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)

Serum levels of alpha 1-antitrypsin (AAT) were determined by an enzymatic assay method in fifty-five asthmatic children and in the same number of controls. The mean AAT level was significantly lower in asthmatics (1.65 mumol/min/ml) than in controls (2.0 mumol/min/ml) (P less than 0.02). A significantly higher proportion of asthmatics than controls (P less than 0.05) had levels below 2.1 mumol/min/ml which is the lower limit of normal, thus suggesting a higher prevalence of partial (heterozygous) AAT deficiency in the asthmatics. There was no relationship between the mean AAT levels and age, duration of asthma or frequency of asthmatic attacks. Although there is some controversy about the relationship between heterozygous AAT deficiency and pulmonary disease, severe (homozygous) AAT deficiency has been linked with emphysema which is also a complication of asthma. There was however, no evidence of emphysema in either the asthmatic child or the control who had no detectable serum AAT. There were three asthmatics whose chest radiographs showed hyperinflation, but had a mean AAT level that was not significantly different from that in those without such changes. Further studies, including phenotype determination in a larger group of asthmatic children, are required in order to determine the prevalence of both homozygous and heterozygous AAT deficiencies which may be risk factors in the development of emphysema and other pulmonary complications of asthma.
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PMID:Serum alpha 1-antitrypsin levels in asthmatic children. 300 75

The cirrhosis and hepatocellular carcinoma associated with alpha 1-antitrypsin deficiency has been exclusively reported with the PI Z allele. We present a 63-yr-old white man with emphysema, cirrhosis, and hepatocellular carcinoma. The latter occurred on a background of diffusely distributed hepatocellular dysplasia. Serum protein electrophoresis suggested a deficiency of alpha 1-antitrypsin quantitated at 13% of normal. PI phenotyping showed that he had only the rare PI Mmalton allele, previously associated only with severe lung disease. Family studies demonstrated the distribution of this rare allele. The liver at autopsy displayed well-differentiated hepatocellular carcinoma in addition to alpha 1-antitrypsin deposits in normal, dysplastic, and malignant cells.
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PMID:Diffuse hepatocellular dysplasia and carcinoma associated with the Mmalton variant of alpha 1-antitrypsin. 303 14

Specific gene probes were used to study restriction fragment length polymorphisms of the human alpha 1-antitrypsin gene. A polymorphism due to loss of a recognition site for the restriction enzyme Taq I was identified in eight of 42 patients with bronchiectasis and nine of 49 patients with pulmonary emphysema, none of whom had alpha 1-antitrypsin deficiency. Among a control group without lung disease the polymorphism was significantly less frequent, being found in only five of 101 apparently healthy blood donors. The deoxyribonucleic acid (DNA) polymorphism was also present in two of 14 unrelated patients with alpha 1-antitrypsin deficiency, indicating a lack of association with any specific alpha 1-antitrypsin protein phenotype. The polymorphism identified in this study may be a new marker for genetic predisposition to chronic lung disease.
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PMID:Deoxyribonucleic acid (DNA) polymorphism of the alpha 1-antitrypsin gene in chronic lung disease. 303 56

The major serum antiprotease is alpha 1-antitrypsin (A1AT). Deficiency of A1AT can result in infantile cirrhosis and premature emphysema, both of which have a high degree of morbidity and significant mortality. Although synthesized primarily by the liver, A1AT has been histochemically localized in monocytes and macrophages in vitro and has been shown to be produced in tissue culture of monocyte-macrophage origin. This study was planned to quantitatively and qualitatively assess the in vivo monocyte-macrophage system contribution to serum A1AT. We used bone marrow transplantation (BMT) as an experimental method because there is commanding evidence that after engraftment, the monocyte-macrophage system of the recipient is replaced by that of donor origin. Protease inhibitor (Pi) typing was done on 150 potential BMT recipients and on their potential donors before transplantation. From these initial recipients, 92 eventually underwent transplantation, and 11 recipient-donor pairs, in which each donor's Pi type contained a band not in the recipient's Pi type, were chosen for the study. Six recipients survived beyond 100 days after BMT, and in these cases the donor contained either an S or an M2 band in his or her Pi type not present in the recipient. Using a silver stain method on diluted serum of known M1M2 and MS types, we were able to detect a 2% dilution of the S band and a 25% dilution of the M2 band. When the same method was applied to gels used in typing recipient Pi after BMT, we were unable to detect any contribution to serum A1AT by the donor monocyte-macrophage system.
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PMID:Contribution of monocyte-macrophage system to serum alpha 1-antitrypsin. 304 64

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

It has been demonstrated experimentally that the bullae observed in autoimmune pemphigus are due to the action of proteases. So far, no case of pemphigus associated with deficiency in antiprotease has been reported. We present a case of pemphigus associated with familial deficiency in alpha 1-antitrypsin (alpha 1-AT), a major human body antiprotease. A 35-year old man presented with pemphigus preceded during 18 months, and accompanied by pruritus. The lesions were polymorphous, being made of solitary bullae, circinate vesiculobullae and squamous scabie plaques. Histopathological examination showed an intraepidermal bulla with acantholysis, a very spongiosis. The diagnosis of autoimmune pemphigus was confirmed by fluorescence of the epidermis in IgG and C3 and by the presence of antibodies directed against the intracellular substance. The initial treatment, which consisted of prednisolone 10 mg/kg/day and 10 plasma exchanges, was rapidly successful, but several relapses occurred thereafter. Two years after the pemphigus was diagnosed, a panlobular emphysema was discovered which made it possible to demonstrate a severe familial deficiency in alpha 1-AT of the Pi phenotype. This is the first published case of alpha 1-AT deficiency associated with autoimmune pemphigus. In our patient the skin disease presented as herpetiform pemphigus (initial features of dermatitis herpetiformis, followed by misleading polymorphous lesions, rare acantholytic cells, good response to corticosteroids), but there was no eosinophilic spongiosis. The frequency of alpha1-AT deficiency (estimated at 1 in 1,000 in northern Europe) and the lack of published cases with such an association may suggest a pure coincidence.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Autoimmune pemphigus combined with alpha 1-antitrypsin deficiency]. 306 24

