Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?

AbstractAlpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but considerably under-recognised. Most patients are diagnosed later in life, by which time they may have accumulated significant lung, liver and multisystem damage. Disease presentation is heterogeneous and not fully explained by deficiency levels alone or exposure to cigarette smoking. This suggests other factors influence AATD-associated pathological processes. Aging itself is associated with organ dysfunction, including emphysema and airflow obstruction, inflammation, altered immune cell responses (termed immunosenescence) and a loss of proteostasis. Many of these processes are present in AATD but at an earlier age and more advanced stage compared with chronological aging alone. Augmentation therapy does not completely abrogate the manifold disease processes present in AATD. New approaches are needed. There is emerging evidence that both age- and AATD-related...
Source: Drugs and Aging - Category: Geriatrics Source Type: research

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α1-Antitrypsin (AAT) encoded by the SERPINA1 gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a ...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research
Authors: Kueppers F Abstract Alpha 1 antitrypsin deficiency (AATD) is a rarely diagnosed hereditary condition characterized by low alpha 1 antitrypsin (AAT) levels, which can lead to early-onset emphysema due to accelerated degradation of lung tissue. Similar to C-reactive protein (CRP), AAT is an acute phase reactant, meaning that blood levels rise in response to inflammation, injury or infection. Testing AAT levels is essential in the diagnosis of AATD; however, the presence of inflammation at the time of AATD testing can provide a false 'normal' level reading of the patient's baseline AAT levels. Researchers fro...
Source: COPD: Journal of Chronic Obstructive Pulmonary Disease - Category: Respiratory Medicine Tags: COPD Source Type: research
Authors: Miravitlles M, Nuñez A, Torres-Durán M, Casas-Maldonado F, Rodríguez-Hermosa JL, López-Campos JL, Calle M, Rodríguez E, Esquinas C, Barrecheguren M Abstract Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed disease that is associated with the development of liver disease in adults and children and pulmonary emphysema in adults. Several studies have shown that there is limited knowledge about the disease and its diagnosis among health care providers, and there is an important inequity in the access to specialized care and appropriate treatment across Europ...
Source: COPD: Journal of Chronic Obstructive Pulmonary Disease - Category: Respiratory Medicine Tags: COPD Source Type: research
Alpha-1 antitrypsin deficiency (AATD) was the first genetic risk factor for chronic obstructive pulmonary disease (COPD) described. In the more than 50  years since its description, the disease continues to provide insights into more common forms of COPD. Although AATD is caused by a single genetic variant, the clinical manifestations of disease include panacinar emphysema, airway hyperresponsiveness, and bronchiectasis. With improved molecular un derstanding of the mechanisms of disease pathogenesis and progression, new therapies in addition to intravenous augmentation therapy are on the horizon.
Source: Clinics in Chest Medicine - Category: Respiratory Medicine Authors: Source Type: research
After the discovery of lung emphysema associated with α1-antitrypsin (AAT) deficiency (AATD) in 1963 by Laurell and Eriksson [1], basic and clinical advances in the AATD field have been dramatic and relatively fast [2]. It was soon confirmed that AATD was an inherited codominant recessive condition, but it took seven more years to associate AATD-related lung emphysema with neutrophil elastase [3, 4], and between 7 to 10 years to discover its causal relationship with childhood and adult liver cirrhosis [5, 6], and with neutrophilic panniculitis [7]. In the 1970s, isoelectric focusing (IEF) became the technique of...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Editorials Source Type: research
Conclusion: Quantitative SPECT/CT is useful in pre-surgical evaluation or radiation treatment planning of patients with pulmonary nodule or lung mass. Larger sample size of patients with underlying emphysema is needed to further evaluate the utility of this technique. We recommend Quantitative perfusion SPECT/CT for lobar assessment than traditional regional quantitative perfusion prior to surgery.
Source: Journal of Nuclear Medicine - Category: Nuclear Medicine Authors: Tags: Infection/Pulmonary/Outcomes (Poster Session) Source Type: research
Bocchino Alpha-1-antitrypsin deficiency (AATd) is a hereditary disease, mainly characterized by early onset and the lower lobes’ predominant emphysema. Bronchiectasis is characterized by dilatation of the bronchial wall and a clinical syndrome whose features are a cough, sputum production and frequent respiratory exacerbations. In the literature, there are many papers concerning these two clinical entities, but there is still a lot of debate about a possible association between them, in particular about the frequency of their association and causal links. The aim of this short communication is to show the li...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Communication Source Type: research
α1-antitrypsin deficiency (AATD) is a hereditary disorder associated with a risk of developing liver disease and pulmonary emphysema, and other chronic respiratory disorders (mainly asthma and bronchiectasis); Z variant is the commonest deficient variant of AAT. Determining AAT concentration in serum or plasma and identifying allelic variants by phenotyping or genotyping are fundamental in the diagnosis of AATD. Initial evaluation and annual follow-up measurement of lung function, including post-bronchodilator forced expiratory volume in 1 s and gas transfer inform on disease progression. Lung densitometry is th...
Source: European Respiratory Review - Category: Respiratory Medicine Authors: Tags: COPD and smoking, Genetics Review Source Type: research
Background: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder. Most of case of severe AAT are caused by Z and S mutations in the SERPINA1 gene, that reduces serum AAT concentrations till to 15% of normal levels. Mutations causing total absence of serum AAT (Null mutations) are very rare. Individuals homozygouse for Null mutations should be considered a subgroup at particularly high risk of emphysema, but their clinical phenotype is poorly described.Objectives: We would like to evaluate the differences between clinical history of AATD in subject with the most prevalent deficient genotype (PI*ZZ) and those with rare...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Molecular pathology and funct. genomics Source Type: research
Introduction: The deficit of alpha 1 antitrypsin (A1AT) is caused by mutations in the A1AT gene (long arm chromosome 14). The aim of this study is to analyze the prevalence of mutations in this gene in patients with pulmonary emphysema without severe A1AT deficiency (
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Monitoring airway disease Source Type: research
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