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)

In untreated patients with inoperable lung cancer, serum levels of alpha1-antitrypsin were found significantly increased in comparison to patients with non malignant diseases of the lung, alpha2-macroglobulin levels were unchanged in both groups of patients. There was also no difference in alpha2-macroglobulins in cancer patients reacting with DNCB and in non-reactors. Thus alpha2-macroglobulin levels do not seem to correlate with the immunestatus of cancer patients. Proteinase inhibitors are involved in a variety of biological processes including blood, clotting, digestion, and sperm capacitation. alpha1-antitrypsin, a alpha-globulin with a molecular weight of about 60,000 has been found to be decreased in patients' serum under several pathological conditions. A clear correlation exists between alpha1-antitrypsin deficiency and hereditary pulmonary emphysema (1, 2), respiratory distress syndrome (3), and juvenile cirrhoses of the liver (4). Elevated serum levels of alpha1-antitrypsin have also been found in some cancer cases. Thirty years ago a cancer test was developed on the basis of differences in the antiproteolytic activity in cancer patients' sera and in patients with other non-neoplastic diseases (5, 6). Several authors have tried to confirm these early data regarding specifity and sensitivity with respect to a screening test for cancer (7, 8). Methods of these authors were based mainly on enzyme substrate inhibition assays by addition of the patients' sera. Recently a commercially available test, based on immune-precipitation according to Mancini (9), has been developed (Behring-Werke, Partigen). By using this standardized method for determinating alpha1-antitrypsin, Harris et al. have recently demonstrated that patients with inoperable lung cancer have significantly elevated levels of this antiprotease in their sera (10), in comparison to patients with non malignant diseases of the lung. alpha2-macroglobulin is a serum protein with a molecular weight of 800,000 and with known antiprotease activity and can therefore bind trypsin, plasmin, elastase, and collagenase and it is known that alpha2-macroglobulin decreases with increasing of age. Changes of alpha-macroglobulin have also been observed in several pathological conditions (11). James et al. 4ave found decreases in serum of myeloma patients (12). An association between the development and function of lymphocytes and alpha2-macroglobulin has been suggested by several authors (13, 14). This alpha2-globulin has also been demonstrated on the surface of peripheral blood lymphocytes (15) and there is evidence that it is synthesized by lymphocytes (16). The purpose of the present study was to determine serum alpha1-antitrypsin levels in patients with inoperable lung cancer and to determine whether there is also an inverse correlation to alpha2-macroglobulin. It was further attempted to correlate alpha2-macroglobulin with general immunological parameters, as it is known that patients with lung cancer show a decreased general immune-reactivity (17).
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PMID:Serum levels of alpha1-antitrypsin and alpha2-macroglobulin in lung cancer. 6 86

A severe deficiency of the serum protein alpha-1-antitrypsin can be expected to occur in 1 in 750 European New Zealanders. It can usually be identified by a faint or absent alpha-1 band on serum protein electrophoresis. Forty-seven cases are presented. 31 phenotype ZZ and 16 phenotype SZ. Eighteen have developed emphysema usually by age 40 years, two show childhood liver disease. One adult died of liver disease and three of the emphysema patients had liver abnormalities at post mortem. The remainder, mainly aged less than 30 years, are as yet asymptomatic. Individuals at risk should be protected from respiratory irritants (cigarettes, dusty environments and chest infections) and liver toxins (e.g., alcohol). The partial deficiency state (MZ) which occurs in 4 percent of the population also predisposes to respiratory and perhaps liver disease.
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PMID:Alpha-1-antitrypsin deficiency in New Zealand. 108 Feb 64

