Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alpha-1 antitrypsin deficiency is a genetic condition that increases the risk of a variety of conditions including pulmonary emphysema and chronic liver disease. We report on a 33-yr-old male fighter pilot with early-onset pulmonary emphysema with bullae who developed spontaneous pneumothorax during in-flight combat training. A CT scan of his chest after removal of the chest tube showed multiple variably sized bullae and pulmonary cysts scattered throughout both lungs. Serum levels of alpha-1 antitrypsin were markedly decreased. Genetic analyses showed a PI ZZ genotype. Alpha-1 antitrypsin deficiency often goes undiagnosed by flight surgeons, which is a risk to flight safety.
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PMID:Spontaneous pneumothorax in flight as first manifestation of alpha-1 antitrypsin deficiency. 1861 32

Alpha-1 antitrypsin deficiency is a recently identified genetic disease that occurs almost as frequently as cystic fibrosis. It is caused by various mutations in the SERPINA1 gene, and has numerous clinical implications. Alpha-1 antitrypsin is mainly produced in the liver and acts as an antiprotease. Its principal function is to inactivate neutrophil elastase, preventing tissue damage. The mutation most commonly associated with the clinical disease is the Z allele, which causes polymerization and accumulation within hepatocytes. The accumulation of and the consequent reduction in the serum levels of alpha-1 antitrypsin cause, respectively, liver and lung disease, the latter occurring mainly as early emphysema, predominantly in the lung bases. Diagnosis involves detection of low serum levels of alpha-1 antitrypsin as well as phenotypic confirmation. In addition to the standard treatment of chronic obstructive pulmonary disease, specific therapy consisting of infusion of purified alpha-1 antitrypsin is currently available. The clinical efficacy of this therapy, which appears to be safe, has yet to be definitively established, and its cost-effectiveness is also a controversial issue that is rarely addressed. Despite its importance, in Brazil, there are no epidemiological data on the prevalence of the disease or the frequency of occurrence of deficiency alleles. Underdiagnosis has also been a significant limitation to the study of the disease as well as to appropriate treatment of patients. It is hoped that the creation of the Alpha One International Registry will resolve these and other important issues.
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PMID:[Alpha-1 antitrypsin deficiency: diagnosis and treatment]. 1869 97

The integrity of lung alveoli is maintained by proper circulating levels of alpha-1 antitrypsin (A1AT). Next to cigarette smoking, A1AT deficiency is a major risk factor for lung emphysema development. We recently reported that in addition to neutralizing neutrophil elastases in the extracellular compartment, A1AT is internalized by lung endothelial cells and inhibits apoptosis. We hypothesized that the intracellular uptake of A1AT by endothelial cells may be required for its protective function; therefore, we studied the mechanisms of A1AT internalization by primary rat lung microvascular endothelial cells and the effect of cigarette smoke on this process both in vitro and in vivo (in mice). Purified A1AT was taken up intracellularly by endothelial cells in a time-dependent, dose-dependent, and conformer-specific manner and was detected in the cytoplasm of endothelial cells of nondiseased human lung sections. Despite a critical role for caveoli in endothelial cell endocytosis in general, specific inhibition of clathrin-mediated, but not caveoli-mediated, endocytosis profoundly decreased A1AT internalization and reversed the A1AT's antiapoptotic action. Further more, A1AT associated with clathrin heavy chains, but not with caveolin-1 in the plasma membrane fraction of endothelial cells. Interestingly, cigarette smoke exposure significantly inhibited A1AT uptake both in endothelial cells and in the mouse lung and altered the intracellular distribution of clathrin heavy chains. Our results suggest that clathrin-mediated endocytosis regulates A1AT intracellular function in the lung endothelium and may be an important determinant of the serpin's protection against developing cigarette smoke-induced emphysema.
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PMID:Mechanism of alpha-1 antitrypsin endocytosis by lung endothelium. 1942 38

The hereditary disorder alpha-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kappaB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease-anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.
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PMID:Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. 2022

Chronic obstructive pulmonary disease is mainly characterized by irreversible airflow limitation, and its major pathological change is alveolar destruction and enlargement, which induces emphysema. In this study, we used stereoscopic microscopy to observe the cut surfaces of 21 surgically resected or autopsied lungs showing centriacinar emphysema. We identified columnar structures of various sizes in the cystic spaces. These columnar structures constituted two types: one that was associated with pulmonary artery and another that was not. We examined these structures in detail by light microscopy and performed statistical analyses. Columnar structures without pulmonary artery showed destruction and accumulation of alveoli, including abnormally aggregated elastic fibers. In contrast, pulmonary architecture was preserved in columnar structures with pulmonary artery. In columnar structures without pulmonary artery, statistically significant correlations were observed between the thickness of columnar structures and size of centriacinar cystic spaces and between the thickness of columnar structures and aggregation of elastic fibers in columnar structures. Electron microscopy showed that the columns were composed of aggregated elastic fibers, collagen fibers, mesenchymal cells, pigmented macrophages, and the alveolar epithelial cells covering them. Immunohistochemistry showed that the aggregated elastic fibers were positive for alpha-1 antitrypsin. We concluded that columnar structures without pulmonary artery are a hallmark of alveolar wall destruction seen in pulmonary emphysema.
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PMID:Considerations on the mechanisms of alveolar remodeling in centriacinar emphysema. 2030 86

