Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The hereditary disorder alpha 1-antitrypsin (alpha 1AT) deficiency results in the development of emphysema due to a diminished anti-neutrophil elastase screen of the lower respiratory tract. Specific therapy for this disorder is available in the form of weekly intravenous infusions of human plasma alpha 1AT, which effectively reconstitute the anti-elastase screen of the lung in these individuals. In an attempt to reduce the frequency of therapy we evaluated the ability of monthly infusions of alpha 1AT to provide equivalent lower respiratory tract protection against neutrophil elastase. Intravenous infusion of 250 mg/kg of alpha 1AT at 28-day intervals to nine individuals with alpha 1AT deficiency and emphysema was carried out for 12 months. Serum alpha 1AT levels exceeded the protective threshold for an average of 25 days after each dose of alpha 1AT was administered. Furthermore, the postinfusion level of alpha 1AT in the nadir lung epithelial lining fluid was fivefold greater than the preinfusion level, and the anti-neutrophil elastase capacity of the nadir epithelial lining fluid also was elevated significantly, nearly threefold above the preinfusion level. These results indicate that monthly administration of human alpha 1AT is fully capable of adequately augmenting serum and lung alpha 1AT levels and anti-elastase capacity and is therefore a rational alternative to weekly therapy.
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PMID:Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. 326 53

When neutrophils invade inflamed areas of the body to remove either dead or foreign components they inadvertently release potent enzymes which can, if not properly controlled, cause severe damage to healthy tissue. This can lead to a myriad of diseases including emphysema, rheumatoid arthritis, and glomuerlopnephritis, all of which are really problems of abnormal connective tissue turnover due to uncontrolled protelysis by neutrophil elastase and cathepsin G. An important step in elucidating the functions of both elastase and cathepsin G has been made by virtue of the fact that the amino acid sequence of each has been determined. Furthermore, the crystal structure of one, neutrophil elastase, is now understood. With this knowledge in mind and with the potential for a similar understanding of the mechanism of action of cathepsin G, it should soon be possible to produce synthetic inhibitors of each enzyme which can act as adjunct inhibitors to those naturally circulating in the blood or present in other tissues. As a result there is great hope for reducing the severity of injury produced by these enzymes and, therefore, in decreasing the risk for development of the debilitating diseases associated with abnormal proteolysis by neutrophil proteinases.
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PMID:Neutrophil elastase and cathepsin G: structure, function, and biological control. 326 7

Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in hepatocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys387); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.
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PMID:Molecular basis of alpha-1-antitrypsin deficiency. 328 85

Alpha-1-antitrypsin (A1AT) deficiency is a genetic disorder characterized by low serum levels of A1AT and a high risk for the development of emphysema. A1AT is the principal inhibitor of neutrophil elastase, such that a deficiency of A1AT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of A1AT augmentation therapy in A1AT deficiency is to raise lung A1AT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human A1AT (60 mg/kg at weekly intervals) demonstrate that serum A1AT levels increased from an average 33 +/- 8 mg/dl pre-infusion to a steady-state trough level of 117 +/- 4 mg/dl, well above the projected threshold protective serum level of A1AT. The infused A1AT diffused into the lung and significantly augmented the epithelial lining fluid A1AT levels, rising from an average 0.44 +/- 0.16 microM (pre-infusion) to 2.62 +/- 1.29 microM at the nadir level just prior to the next infusion. Of critical importance is the fact that the A1AT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection. In the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of A1AT is a rational, safe, and biochemically effective therapy for A1AT deficiency.
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PMID:Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency. 328 87

Previous ultrastructural studies of human neutrophils showed two distinctive granule types, the azurophil (peroxidase-positive) and the specific (peroxidase-negative). By identification of granules with peroxidase activity and those immunopositive for elastase antigen, the authors defined two subpopulations of azurophil granules, one that contained peroxidase activity and no measurable elastase antigen and another that contained elastase antigen associated with a small amount of peroxidase activity. They quantitated the peroxidase-positive as well as the elastase-positive granules in human peripheral blood neutrophils and found an average of 1536 +/- 69 peroxidase-positive granules per neutrophil. Of these, 399 +/- 20 were also elastase-positive. The average elastase concentration per neutrophil was 1.59 pg, and the average concentration per granule was 4 X 10(-3) pg. It is concluded that in normal individuals approximately one-third of the azurophil granules contain elastase antigen. Because neutrophil elastase has been implicated in the pathogenesis of emphysema, quantitation of its distribution within the cell presents an approach that may help define selective azurophil granule release and its relationship to the development of emphysema.
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PMID:Ultrastructural quantitation of peroxidase- and elastase-containing granules in human neutrophils. 335 53

A series of 4-(acyloxy)- and 4,4'-bis(acyloxy)benzophenones were synthesized. Some of them, pivalates (trimethylacetates) and isobutyrates in particular, were found to be potent and selective inhibitors of human neutrophil (leukocyte) elastase. A series of 2-[(acyloxy)methyl]-5-(acyloxy)-4-pyrones were synthesized regioselectively from kojic acid. The 4-pyrones bearing a long chain acyl group at the 2-position and either pivaloyloxy or isobutyryloxy at the 5-position were potent and selective inhibitors of the human elastase. A number of analogues and derivatives in both series were synthesized in order to study the structure-activity relationship as summarized in Tables I-VI and in Tables IX and X. The inhibition was selective to human neutrophil elastase. No inhibition of porcine pancreatic elastase or bovine pancreatic chymotrypsin (Tables VII and XI) was observed. The most likely mechanism of inhibition is discussed. The implication of these findings for the treatment of rheumatoid arthritis and emphysema is outlined.
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PMID:(Acyloxy)benzophenones and (acyloxy)-4-pyrones. A new class of inhibitors of human neutrophil elastase. 336 75