The serum protein alpha 1-antitrypsin (alpha 1-AT) serves as the major inhibitor of neutrophil elastase. The most common allele of the alpha 1-AT gene is designated as PiM. The Z mutation is a single-base substitution of the normal M allele, causing a Glu----Lys change at position 342 in the molecule. The ZZ phenotype is associated with a severe deficiency of alpha 1-AT, serum concentrations of the protein being 10% of normal. Individuals with an alpha 1-AT deficiency are at an increased risk of developing emphysema. To generate antibodies that specifically detect the 342 position in the context of the flanking sequences, we synthesized several peptides that included the 342 position for both the M and the Z variant. Immunization with variant-specific peptide-carrier conjugates elicited alpha 1-AT variant-specific responses, as determined in a direct enzyme-linked immunoassay. Monoclonal antibodies (MAbs) were selected with different specificity for the 342 region: MAbs F43 recognize only the alpha 1-AT sequence with 342Glu, i.e., all variant proteins that are non-Z, either from hetero- or homozygous individuals; MAbs F50 recognize only the sequence with 342Lys, i.e., all Z-variant proteins in ZZ or heterozygous individuals; MAbs F46 recognize alpha 1-AT with either 342Lys or 342Glu, all variant proteins with sequences as in the peptides used. Z homo- and heterozygotes were detected with our MAbs in a rapid and simple immunoblot assay. Other variants (M, S, and F) can also be assigned on the basis of the electrophoretic pattern. This sensitive detection method is very easy, rapid, and straightforward and provides a powerful tool for diagnosis of the alpha 1-AT deficiencies, allowing early treatment (augmentation of alpha 1-AT) and proper advice on lifestyle practices.
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PMID:Detection of genetic variants of alpha 1-antitrypsin with site-specific monoclonal antibodies. 189 97

Inherited defects of the gene coding for a serum protein that protects alveolar walls from proteolysis constitute one cause of emphysema, with or without liver disease. The deficiency can be reversed with intravenous administration of the antiprotease, keeping serum levels above the minimum needed for lung protection.
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PMID:Alpha 1-antitrypsin deficiency: pathogenesis and treatment. 189 56

Advanced emphysema with bronchitis is associated with significant weight loss and malnutrition, the true cause of which has not been clearly identified. The purpose of this exploratory study was to compare plasma amino acids and related compounds and catecholamines in a group of patients with advanced end-stage emphysema with a control group of similar age and sex in an effort to further understand this malnourished state. Fasting blood samples were obtained by venipuncture after a rest period. Plasma amino acid levels were determined by ion exchange high pressure liquid chromatography with fluorometric detection. Plasma catecholamines were determined by radioenzymatic analysis. Anthropometric measurements, the usually accepted biochemical markers of nutrition, dietary analysis, pulmonary function tests, and a historical analysis of the state of health including drug use and smoking history in each subject were analyzed. Ages and heights were comparable, whereas weights were significantly decreased in the patients with emphysema. Total serum protein and serum albumin values were significantly lower in the patient group. Significant respiratory muscle weakness was indicated by reduced negative inspiratory force in these end-stage patients, contrasting with well-preserved muscle strength usually found in obstructive lung disease. The dietary caloric intake of the patients was comparable to that of the control subjects. We conclude that the fine balance of the amino acid pool in patients with bronchitis and emphysema is well preserved, except for significant elevations of aspartic acid, glutamine, and cystine, and a decreased level of leucine. In addition, norepinephrine levels were significantly increased. Weight loss in patients with emphysema and bronchitis is likely due to increased energy demands related to hypermetabolism.
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PMID:The nutritional status in advanced emphysema associated with chronic bronchitis. A study of amino acid and catecholamine levels. 232 54

The possibility of in situ isolated lung perfusion as a means of treating nonresectable pulmonary cancers unresponsive to conventional chemotherapy has been investigated. The present study has examined the biochemical and morphological effects of in situ isolated lung perfusion in dogs with doxorubicin (DOX). A dose related complication was seen in the animals following lung perfusion. Lactate dehydrogenase (LDH) activity in the perfusate increased as dose was increased, indicating tissue damage during the perfusion. Up to 7 days postperfusion, marked changes were seen in the serum protein concentrations although these were independent of doxorubicin concentrations. Serum lactate dehydrogenase showed a dose dependent increase 2 hour and 1 day after the lung perfusion. Plasma angiotensin converting enzyme activities up to 14 days postperfusion suggested that DOX produced pulmonary endothelial cell injury at higher drug doses. Histopathologic examination of the lungs from dogs receiving the highest concentrations of drug indicated that necrosis of arterial endothelia and alveolar epithelia accompanied by periarterial edema, subplural edema and emphysema of the lungs were the probable causes of acute animal mortality. The study has demonstrated that doxorubicin produces dose-dependent damage to the pulmonary tissue. However, the observed injury only appeared life-threatening at perfusate drug concentrations in excess of 20 nmol/ml. In situ lung perfusion for the treatment of unresectable pulmonary tumors may be clinically applicable.
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PMID:Pulmonary toxicity of doxorubicin administered by in situ isolated lung perfusion in dogs. 283 Sep 58

