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)

The Mmineral springs alpha 1-antitrypsin (alpha 1AT) allele, causing alpha 1AT deficiency and emphysema, is unique among the alpha 1AT-deficiency alleles in that it was observed in a black family, whereas most mutations causing alpha 1AT deficiency are confined to Caucasian populations of European descent. Immobilized pH gradient analysis of serum demonstrated that alpha 1AT Mmineral springs migrated cathodal to the normal M2 allele. Evaluation of Mmineral springs alpha 1AT as an inhibitor of neutrophil elastase, its natural substrate, demonstrated markedly lower than normal function. Characterization of the alpha 1AT Mmineral springs gene demonstrated that it differed from the common normal M1(Ala213) allele by a single-base substitution causing the amino acid substitution Gly-67 (GGG)----Glu-67 (GAG). Capitalizing on the fact that this mutation creates a polymorphism for the restriction endonuclease AvaII, family analysis demonstrated that the Mmineral springs alpha 1AT allele was transmitted in an autosomal-codominant fashion. Evaluation of genomic DNA showed that the index case was homozygous for the alpha 1AT Mmineral springs allele. Cytoplasmic blot analysis of blood monocytes of the Mmineral springs homozygote demonstrated levels of alpha 1AT mRNA transcripts comparable to those in cells of a normal M1 (Val213) homozygote control. Evaluation of in vitro translation of Mmineral springs alpha 1AT mRNA transcripts demonstrated a normal capacity to direct the translation of alpha 1AT. Evaluation of secretion of alpha 1AT by the blood monocytes by pulse-chase labeling with [35S]methionine, however, demonstrated less secretion by the Mmineral springs cells than normal cells. To characterize the posttranslational events causing the alpha 1AT-secretory defect associated with the alpha 1AT Mmineral springs gene, retroviral gene transfer was used to establish polyclonal populations of murine fibroblasts containing either a normal human M1 alpha 1AT cDNA or an Mmineral springs alpha 1AT cDNA and expressing comparable levels of human alpha 1AT mRNA transcripts. Pulse-chase labeling of these cells with [35S]methionine demonstrated less secretion of human alpha 1AT from the Mmineral springs cells than from the M1 cells, and evaluation of cell lysates also demonstrated lower amounts of intracellular human alpha 1AT in the Mmineral springs cells than in the normal M1 control cells. Thus, the Gly-67 --> Glu mutation that characterizes Mmineral springs causes reduced alpha 1AT secretion on the basis of aberrant posttranslational alpha 1AT biosynthesis by a mechanism distinct from that associated with the alpha 1AT Z allele, whereby intracellular aggregation of the mutant protein is etiologic of the alpha 1AT-secretory defect. Furthermore, for the alpha 1AT protein that does reach the circulation, this mutation markedly affects the ability of the molecule to inhibit neutrophil elastase; i.e., the alpha 1AT Mmineral springs allele predisposes to emphysema on the basis of serum apha 1AT deficiency coupled with alpha AT dysfunction.
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PMID:Molecular basis of alpha 1-antitrypsin deficiency and emphysema associated with the alpha 1-antitrypsin Mmineral springs allele. 196 87

