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)

Hepatocytes are considered to be the predominant source of alpha 1-antitrypsin (AAT), the major antiprotease in human plasma. The development of emphysema in the hereditary PiZ AAT deficiency state suggests that inhibition of leukocyte elastase in the lung is a major function of this protein. In addition, patients with AAT deficiency are at increased risk for developing cholestasis in infancy and chronic liver disease as adults. The mechanism for hepatic cell injury, however, is not understood. Transgenic mice that express the normal human AAT gene demonstrate abundant AAT in hepatocytes and specific cell types of numerous nonhepatic tissues. Immunoperoxidase techniques have previously disclosed AAT in many of the cell types seen in transgenic mice; however, the issue of local synthesis vs. endocytosis in these cell types has remained unresolved. In this study, AAT mRNA was seen in a variety of tissues in the transgenic mouse. Immunoelectron microscopy of renal tubular and small intestinal epithelial cells in the transgenic mice demonstrated AAT within the cisternae of the rough endoplasmic reticulum, as in hepatocytes. These findings support the possibility of local synthesis in the various cell types. The results suggest that in addition to maintaining tissue integrity in the lung, the protease/antiprotease balance may have physiological functions in other organs as well.
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PMID:Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. 326 Jun 5

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

The gene coding for alpha 1-antitrypsin (AAT) is mutated in some individuals to code for a protein, the PiZ variant, associated with alpha 1-antitrypsin serum deficiency. Homozygotes for this defect are at high risk for various liver diseases and for early onset emphysema. Here, we employ an enzymatic amplification procedure for diagnosis of a Z-specific gene mutation in cellular DNA, and we describe a new procedure for selective enhancement of the mutated sequence. We have synthesized 2 oligonucleotides which prime amplification of a 156 bp region of exon V including a single base mutation specific for the PiZ variant. Amplification of 2 to 6 X 10(5)-fold is obtained allowing rapid detection of the Z mutation, using selective oligonucleotide probes, in unseparated genomic DNA of cells from family members homozygous or heterozygous for the defect. New methodology allows enzymatic amplification at elevated temperatures. To take advantage of this, we have developed a method using discriminating oligonucleotides as primers that allows enhanced sensitivity of hybridization. These methods allow diagnosis of the Z form of AAT deficiency within a single day using submicrogram quantities of DNA.
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PMID:Rapid DNA analysis of alpha 1-antitrypsin deficiency: application of an improved method for amplifying mutated gene sequences. 326 17

To study further the role of intermediate alpha 1-antitrypsin (AAT) deficiency in chronic obstructive pulmonary disease (COPD), AAT Pi-types and serum-trypsin-inhibitory-capacity (STIC) were measured in 965 patients with COPD. Heterozygosity of the Z variant was the major cause of intermediate AAT deficiency (primarily the MZ phenotype), accounting for 8.0 percent of the patients compared to 2.9 percent of control subjects (p less than .0005). ZZ homozygosity was detected in 1.9 percent of the patients, compared to 0.04 percent of control studies performed by others (none was present in our own control group of 1,380 subjects). The mean age for MS or MZ patients did not differ from that of the COPD patients as a whole, whereas the ZZ homozygotes were younger (55.9 +/- 9.8 vs 65.3 +/- 7.5 years). These results resemble those of a previous study in 66 male veterans with pulmonary emphysema suggesting that the MZ phenotype, or intermediate AAT deficiency in general, probably does predispose to the development of COPD. However, the prevalence of AAT deficiency in COPD patients is small (approximately 10 percent). The number with an MS phenotype was not increased in this group of COPD patients.
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PMID:Alpha 1-antitrypsin Pi-types in 965 COPD patients. 348 34

We studied the volume of trapped gas (VTG), using a nitrogen washout method, before and after bronchodilation in four groups with theoretically increasing risk of developing pulmonary emphysema: (1) nonsmoking healthy controls (PiMn), (2) nonsmoking subjects with an intermediate alpha 1-antitrypsin deficiency (PiMZn), (3) smoking subjects with normal concentration of alpha 1-antitrypsin, and (4) smoking PiMZ subjects. VTG was the only lung function variable that showed a significant difference between PiMZn and PiMn subjects but only after bronchodilation. Some conventional lung function tests also distinguished smokers from nonsmokers of both genotypes but VTG was the most sensitive test. VTG decreased after salbutamol inhalation in the control group but showed a consecutively larger increase with more risk factors of developing emphysema. An increase in VTG after bronchodilation may be a sign of alveolar abnormality preceding development of clinical lung emphysema.
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PMID:Changes of volume of trapped gas after bronchodilation in subjects with suspected subclinical emphysema. 348

