaplan Meier (KM) curves, log-ranks tests, and Cox regression models using time-varying covariates. Best models were created using backward selection models (10% probability of removal) and pre-defined clinical models.Results:Of the 21,525 eligible RA patients, 13.8% had LD+ at the time they initiated a DMARD (follow-up: 69,597 pt-yrs (median 1.9 yrs/pt)). LD+ patients tended to have more severe RA outcomes and comorbidities. MTX-monotherapy (48% vs 44%, p<0.001) and NTNFi were initiated more frequently in LD+ pts with lower use of TNFi (Figure). DMARD discontinuation rates were higher among LD+ patients for all DMARD groups, but KM curves were only significantly different for csDMARDs and TNFi. Different HRs for LD+ were found depending on the model used ranging from 1.18 to 1.28, and all models revealed an increased risk of discontinuation for LD+ patients. Compared to csDMARDs, TNFi were more often discontinued (Table). Other variables associated with an increased risk of discontinuation included: HAQ, Rheumatoid Disease (RD) comorbidity index, pain, prior bDMARDs, and csDMARDs.Conclusion:Different DMARD treatment patterns were found for LD+ patients, who tended to initiate more csDMARD and NTNFi and less likely to initiate a TNFi. LD+ patients were at a higher risk of discontinuation irrespectively of the DMARD treatment, but with greater risk for TNF users.References:[1]England BR, et al. Arth Care Res. doi:10.1002/acr.24043.Figure.DMARD treatment initiators by disease groupTable .Cox models for DMARD discontinuation by stepwise (removal probability 10%) and clinical models including DMARD treatment.Model of DMARD persistence*Model 1- Stepwise-Without drugsModel 2 – StepwiseModel 3 - ClinicalLD+ vs LD–1.181.281.20(1.08 - 1.29)(1.13 - 1.45)(1.08 - 1.34)TNF vs csDmard1.321.22(1.08 - 1.63)(1.04 - 1.44)NTNF vs csDmard1.131.13(0.83 - 1.52)(0.90 - 1.41)tsDmard vs csDmard1.301.02(0.65 - 2.60)(0.64 - 1.62)*Best models searched/Clinical adjusted for LD+/LD-, DMARDs, age, sex, education, HAQ disability, RD comorbidity index, smoking, pain, glucocorticoids, year of entry, prior bDMARDs and csDMARDs counts and MRC breath scale.Disclosure of Interests:Sofia Pedro: None declared, Ted Mikuls Grant/research support from: Horizon Therapeutics, BMS, Consultant of: Pfizer, Joe Zhuo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Kaleb Michaud: None declared

scholarly journals Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lukas Wettstein ◽  
Tatjana Weil ◽  
Carina Conzelmann ◽  
Janis A. Müller ◽  
Rüdiger Groß ◽  
...  
Keyword(s):  
Serine Protease ◽  
Immune Defense ◽  
Innate Immune ◽  
Respiratory Pathogen ◽  
The Novel ◽  
Airway Epithelial ◽  
Protein Library ◽  
Epithelial Cultures ◽  
Alpha 1 Antitrypsin ◽  
Novel Coronavirus

AbstractSARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

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