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)

Two unreleated adult males were found to be suffering from an association of pan-lobular severe emphysema and hepatomegally of unknown origin which led to the discovery of a marked deficit in alpha-1 antitrypsin (A1-AT) in relation to a PiZ phenotype. Liver biopsy revealed cirrhosis with portal fibrosis in one case and in both cases fatty infiltration with the accumulation of a glycoprotein antigenically identical to A1-AT. Electron microscopy showed this protein to be situated within the dilated lumina of the endoplasmic reticulum of the hepatocytes. A1-AT deficiency is usually associated with pulmonary involvement only in the adult and liver involvement only in the child. The association of the two remains rare--hence the interest of the two cases reported.
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PMID:[Pulmonary emphysema and hepatic involvement by alpha-1 antitrypsin deficiency in two adults with a PiZ phenotype (author's transl)]. 30 25

Extremely deficient levels of alpha-1-antitrypsin (ALPHA1AT) predispose such deficient individuals to the development of emphysema and cirrhosis. Protease inhibitor (Pi) typing has clarified that the inherited deficiency is codominant. A glycoprotein with antigenic characteristics of alpha1AT is found in the endoplasmic reticulum of the hepatocytes of individuals with PiZ phenotype. No therapy is available except liver transplantation. Although biochemical advances in defining the nature of alpha1AT deficiency are progressing, the pathogenesis of the liver disease remains an enigma.
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PMID:The current status of alpha-1-antityrpsin, a protease inhibitor, in gastrointestinal disease. 76 97

Human and bovine respiratory syncytial viruses resemble each other closely. During annual winter outbreaks, they cause similar respiratory tract disease in infants and calves. The disease is most severe in children and calves between 1 and 3 months old, when maternal antibodies against the virus are usually present. Reinfections, which are common, are accompanied by progressively milder illnesses in children, but are symptomless in calves. Because maternal antibodies suppress serum and mucosal antibody responses of all isotypes, the development of a vaccine that is effective in young children and calves with high levels of maternal antibodies has been severely hampered. Although virus administered intranasally to young calves with maternal antibodies does not evoke antibody responses, it can prime these calves for a protective memory response upon reinfection. Protection appears to be associated with the capacity to mount a mucosal memory IgA response. There are several indications that one or more immunopathologic mechanisms contribute to the disease. An Arthus reaction (type III) may have a role in the pathogenesis, because activated complement may cause most of the pathologic lesions, including edema and emphysema in uninfected parts of the lung. Lungs from calves with severe or fatal disease have depositions of complement component C3 and a low histamine content. The most immunogenic and protective antigen of the virus is the fusion (F) glycoprotein, which evokes a strong antibody response and is a target for cytotoxic T cells. On the F protein, epitopes that induce neutralizing and non-neutralizing antibodies, both of which may enhance complement activation, were identified. Immunity to the F protein may have beneficial and harmful effects.
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PMID:Immunity to human and bovine respiratory syncytial virus. 219 33

LSP contents of sputum samples from patients with chronic airway diseases were measured by an enzyme-linked immunosorbent assay (ELISA) kit which was designed by Kuroki et al to examine whether a substance identical to lung surfactant contained in alveolar lining layer, is also contained in respiratory tract fluid or not in the ELISA kit. One antibody to LSP was conjugated to peroxidase and another one to LSP was fixed onto a bead. A neo-anionic detergent, Triton X-100 and an anionic detergent, sodium dodecyl sulfate (SDS) were added to extraction medium to separate LSP from lung surfactant, and LSP reaction of sputum sample was maximal when the ratio of Triton X-100 to SDS was in range of 1 to 4. Airway mucous glycoprotein (AMG) purified from sputum sample did not show any LSP reaction. In CsCl density gradient ultracentrifugation of whole sputum, the LSP reaction was detectable only in the top fraction with density of about 1.40 and AMG was located in the fraction with a density of about 1.50. These results indicate that the LSP reaction of sputum sample is not due to false reaction caused by nonspecific binding of viscous AMG to the two antibodies to LSP, but to the existence of LSP. Therefore it was concluded that lung surfactant is contained in respiratory tract fluid. In general, the LSP concentrations in sputum samples were lower in purulent sputa than in mucoid or mucopurulent sputa, and lower in patients with diffuse panbronchiolitis and bronchiectasia than in those with pulmonary emphysema and chronic bronchitis. It was shown that LSP was hydrolyzed by neutrophil leucocyte homogenate. These results suggest that LSP content of sputum is influenced by various factors such as infection and disease in the respiratory tract, and thus is useful to estimate pathological states of chronic airway diseases.
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PMID:[Lung surfactant apoprotein (LSP) content of sputum samples from patients with chronic airway diseases]. 221 2