The increased risk of developing emphysema among individuals who smoke cigarettes and who have normal levels of alpha 1-antitrypsin (alpha 1AT) is hypothesized to result from a decrease in the antineutrophil elastase capacity of the lower respiratory tract alpha 1AT of smokers compared with nonsmokers. To evaluate this hypothesis we compared the time-dependent kinetics of the inhibition of neutrophil elastase by lung alpha 1AT from healthy, young cigarette smokers (n = 8) and nonsmokers (n = 12). alpha 1-antitrypsin was purified from lavage fluid using affinity and molecular sieve chromatography, and the association rate constant (k assoc) for neutrophil elastase quantified. The k assoc of smoker plasma alpha 1AT (9.5 +/- 0.5 X 10(6) M-1s-1) was similar to that of nonsmoker plasma (9.3 +/- 0.7 X 10(6) M-1s-1, P greater than 0.5). In marked contrast, the k assoc of smoker lower respiratory tract alpha 1AT was significantly lower than that of nonsmoker alpha 1AT (6.5 +/- 0.4 X 10(6) M-1s-1 vs. 8.1 +/- 0.5 X 10(6) M-1s-1, P less than 0.01). Furthermore, the smoker lower respiratory tract alpha 1AT k assoc was significantly less than that of autologous plasma (P less than 0.01). When considered in the context of the concentration of alpha 1AT in the lower respiratory tract epithelial lining fluid, the inhibition time for neutrophil elastase of smoker lung alpha 1AT was twofold greater than that of nonsmoker lung alpha 1AT (smoker: 0.34 +/- 0.05 s vs. nonsmoker: 0.17 +/- 0.05 s, P less than 0.01). Consequently, for concentrations of alpha 1AT in the lower respiratory tract it takes twice as long for an equivalent amount of neutrophil elastase to be inhibited in the smoker's lung compared with the nonsmoker's lung. These observations support the concept that cigarette smoking is associated with a decrease in the lower respiratory tract neutrophil elastase inhibitory capacity, thus increasing the vulnerability of the lung to elastolytic destruction and thereby increasing the risk for the development of emphysema.
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PMID:Risk factors for emphysema. Cigarette smoking is associated with a reduction in the association rate constant of lung alpha 1-antitrypsin for neutrophil elastase. 199 86

Between December 1983 and April 1989, 222 combined heart and lung transplant operations were performed for treatment of pulmonary vascular disease and parenchymal lung disease at Harefield Hospital. Seventeen of these patients had emphysema, and 11 of them were followed up for a minimum of 1 year. There were nine male and two female patients. Their mean age was 39 (range, 32 to 54) years. Seven had alpha 1-antitrypsin deficiency. Six patients were receiving continuous oxygen therapy, and two patients were dependent on a ventilator. Postoperatively, the patients' lungs were ventilated for a median of 3 days (range, 24 hours to 2 weeks). Two patients subsequently required further periods of ventilation. Immunosuppression consisted of azathioprine and cyclosporine. Three patients also received low-dose oral steroids. There was one early death, which occurred on the second postoperative day. The remaining patients were followed up for 12 to 53 (mean, 22) months. One patient had cytomegalovirus pneumonitis 6 weeks postoperatively that responded to treatment. There was one late death at 14 months after reoperation for treatment of obliterative bronchiolitis. The overall survival was 91% at 1 year. All survivors achieved an excellent level of rehabilitation. It is concluded that the medium-term results of heart and lung transplantation for treatment of emphysema are good and that patients with alpha 1-antitrypsin deficiency may undergo transplant procedures without substitution therapy.
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PMID:Medium-term results of combined heart and lung transplantation for emphysema. 200 66

Inherited or "acquired" deficiency of alpha 1-antitrypsin (believed to be the cause of pulmonary emphysema) will probably be treated in the future by replacement with alpha 1-antitrypsin purified from human plasma or produced by recombinant DNA, which seems promising because it permits site-specific mutagenesis in the oxidizable active site of the normal human alpha 1-antitrypsin. The aim of this in-vitro study was to investigate the elastase inhibitory activity and the resistance to oxidizing agents of normal human alpha 1-antitrypsin, a recombinant yeast-produced variant (VAL 358) and a recombinant E. coli-produced variant (LEU 358). The inhibitors were exposed to chemical oxidants (NCS, H2O2, xanthine/xanthine oxidase, chloramine-T) and to PMA-activated neutrophils. The elastase inhibitory activity was assayed on porcine pancreatic elastase and neutrophil elastase. Normal alpha 1-antitrypsin and VAL 358 variant were good inhibitors of both elastases. LEU 358 variant was the best inhibitor for neutrophil elastase, but it poorly inhibited the porcine pancreatic elastase. Normal alpha 1-antitrypsin was affected by all oxidants; both variants were almost totally resistant to chemical oxidants and to activated neutrophils. We conclude that recombinant alpha 1-antitrypsin variants differ in their elastase inhibitory activity and offer increased resistance to oxidant agents.
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PMID:Alpha 1-antitrypsin variants produced by recombinant DNA: differences in elastase inhibitory activity and resistance to oxidant agents. 210 1