The null-null phenotype of alpha 1-antitrypsin (alpha 1AT), a phenotype characterized by no detectable alpha 1AT in serum, presents a rare opportunity to examine the contribution of alpha 1AT to the antineutrophil elastase protection of the lower respiratory tract. The subject, a 35-yr-old lifetime non-smoker with moderate emphysema, has been characterized as having alpha 1AT serum levels of zero resulting from the homozygous inheritance of alpha 1AT genes that do not express detectable alpha 1AT mRNA transcripts. Evaluation of the antineutrophil elastase capacity of the null-null serum showed it was less than 5% of normal, whereas that of the epithelial lining fluid (ELF) of the lower respiratory tract was 13% of normal. However, after 60 mg/kg of intravenously administered alpha 1AT augmentation therapy once weekly for 4 wk, the serum alpha 1AT levels peaked at greater than 300 mg/dl, trough levels just prior to the next infusion were 81 +/- 2 mg/dl, and the average serum level integrated for the month of infusions was 138 mg/dl. Consistent with this serum rise in alpha 1AT, the serum antineutrophil elastase capacity increased in parallel(r = 0.98). Importantly, evaluation of the ELF 2 and 6 days after infusion demonstrated increases of alpha 1AT levels (range, 1.4 to 2.1 microM) and antineutrophil elastase capacity (range, 1.6 to 2.5 microM), values within the lower range of normal. Furthermore, the lung ELF alpha 1AT levels rose in direct proportion to the serum alpha 1AT levels, and the ELF antineutrophil elastase capacity rose in direct proportion to the ELF alpha 1AT levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of alpha-1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha-1-antitrypsin phenotype null-null before and during alpha-1-antitrypsin augmentation therapy. 349 19

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

The alpha 1-antitrypsin (AAT) or protease inhibitor (Pi) genetic polymorphism was studied in 144 white, 100 coloured, 104 Indian and 127 black (Northern Sotho) healthy individuals (controls), in the Pretoria area. Their Pi phenotype and gene frequency distributions are compared with world-wide data on other population groups. The severely deficient Pi phenotypes S, Z and SZ jointly attain frequencies of 0.3-0.4% in coloureds and whites; in blacks and Indians the corresponding frequencies are very much lower. The implication for preventive medicine and public health is that in South Africa the sequelae of Pi deficiencies such as cirrhosis of the liver and/or emphysema of the lung are of practical importance in whites and coloureds and much less so in blacks and Indians. In 176 white breast cancer patients studied, the Pi phenotype and gene frequency distributions were found to be similar to those of healthy controls (not statistically significant). Cohorts of other patients were also phenotyped because of their low alpha 1-globulin concentrations in routine serum protein electrophoresis and/or their specific disease condition (cirrhosis of the liver or emphysema of the lung) known to be associated with AAT deficiency. These results are discussed in terms of their significance for family follow-up, genetic counselling and a preventive service. The need to avoid atmospheric pollution, especially cigarette smoke, is emphasised as a major and cost-effective preventive measure.
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PMID:Alpha-1-antitrypsin genetic polymorphism in South Africa. 349 69

Genetic deficiency of alpha 1-antitrypsin in man is a predisposing factor to emphysema and a disorder potentially correctable by somatic gene therapy. A full-length human alpha 1-antitrypsin cDNA was cloned into a retroviral vector and introduced into cells which package the recombinant gene in a retroviral capsule. Cells infected with the recombinant retrovirus express human alpha 1-antitrypsin mRNA and protein. The recombinant protein is glycosylated, secreted and exhibits anti-protease activity against human neutrophil elastase.
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PMID:Retroviral mediated transfer and expression of human alpha 1-antitrypsin in cultured cells. 350 2

Emphysema is an increase in size of the air spaces distal to the terminal bronchioles, and can thus only be diagnosed pathologically, but new quantitative CT methods hold promise, diagnosing, quantitating and locating the lesions in man, in life, non-invasively. The protease/antiprotease theory of the pathogenesis of emphysema proposes that cigarette smoke attracts alveolar macrophages to distal terminal bronchioles, these in turn releasing neutrophil chemotactic factors which attract circulating polymorphonuclear leucocytes, to release potent proteolytic enzymes (serine protease) in addition to the alveolar macrophage protease. These enzymes, which can cleave all the macromolecules of the lung interstitium, are antagonized (at least the serine elastase) in health by alpha 1-antitrypsin, a normal constituent of lung lining fluid. However, this can be oxidized by oxidants in cigarette smoke, and oxidants released by polymorphonuclear leucocytes in microbial killing. The role of these actions, and of antioxidants (both natural and therapeutic) and antielastases are reviewed, as well as the activities of lung defence cells in this process. Despite this explosion of recent knowledge, we are still unable to answer the all important question "Why don't all smokers develop emphysema?", and further research is needed into variability in these multiple factors involved in this important new theory of the pathogenesis of this, possibly the commonest of all respiratory disorders of a chronic disabling nature.
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PMID:The pathogenesis of emphysema. 351 67


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