This article reviews some properties of human leucocyte elastase. This 30 kDa glycoprotein formed of 218 amino acid residues, is a serine proteinase which cleaves proteins at Val-X, Ala-X, Leu-X or Met-X bonds. Leucocyte elastase solubilizes fibrous elastin and also degrades other extracellular matrix proteins. It hydrolyses and inactivates a number of plasma proteins. Synthetic substrates are more convenient than elastin to measure elastase activity. A large number of natural and synthetic inhibitors of leucocyte elastase have been described. The former include alpha 1-proteinase inhibitor or alpha 1-antitrypsin, inter-alpha-inhibitor, alpha 2-macroglobulin, bronchial and cervical mucous inhibitor and a number of animal and plant proteins. Numerous synthetic inhibitors with therapeutic potentials have been designed. The efficiency of an inhibitor depends, among others, upon its rate of association with the enzyme and upon the stability of the enzyme-inhibitor complex. Elastase probably plays a physiological function in neutrophil migration, phagocytosis and tissue remodeling. It apparently plays a pathological role in pulmonary emphysema, rheumatoid arthritis, infections and inflammation. The pathogenic role of leucocyte elastase is best understood in emphysema.
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PMID:[Human leukocyte elastase]. 306 2

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 (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

A population (n = 526), consisting of employees with COPD, was compared with 2 control populations for the prevalence of Pi-phenotypes. In the patient group, the proportions of ZZ, SZ and MZ were significantly elevated. Among the patient population a prospective study was carried out to evaluate the role of alpha 1-antitrypsin deficiency as a cofactor in COPD. Severity of disease was estimated by standard pulmonary function tests, X-ray signs for emphysema and clinical assessment. Patients with ZZ, SZ and MZ were significantly worse than their MM partners. An influence of MS cannot be rejected. Phenotyping of all patients with COPD is advocated. Screening can also be by determining the ratio of alpha 1-antitrypsin and acid alpha 1-glycoprotein concentrations, which allowed detection of all ZZ, SZ, MZ and about 60% of the MS patients.
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PMID:Heterozygosity in the Pi-system as a pathogenetic cofactor in chronic obstructive pulmonary disease (COPD). 387 84

Parenchymal liver cells from emphysema patients with an inherited deficiency of alpha(1)-antitrypsin contain globules of glycoprotein that bind fluorescent antibody to alpha(1)-antitrypsin. The globules can be seen after hematoxylin and eosinstaining or on electron microscopy, but are more readily demonstrated by PAS stain of amylase-treated liver sections. It appears that an inappropriately large amount of alpha(1)-antitrypsin is found in the liver even when there is a deficiency in the serum. Genetic variants of the normal antitrypsin molecule may be unable to leave their site of synthesis in the liver cell because of some molecular aberration.
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PMID:Alpha 1 antitrypsinin the livers of patients with emphysema. 410 12

alpha 1-Antitrypsin, the major serum protease inhibitor, is a glycoprotein synthesized in the liver. Severe deficiency results in protease-antiprotease imbalance, which predisposes to severe emphysema at a young age. Reduced serum levels reflect inadequate release of alpha 1-antitrypsin by the liver, which may be caused by specific defects in biosynthesis. The deficiency is inherited, with multiple codominant alleles at a single autosomal locus. Homozygous individuals, with severely reduced alpha 1-antitrypsin levels, have dyspnea, pulmonary function abnormalities, and respiratory disability from emphysema, usually in the fifth decade of life, with smokers being affected one decade earlier. Heterozygous individuals have intermediate alpha 1-antitrypsin levels and a more benign clinical course. Heterozygous smokers may have mild pulmonary function abnormalities, but these are of uncertain clinical significance. Hepatic involvement with transient neonatal hepatitis and cirrhosis with subsequent liver failure in adulthood represent the major extrapulmonary manifestations, occurring in 10% of homozygous individuals.
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PMID:alpha 1-Antitrypsin deficiency. 632 84


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