To test the role of elastase in the pathogenesis of emphysema human neutrophil elastase (HNE) was localised by electron microscopy using an immunogold staining technique. Specific localisation of HNE to elastic tissue in emphysema did not occur, but non-specific binding of immunoglobulin G (IgG) to elastic tissue in emphysematous and normal lung tissue, which was completely blocked by the non-immune serum that was homologous to the gold labelled second antibody, was found. HNE was also present, however, in the granules of neutrophils in the same sections. Non-specific labelling associated with elastin was probably due to binding of IgG to the high numbers of hydrophobic and charged regions known to be present in this molecule, and it is concluded that our findings do not support the existence of high concentrations of elastase in association with elastin in emphysematous lung tissue.
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PMID:Is neutrophil elastase associated with elastic tissue in emphysema? 292 38

Alpha 1-antitrypsin (alpha 1AT), a 52,000-mol-wt serum glycoprotein produced by hepatocytes and mononuclear phagocytes, functions as the major inhibitor of neutrophil elastase. The alpha 1AT haplotype S is associated with childhood liver disease and/or adult emphysema when inherited with the Z haplotype to give the phenotype SZ. To accurately identify the SZ phenotype at the level of genomic DNA, four 32P-labeled 19-mer synthetic oligonucleotide probes were prepared; two to identify the M and S difference in exon III, and two to identify the M and Z difference in exon V. These probes were hybridized with various cloned DNAs and genomic DNAs cut with the restriction endonucleases BgII and EcoRI; the genomic DNAs represented all six possible phenotype combinations of the M, S, and Z haplotypes (MM, MS, MZ, SS, ZZ, and SZ). Using the four probes to evaluate 42 samples of genomic DNA, the "at risk" SZ and ZZ phenotypes were correctly identified in all cases, as were the "not at risk" phenotypes SS, MS, MM, and MZ, demonstrating that both exon III and exon V directed probes are necessary to properly identify all of the major "at risk" alpha 1AT genes. However, when used to evaluate a very rare family carrying a null allele, these four oligonucleotide probes misidentified the "at risk" null-null and S null phenotypes as "not at risk" MM and SM combinations. These observations indicate that oligonucleotide gene probes yielded reliable and accurate assessment of "at risk" alpha 1AT genotypes in almost all situations, but in the context of prenatal diagnosis and genetic counseling this approach must be used with caution and in combination with family studies so as not to misidentify rare genotypes that may be associated with a risk for disease.
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PMID:Evaluation of "at risk" alpha 1-antitrypsin genotype SZ with synthetic oligonucleotide gene probes. 348 54

The human protease inhibitor genes alpha 1 antitrypsin (alpha 1-PI) and alpha 1-antichymotrypsin (alpha 1-ACT) are acute-phase proteins which are induced in response to inflammation. These inhibitors function to limit the activity of serine proteases in vivo. alpha 1-PI acts as an inhibitor of neutrophil elastase to protect the elastin fibers of the lung. Genetic deficiencies of alpha 1-PI result in development of chronic pulmonary emphysema. The physiologic role of alpha 1-ACT has not been clearly defined, but it also appears to function in the maintenance of protease-protease inhibitor equilibrium in the lung. Nucleic acid and protein sequence homologies detected between alpha 1-PI and alpha 1-ACT suggested an evolutionary relationship. Gene mapping experiments were performed to determine if these protease inhibitor genes reside at the same chromosomal locus in man. In situ hybridization data demonstrate that both alpha 1-PI and alpha 1-ACT map to the same region, q31-q32.3, on chromosome 14.
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PMID:Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14. 348 24

In patients with alpha 1-antitrypsin deficiency, the development of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We evaluated the feasibility, safety, and biochemical efficacy of intermittent infusions of alpha 1-antitrypsin in the treatment of patients with alpha 1-antitrypsin deficiency. Twenty-one patients were given 60 mg of active plasma-derived alpha 1-antitrypsin per kilogram of body weight, once a week for up to six months. After a steady state had been reached, the group had trough serum levels of alpha 1-antitrypsin of 126 +/- 1 mg per deciliter as compared with 30 +/- 1 mg per deciliter before treatment, and serum anti-neutrophil elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin level in the epithelial-lining fluid of the lungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophil elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophil elastase capacities (1.65 +/- 0.13 microM) in the lining fluid were significantly increased (P less than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of lung destruction, the clinical efficacy of this therapy could not be studied rigorously. No changes in lung function were observed in our patients over six months of treatment. The only important adverse reactions to the 507 infusions were four episodes of self-limited fever. This study demonstrates that infusions of alpha 1-antitrypsin derived from plasma are safe and can reverse the biochemical abnormalities in serum and lung fluid that characterize this disorder. Together with lifetime avoidance of cigarette smoking, replacement therapy with alpha 1-antitrypsin may be a logical approach to long-term medical treatment.
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PMID:Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. 349 98


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