Homozygous inheritance of the null bellingham alpha 1-antitrypsin (alpha 1AT) gene is associated with early-onset emphysema, resulting from the lack of alpha 1AT to protect the lung from neutrophil elastase. Cloning and sequencing of the null bellingham gene demonstrated that the promoter region, coding exons, and all exon-intron junctions were normal except for a single base substitution in exon III, causing the normal lys217 (AAG) to become a stop codon (TAG). Evaluation of genomic DNA of family members by using oligonucleotides directed toward this region demonstrated that the index case had inherited this mutation in a homozygous fashion. Although the consequences to the individual (i.e., emphysema) are identical to those associated with the common homozygous Z mutation, the homozygous null bellingham form of alpha 1AT deficiency has a very different genetic basis.
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PMID:Emphysema associated with complete absence of alpha 1- antitrypsin in serum and the homozygous inheritance [corrected] of a stop codon in an alpha 1-antitrypsin-coding exon. 325 51

The major physiological role of the serine protease inhibitor alpha 1-antitrypsin (alpha 1-AT) is to protect elastic fibers in the lung from excessive hydrolysis by neutrophil elastase. Genetic deficiency of alpha 1-AT predisposes individuals toward the development of emphysema. We have cloned and characterized a mutant alpha 1-AT gene from an individual exhibiting a total absence of immunoreactive alpha 1-AT in serum. Nucleotide sequence analysis of this "null" allele has demonstrated a TC dinucleotide deletion within the codon for Leu318 in exon IV. This frame-shift mutation results in the generation of a premature termination codon at residue 334, which is upstream of the active inhibitory site. To determine the biochemical basis of the null phenotype, the mutant and normal genes were transferred into mouse hepatoma cells for expression analysis. Pulse-chase experiments demonstrated that the mutant gene is expressed into a truncated protein of 45 kDa, which is retained within the rough endoplasmic reticulum. The complete lack of secretion of the truncated protein is consistent with the absence of immunoreactive alpha 1-AT in the patient's serum. In addition, a G to A transition was identified in exon II of the mutant gene, changing the codon for Arg101 to His101. Finally, an A to C transversion was identified in exon V changing the codon for Glu376 to Asp376. Since the latter conservative amino acid substitution has previously been identified in the common PiM2 variant, the frame-shift mutation might have occurred on a PiM2 background chromosome. Using the birthplace of this index case, this mutant alpha 1-AT allele has been designated "nullHong Kong."
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PMID:A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. 325 32

Alpha 1-Antitrypsin is the principal serum protease inhibitor. In addition to the well-recognized association with early-onset emphysema and cirrhosis, alpha 1-antitrypsin deficiency may be associated with panniculitis. In this article we describe three patients in whom the recognition of certain clinical and histologic features of panniculitis eventually led to the diagnosis of alpha 1-antitrypsin deficiency. Two of our patients were young adults and one was a child. All three had draining, panniculitis, or cellulitis-like lesions at sites of prior trauma. The histopathologic findings were characterized by liquefactive dermal necrosis and collagenolysis of the fibrous septa of the subcutis. The combination of these clinical and microscopic findings should suggest the diagnosis of alpha 1-antitrypsin deficiency panniculitis. The suspicion can be verified by obtaining quantitative serum levels and enzyme phenotyping. The identification of the alpha 1-antitrypsin deficiency state as the cause of a distinct type of panniculitis adds additional evidence for the elimination of the term Weber-Christian disease.
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PMID:Alpha 1-antitrypsin deficiency associated with panniculitis. 325 92

Nine patients with moderate pulmonary emphysema, six of PiZ phenotype and three of PiM phenotype, have received a single intravenous infusion of alpha-1-proteinase inhibitor (human) (A1PI), in a dose of 60 mg/kg over a 30-minute period. They also received a tracer dose (300 microCi) of 131I-labeled A1PI. No active or passive immunization against hepatitis was given. No acute toxicity was observed. Compared with baseline data, significant elevations of serum A1PI (measured both antigenically and as anti-elastase activity) occurred, with a serum half-life approximating 110 hours. Bronchoalveolar lavage fluid, obtained 48 hours after infusion, reflected a significant increase in A1PI concentration versus baseline bronchoalveolar lavage fluid values. Serial gamma camera images of the lungs confirmed persistence of enhanced lung radioactivity for several days. Urinary desmosine excretion did not change following A1PI infusion. During the period of follow-up thus far, no patient has had chronic toxicity, results of liver function tests have been stable, and there has been no development of hepatitis B antigen or antibodies to hepatitis B surface or core antigens.
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PMID:Intravenous administration of alpha-1-proteinase inhibitor in patients of PiZ and PiM phenotype. Preliminary report. 326 74


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