The author reviews the early history of alpha 1-antitrypsin (AAT) deficiency; the biochemical characterization of this inborn error of metabolism, its pattern of inheritance, frequency and predisposition to early, panacinar emphysema. The importance of the destructive element in emphysema and the gradual focusing on neutrophil elastase as a key enzyme in the pathogenesis of emphysema in alpha 1-antitrypsin deficiency is emphasized. The deficiency state as a prototype of an endoplasmic reticulum storage disease is discussed.
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PMID:Discovery of alpha 1-antitrypsin deficiency. 211 60

Severe alpha 1-antitrypsin (AAT) deficiency is a relatively common inherited condition in populations of Northern European heritage. Current estimates of the prevalence of the PiZ phenotype range between 1/3500 and 1/1670 in the United States. Clues to the whereabouts of the undiagnosed individuals with severe hereditary AAT deficiency can come from the existing information about the natural history and clinical course of disease. In the PiZ smoker, dyspnea develops soon after age 30 years or at least before age 40, and death from emphysema is likely by age 50. The PiZ nonsmoker has a prognosis only marginally worse than that of the susceptible smoker without AAT deficiency. Dyspnea often does not appear until after age 50 years, and clinically significant emphysema not usually until after age 60. All infants presenting with liver disease in the neonatal period should be tested for the deficiency. In adults, clinically significant dyspnea in the 30s and 40s, in association with abnormal lung function, should raise the suspicion of AAT deficiency. In nonsmokers, dyspnea at any age justifies further investigation. A serum AAT level below 80 mg/dl (11 microM) is considered abnormal; individuals falling in this range should be phenotyped. The formation of a Registry for severe hereditary AAT deficiency in the United States, under the auspices of the National Heart, Lung and Blood Institute of the NIH, is also described.
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PMID:Alpha 1-antitrypsin deficiency--diagnosis, treatment, and control: identification of patients. 211 63

Sixty-five patients with severe alpha 1-antitrypsin (AAT) deficiency (phenotype PiZ) were followed with spirometry at regular intervals of one year and a median observation period of four years. The annual decline in pulmonary function was adjusted for sex, age and height by division with the predicted normal pulmonary function. The median decline in FEV1 was 1.9% predicted/year. The rate of decline was independent of age and pulmonary function, except for patients with FEV1 below 25% of predicted normal. There was a tendency towards a slower median decline in FEV1 in ex-smokers (1.7% predicted/year) compared to smokers (3.8% predicted/year) and never-smokers (3.7% predicted/year), however, this difference was not significant (p greater than 0.01). At the time of diagnosis smokers and ex-smokers had a lower FEV1 (44 and 38% predicted) than never-smokers (85% predicted) (p less than 0.02), and smokers and ex-smokers were generally younger (median age 44 and 42 years, respectively) than never smokers (median age 55 years) (p greater than 0.1). Our data indicate that smokers as well as nonsmokers with severe AAT deficiency are at risk of developing pulmonary emphysema. The disease seems to appear later in nonsmokers, though once initiated it progresses at the same rate.
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PMID:Decline in pulmonary function in patients with alpha 1-antitrypsin deficiency. 211 66

Homozygous PiZZ individuals with a serum deficiency due to a defect in the secretion of the alpha 1-antitrypsin protein are at risk of developing severe panlobular emphysema. Tobacco smokers are particularly exposed to the disease which begins at an earlier age. Treatment by substitutive therapy with alpha 1-antitrypsin concentrates seems to be the only possibility. A two years' clinical trial was performed in 9 PiZZ patients, with more than 1,500 infusions being administered weekly. Serum AAT levels were used as guidelines to follow biochemical changes in the protease-antiprotease balance. From 0.16 g/l initially, the AAT level rose to 0.57 g/l after 7 months. No adverse reaction was observed during the trial; the concentrated protein was well accepted, ant the antielastase activity of the protein recovered after injection was equivalent to the activity injected. An attempt to administer the infusions monthly was stopped when we observed a dramatic decrease of the serum AAT level. Clinically, stabilization of the symptoms was noted. No degradation was observed in the patients who took part in the trial, even if no real improvement was detected.
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PMID:[Evaluation after 2 years of substitutive treatment of PiZZ emphysema with alpha-1 antitrypsin. 9 cases]. 213 50

