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 an attempt to find a molecular marker for the putative abnormal allele in heterozygous alpha 1-antichymotrypsin (ACT) deficiency (a rare trait associated with early emphysema, childhood asthma and chronic "cryptogenic" liver disease) the isoelectric focusing pattern of neuraminidase treated plasma samples from subjects of ACT deficiency families as well as acute phase plasma were compared. There was no difference in the isoform pattern of plasma from ACT deficiency heterozygotes, normal subjects or patients with acute phase response. However, in acute phase plasma there was a disproportional increase in two isoforms, one of which conceivably may be used to mark the early phase of the acute phase response.
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PMID:The isoelectric focusing pattern of desialylated alpha 1-antichymotrypsin of heterozygous alpha 1-antichymotrypsin deficiency and of acute phase plasma. 213 May 41

Heterozygous alpha 1-antichymotrypsin (ACT) deficiency is inherited in an autosomal dominant mode independently of alpha 1-antitrypsin with a gene frequency (q) of 0.003. In a previous study, a high prevalence of enlarged residual volumes in subjects with the trait were noted. Neutrophil cathepsin G, the target proteinase of ACT, enhances the elastolytic action of elastase. Thus, hypothetically, subjects with the trait may have increased risk for developing pulmonary emphysema. To test whether heterozygous ACT deficiency predisposes to lung disease, plasma ACT concentrations were determined in a cohort of 1,872 middle-aged women. Women with subnormal levels were studied with respect to heredity, airway symptoms, and lung function. Twelve women (0.64% of the cohort) were classified as heterozygotes after family studies and were compared with control subjects, matched for age, weight, sex, and smoking status. There were no significant differences in airway symptoms between heterozygotes and control subjects. However, the prevalence of ex-smokers was significantly higher among heterozygotes than among the screened population as a whole (prevalence ratio, 2.18; 95% confidence interval, 1.004-4.72). There were no differences between the heterozygotes and the control subjects in the basal spirometry. However, after bronchodilation, five of the 12 heterozygotes manifested residual volumes greater than 2.5 standard deviations above normal mean compared with one of 24 control subjects (p = 0.012). The present investigation thus confirms our previous findings of an increased prevalence of enlarged residual volumes in heterozygous ACT deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary function in middle-aged women with heterozygous deficiency of the serine protease inhibitor alpha 1-antichymotrypsin. 232 51

Cigarette smoking results in variable degrees of inflammation in the lower respiratory tract. Furthermore, smoking produces oxidant-mediated changes in the lung, important to the pathogenesis of emphysema. Since glutathione can neutralize reactive oxygen species and prevent peroxidation of unsaturated lipids, it may constitute an important component of the lung's defense against oxidant and inflammatory injury. In the present study, broncholaveolar lavage (BAL) was performed in 27 smokers, and the concentrations of total glutathione as well as the cellular and humoral markers of inflammatory activity were studied. There were significant correlations between total glutathione and neutrophils; two neutrophil granule components, myeloperoxidase and elastase; and chemotactic activity for neutrophils. Moreover, the total glutathione correlated with the eosinophil cationic protein (ECP), a granule constituent of the eosinophil, with two locally produced antiproteases, secretory leukocyte protease inhibitor (SLPI) and antichymotrypsin (ACHY), but not with an alpha 1-protease inhibitor and albumin. These data suggest that the total glutathione levels in BAL fluid may reflect a degree of oxidative and inflammatory stress caused by cigarette smoke, and they are therefore likely to contribute to the protection against this stress.
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PMID:Glutathione in bronchoalveolar lavage fluid from smokers is related to humoral markers of inflammatory cell activity. 261 93

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

The elastase inhibitory capacity per mg of alpha 1-proteinase inhibitor (alpha 1 PI) was measured in the bronchoalveolar lavage (BAL) fluid from 26 healthy smokers and 24 nonsmokers. Activity was decreased by 40% in smokers' BAL fluid compared to nonsmokers. This effect was demonstrable by using human neutrophil elastase as well as porcine pancreatic elastase as test enzyme (elastase, EC 3.4.21.11) and was reproducible when selected individuals in each group underwent lavage on repeated occasions. In contrast, the functional activity of alpha 1-antichymotrypsin was not decreased in smokers' BAL fluid. Crossed antigen-antibody electrophoresis confirmed that inactivation of alpha 1 PI was responsible for the decrease in the elastase inhibitory capacity of smokers' BAL fluid. alpha 1 PI purified from smokers' BAL fluids contained methionine sulfoxide (4 mol/mol of inactive alpha 1 PI), whereas alpha 1 PI from nonsmokers' BAL fluid did not. Smokers' alpha 1 PI was indistinguishable from nonsmokers' alpha 1 PI on the basis of electrophoretic mobility, molecular weight, and immunoreactivity. Thus, oxidation of methionine residues in lung alpha 1 PI is associated with cigarette smoking. Because chemical oxidation of alpha 1 PI in vitro causes loss of its elastase inhibitory activity, the present observations suggest that methionine oxidation may also be the cause of decreased functional activity of lung alpha 1 PI in smokers. Oxidative inactivation of alpha 1 PI in the lungs of cigarette smokers may play a role in the development of pulmonary emphysema in this group.
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PMID:Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. 697 49