Alpha-1 antitrypsin deficiency is a hereditary metabolic disorder predisposing its carrier to lung and liver damage. Organ damage results from decreased secretion of alpha-1 antitrypsin from hepatocytes to circulation, caused by a genetic mutation. Decreased alpha-1 antitrypsin level predisposes to early-onset pulmonary emphysema. Unsecreted alpha-1 antitrypsin accumulating into hepatocytes may in turn lead to an inflammatory reaction, increase in fibrous tissue and finally to liver cirrhosis.
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PMID:[Alpha-1 antitrypsin deficiency]. 2203 28

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.
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PMID:Alpha-1-antitrypsin and other proteinase inhibitors. 2236 3

A 44-year-old woman, who had been diagnosed as having null type alpha-1 antitrypsin (AAT) deficiency, was admitted with right recurrent pneumothorax. She had undergone right visceral pleural strengthening and pleural adhesion-preventing surgery, the total pleural covering technique (TPC), with oxidized regenerative cellulose (ORC). Three years after the operation, she developed left recurrent pneumothorax and underwent left TPC. AAT deficiency is a rare inherited disease in Japan that causes early-onset emphysema and secondary pneumothorax. In addition, null/null phenotype has the highest risk of emphysema and may require lung transplantation. For future lung transplantation, pleural adhesion should be prevented. However, pleurodesis and surgery for pneumothorax generally cause adhesion. TPC with ORC is a surgical treatment for pneumothorax that is done to strengthen visceral pleura and prevent pleural adhesions. The patient has had no recurrence of pneumothorax 3.5 years after right TPC and 6 months after left TPC.
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PMID:Null allele alpha-1 antitrypsin deficiency: case report of the total pleural covering technique for disease-associated pneumothorax. 2254 22

The past 50 years have seen huge advances in our understanding of the pathogenesis of alpha-1 antitrypsin deficiency. It is widely accepted that the common severe Z deficiency allele causes mutant alpha-1 antitrypsin to be retained as inclusions of ordered polymers within hepatocytes. This causes circulating deficiency of an important proteinase inhibitor, an excess of neutrophil elastase and therefore tissue destruction and emphysema. However, the past two decades have led to a shift in the paradigm from a disease that results from simply an imbalance of enzymes and inhibitors to one in which there is growing recognition that the polymers themselves play a role, not only in the liver disease, but also in the associated emphysema, vasculitis and panniculitis. Much of this has been dealt with in previous, more detailed reviews. I have therefore taken this opportunity of the 50th anniversary of the discovery of alpha-1 antitrypsin deficiency to present a personal overview of the past 22 years. This review considers the description of alpha-1 antitrypsin polymers, an assessment of their role in the different components of alpha-1 antitrypsin deficiency, the role of polymers in other diseases and how our understanding of polymerisation can be exploited to develop novel therapeutic strategies. The ultimate aim of our work is to develop a cure for alpha-1 antitrypsin deficiency.
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PMID:Twenty years of polymers: a personal perspective on alpha-1 antitrypsin deficiency. 2352 23

Alpha-1 antitrypsin Deficiency (AATD) is a common, but under recognized metabolic genetic disease. Although many mutations in the alpha-1 antitrypsin (AAT) gene are described, the Z variant is the allele overwhelmingly associated with liver disease. PI*ZZ homozygotes occur in approximately 1 in 2,000-5,000 births in North American and European populations. The AAT protein is synthesized in large quantities by the liver, and then secreted into serum. Its physiologic function is to inhibit neutrophil proteases in order to protect host tissues from non-specific injury during periods of inflammation. The mutant Z gene of AAT directs the synthesis of a mutant protein which folds abnormally during biogenesis in the endoplasmic reticulum of hepatocytes and is retained intracellularly, rather than efficiently secreted. Intracellular proteolysis pathways, including the proteasome and autophagy, are activated as a response to the intracellular burden of misfolded protein. The lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. The intracellular accumulation of AAT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma by triggering a cascade of chronic hepatocellular apoptosis, regeneration, and end organ injury. There is no specific treatment for PI*ZZ associated liver disease, other than standard liver supportive care and liver transplantation. There is a high degree of variability in the clinical manifestations among PI*ZZ homozygous patients, suggesting a strong influence of as yet poorly characterized, genetic and environmental disease modifiers. Studies of the processes of intracellular injury have led to a new era of rational therapeutic development.
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PMID:Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. 2352 37


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