Cigarette smoke can inactivate the alpha-1-proteinase inhibitor (alpha 1PI) by oxidative mechanisms and thus predisposes to the development of pulmonary emphysema. There are differences between the whole smoke and gas phase acting as alpha 1PI inactivators in vitro which suggests that the whole smoke is less oxidizing than the gas phase. Also studies on alpha 1PI oxidative inactivation in the lung of cigarette smokers gave controversial results. The reductive properties of cigarette tar which contains most of smoke nicotine may be some explanation of it. Therefore in this study we have investigated the effect of nicotine (0.4 mumol/l to 4 mmol/l) on the oxidative inactivation of human alpha 1PI by phorbol myristate acetate-activated polymorphonuclear leukocytes (PMNL), chloramine-T (15 mumol/l), hydrogen peroxide (15 mmol/l) and the superoxide radical (O2-.) generating system-xanthine (0.2 mmol/l)-xanthine oxidase (80 U/l). Nicotine at concentrations of greater than 40 mumol/l protected alpha 1PI from stimulated PMNL. The preincubation of PMNL with these concentrations of nicotine did not diminish their ability to inactivate alpha 1PI after stimulation. Nicotine (above 0.4 mumol/l) also protected alpha 1PI from chloramine-T but not from H2O2. The inhibition of O2-.-mediated alpha 1PI inactivation by nicotine was low and was observed only at a concentration of 4 mmol/l. This nicotine concentration did not affect xanthine oxidase activity. It is suggested that cigarettes with low nicotine contents can cause greater oxidative lung injury than their high nicotine counterparts and be a greater risk factor for the development of lung emphysema.
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PMID:Nicotine inhibits alpha-1-proteinase inhibitor inactivation by oxidants derived from human polymorphonuclear leukocytes. 216 36

Long-term replacement with human alpha 1-antitrypsin (60 mg/kg once a week intravenously) was carried out in seven patients with homozygous alpha 1-antitrypsin deficiency (7 males, mean age 50.8 [40-59] years) and progressive pulmonary emphysema for an average of 16 (13-20) weeks. After at least 12 weeks' therapy the concentrations of alpha 1-antitrypsin, elastase-alpha 1-antitrypsin complex, alpha 2-macroglobulin, lactoferrin and elastase inhibition capacity in plasma and sputum were assayed, these assays being performed before starting the alpha 1-antitrypsin infusion and at various times during the following week. After the infusion the plasma concentration of alpha 1-antitrypsin rose from a depressed initial level (median 1.22 g/l) to a level approximately five times higher (median after 1 hour: 5.96 g/l, P less than 0.001), and then declined exponentially, though it never fell below the threshold of 35% of normal which is regarded as the protective level. Elastase inhibition capacity displayed similar changes (r = 0.85). The sputum concentration of alpha 1-antitrypsin rose more slowly than the plasma concentration; from the initial level (median 8 mg/l) it reached a maximum about four times higher after 24 hours (median 36 mg/l; P less than 0.02). Elastase inhibition capacity rose from 151 mIU/ml (median) before the alpha 1-antitrypsin infusion to 450 mIU/ml at 24 hours. These findings suggest that alpha 1-antitrypsin replacement will have beneficial effects on proteinase-antiproteinase equilibrium. Determination of elastase inhibition capacity in the sputum is suitable for monitoring dosage during replacement therapy.
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PMID:[Long-term substitution in homozygous alpha 1-antitrypsin deficiency. Effect of the proteinase-antiproteinase equilibrium in plasma and sputum]. 219 43


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