The aim of the study was to evaluate the protease and antiprotease activity in the fluid obtained from the culture of cells isolated from the lungs of animals with experimental emphysema. An attempt was made to correlate the results of biochemical examinations with adherence degree and ultrastructural changes of the surface of BAL-isolated cells. The experiment was carried out on male Wistar rats, of 180-220 g b.w. Two i.p. injections of BCG-vaccine (4 x 10(8) microorganisms) on the 1st and 14th day were applied as macrophage mobilizing and activating agent. Papain (2 mg/l ml/100 g b.w.) was given once i.t. on the 21st day. The animals were sacrificed on the 28th day of the experiment. We found a correlation between the increase in the cell adherence and ultrastructural changes (in SEM), suggesting an increased activity of the cells isolated from BCG-treated rats. In the culture medium of cells isolated from the rats which were given BCG or papain and BCG+papain we observed an increased base protease activity and decreased Cathepsin D activity comparing with the control group. Increased antitrypsin activity in the BCG and BCG+papain-treated rats and decreased antitrypsin activity in papain-treated rats only was observed, too. There was no obvious difference in the levels of the antiplasmin and antichymotrypsin activities between the groups. The present results indicate that activated pulmonary macrophages are one of the sources of the protease-antiprotease intraalveolar imbalance. However, an increased production of proteolytic enzymes may not be the only factor responsible for the progression of lung emphysema in BCG-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of morphological and biochemical changes of BAL-isolated cells in experimental lung emphysema. 749 38

Alpha 1-antichymotrypsin (alpha 1-ACT) is a serine proteinase inhibitor (serpin) with cathepsin G, mast cell chymase and chymotrypsin as target enzymes. We present the case of a middle-aged man with low plasma levels of alpha 1-ACT, asthma with progression to emphysema, and chronic HCV positive liver disease with selective accumulation of alpha 1-ACT in hepatocytes. This secretory defect is analogous to that seen in Pi Z alpha 1-antitrypsin deficiency. The molecular basis of alpha 1-ACT deficiency in this patient has been characterized by direct sequencing of the alpha 1-ACT genes from the patient and his father. A C-->G transversion in exon III causing a 229Pro-->Ala substitution is proposed to cause a conformational change resulting in abnormal transport through the RER. This mutation was found in one of 20 additional tested patients with chronic obstructive lung disease, but in no control. Two additional polymorphisms of the gene have been identified in unrelated healthy individuals with normal plasma alpha 1-ACT levels. The alpha 1-ACT deficiency state may predispose to obstructive lung disease and influence the course of liver disease. Identification of a specific mutation allows identification of heterozygotes for this deficiency allowing future evaluation of its clinical significance.
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PMID:The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. 822 25

Aim of the present study was to evaluate cathepsin D, base protease, antiplasmin, antitrypsin and antichymotrypsin activities and protein content in the 24h culture medium of the alveolar macrophages (AM) deriving from the rats treated BCG-vaccine and from rats with papain-induced emphysema. In the culture medium of cells isolated from the rats which were given BCG or papain and BCG+papain we observed an increase of base protease activity and a decrease of cathepsin D activity comparing with control group. Increased antitrypsin activity in BCG and BCG+papain-treated rats and decreased antitrypsin activity in papain-treated rats were observed. There were not significant differences in antiplasmin and antichymotrypsin activities between examined groups. The obtained results indicate that activated pulmonary macrophages are one of the sources of the protease-antiprotease intraalveolar imbalance. However, increased production of proteolytic enzymes may not be the only factor responsible for the progression of lung emphysema in BCG-treated rats.
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PMID:The effect of activated alveolar macrophages on experimental lung emphysema development. I. Protease and antiprotease activities in the culture medium of alveolar macrophages. 883 14

The serpin superfamily of serine proteinase inhibitors contains many members but the best-characterized is the plasma protein alpha 1-antitrypsin. its genetic deficiency is associated, in the homozygote, with hepatic damage that may progress to cirrhosis and hepatocellular carcinoma. Low levels of circulating alpha 1-antitrypsin fail to protect the lungs against proteolytic attack and predispose the homozygote to early onset pan-lobular emphysema, bronchiectasis and asthma. The major cause of alpha 1-antitrypsin deficiency, the Z mutation (Glu342Lys), results in the accumulation of protein in the endoplasmic reticulum of the liver. Using a structural approach, we have shown that the hepatic inclusions result from a protein-protein interaction between the reactive centre loop of one molecule and the beta-pleated sheet of a second. This loop-sheet polymerization is now also recognized to be the basis of deficiencies associated with mutations of C1-inhibitor, antithrombin and alpha 1-antichymotrypsin. Our recent solution of a crystal structure of a thermostable mutant of alpha 1-antitrypsin shows the detailed interactions that result in loop-sheet linkage and helps to explain the mechanism of action of this family of proteinase inhibitors.
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PMID:New insights into the structural basis of alpha 1-antitrypsin deficiency. 897 59

The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into beta-sheet A after cleavage by the target proteinase. Point mutations within the protein can allow aberrant conformational transitions characterized by beta-strand exchange between the reactive loop of one molecule and beta-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia. We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55-Pro) of the plasma serpin alpha(1)-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into beta-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A. This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins. In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.
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PMID:Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease. 1061 72


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