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

alpha 1-Antitrypsin (AAT) has been purified from human plasma supernatant A (equivalent to COHN fraction II + III) by a large-scale chromatographic procedure involving anion-exchange adsorption on DEAE Sepharose CL-6B fast flow and size-exclusion chromatography on Sephacryl S-200. Before freeze-drying, the liquid concentrate was heat-treated at 60 degrees C for 10 h to reduce the risk of transmission of blood-born viral diseases. Using this procedure, AAT is recovered with 80-90% purity in 65-75% yield from supernatant A. The heterogeneity of AAT is preserved across the purification steps. In addition, purified AAT exhibits inhibitory activities against trypsin and elastase equivalent to that of the serum protein. The mean association rate constant for elastase was found as high as 2.15 X 10(5) M-1 s-1. Thus, purifying active AAT from supernatant A contributes to improving the availability of this protein which may be potentially useful in the treatment of hereditary emphysema.
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PMID:Biochemical and biological properties of an alpha 1-antitrypsin concentrate. 349 60

Cumulative damage to lung tissue by leukocyte elastase is thought to be responsible for the development of pulmonary emphysema, an irreversible lung disease characterized by loss of lung elasticity. It is also thought to be involved in the rapidly developing and usually fatal adult respiratory distress syndrome. The primary defence against elastase damage is the anti-protease known as alpha 1-antitrypsin, a glycosylated serum protein of 394 amino acids. Oxidation of the methionine 358 residue located at the active centre of alpha 1-antitrypsin results in a dramatic decrease in inhibitory activity towards elastase which effectively inactivates the protective function. It has been suggested that this oxidation sensitivity has a regulatory function and allows tissue breakdown at sites of inflammation by inactivation of alpha 1-antitrypsin by oxygen radicals released by phagocytes. In the above diseases, however, the oxidative inactivation of alpha 1-antitrypsin is probably of major importance in allowing lung damage by elastase. An oxidation-resistant alpha 1-antitrypsin required for emphysemics and provide treatment for acute inflammatory respiratory conditions. To further the possibility of therapy for the above conditions, we describe here the synthesis in yeast of active, non-glycosylated, human alpha 1-antitrypsin. Site-directed mutagenesis has been used to construct an active, oxidation-resistant derivative containing a single methionine to valine substitution at the active centre. This demonstrates the potential of engineered modifications to protein molecules designed to improve their physiological function.
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PMID:Synthesis in yeast of a functional oxidation-resistant mutant of human alpha-antitrypsin. 638 9

(1) Deficiency of alpha AT is one of the most common hereditary diseases affecting Caucasians in Europe. The alpha 1AT protein is extremely pleomorphic, and around 90 variants due to mutations have been recognized. The prime functions of alpha 1AT is to inhibit neutrophil elastase, and a proportion of individuals who are deficient in alpha 1AT develop emphysema. The most common deficiency variant (Z) is also associated with liver disease. The main site of alpha 1AT synthesis is in the liver. Not all deficient individuals are affected by lung or liver disease, however, so that other factors (genetic and environmental) are clearly important. (2) Investigation of alpha 1AT status is essential in any child or adult presenting with chronic liver disease. The genetic cause cannot be identified clinically or by any other laboratory investigation. The diagnosis carries important prognostic consequences and is important for other family members. Patients with emphysema should have their Pi type determined, especially if they are under the age of 50, have never smoked or there is a suggestive family history. Asymptomatic individuals who are homozygous type Z should be referred to a chest physician for a clinical and radiological assessment together with lung function tests. (3) Several laboratory tests are available to detect alpha 1AT deficiency, and the choice of test(s) will depend on circumstances. Quantitation of the serum protein is simple and cheap. Because alpha 1AT is an acute phase protein, however, quantitation used in isolation may give false negative results which are clearly unacceptable, particularly in association with paediatric liver disease. Phenotyping by isoelectric focusing requires some experience in distinguishing SZ and ZZ phenotypes, and phenotyping should ideally be used in conjunction with quantitation because heterozygous null phenotypes may appear identical to homozygous normal phenotypes. (4) Prenatal diagnosis is usually performed by DNA analysis of CVS samples obtained at 11-13 weeks. Because of the risk that CVS samples might be contaminated by maternal tissue, assays which are less likely to detect minor contaminants are preferable. At present, use of DNA tests is confined to prenatal diagnosis, but the availability of simple tests and the possibility of unequivocal identification of S and Z alleles means that these tests are likely to find greater use in the near future.
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PMID:Molecular basis, clinical consequences and diagnosis of alpha-1 antitrypsin deficiency. 968 Oct 66


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