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)

Current concepts of the pathogenesis of emphysema suggest that it results from an imbalance of elastase and antielastase activity within the alveolar structures. Although emphysema that is associated with hereditary deficiency of serum alpha 1-antitrypsin conforms to this scheme, the major risk factor in the more common form of emphysema is cigarette smoking. A study was designed to evaluate the premise that cigarette smoking may be associated with an acquired, functional defect in lung alpha 1-antitrypsin. Determination of the antielastase activity of alpha 1-antitrypsin obtained from the lungs of smoking and nonsmoking individuals revealed a nearly twofold reduction in the functional activity of this elastase inhibitor in the lungs of cigarette smokers. These data suggest that cigarette smokers may lose some of the normal antielastase protective screen of the lower respiratory tract, making them more vulnerable to destructive lung disease.
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PMID:Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. 31 88

Cigarette smoking is the major risk factor for development of emphysema. Many people are unable to stop smoking despite skilled support. The elastase-antielastase imbalance hypothesis for the pathogenesis of emphysema suggests that treatment with a supplemental elastase inhibitor might prevent development of emphysema in susceptible people. Many elastase inhibitors have been developed. Poorly soluble inhibitors do not prevent emphysema when tested in an animal model of elastase-induced emphysema. Irreversible inhibitors are effective in a dose-response manner. Reversible but tight-binding large molecular weight inhibitors, which clear slowly from the lungs, are effective in vivo. Small molecular weight, reversible inhibitors prevent haemorrhage after human neutrophil elastase instillation into the lungs but may potentiate emphysema. Only 15% of long-term smokers are susceptible to the development of emphysema. Susceptible smokers can be identified by the development of airflow obstruction. An outcome study of efficacy of elastase inhibitor therapy would be prohibitively expensive. However, a study of the process of development of elastase-induced emphysema is feasible. Measurement of alterations in elastase load of the lungs, elastase derived fibrinopeptides, circulating elastin peptides and urinary desmosines could be used for this purpose.
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PMID:The specific treatment of emphysema. 218 48

The in vitro and in vivo effects of heparin fragments (CY 216; CY 222) towards elastase(s) and elastase inhibitor (alpha 1 Pi) were studied. Heparin as well as its lower Mr fragments were shown to inhibit rat leucocyte elastase. The interaction between this enzyme and heparins appears to occur via electrostatic forces. Porcine pancreatic elastase is unaffected by heparin(s) but CY 216 and CY 222 could partly abolish the hydrolytic activity of hamster serum on Suc-Ala-Ala-Ala-N-PhNO2. N desulphated N acetylated CY 142 and CY 143 had no effect. CY 216 and CY 222 decreased in vitro the inhibitory potential of alpha 1 proteinase inhibitor (alpha 1 Pi) as well as the elastase inhibitory capacity of hamster serum. Maximum effect (30% decrease) was observed at ng concentrations of CY 216 and CY 222. Their N desulphated N acetylated counterparts (CY 142 and CY 143), but not heparin, exhibited similar effects. CY 216 and CY 222 were administered daily subcutaneously to hamsters and blood was collected 1, 2, 4, 7 and 24 hr after treatment for determining both serum elastase activity (E.A.) and serum elastase inhibitory capacity (E.I.C.). E.A. levels dropped by 30% 2 hr after CY 216 or CY 222 injection but returned to original values 4-7 hr later. This effect is independent of the duration of the treatment. Hamster serum E.I.C. was significantly increased (greater than 30%) after 3-4 weeks of treatment with CY 216 and CY 222. These findings point towards the potential use of these compounds in elastase-related diseases such as emphysema.
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PMID:Influence of heparin fragments on the biological activities of elastase(s) and alpha 1 proteinase inhibitor. 284 23

Pulmonary emphysema is currently thought to be due to an elastase-antielastase imbalance with resultant destruction of alveolar structures. The present study was aimed at testing whether alpha 1-proteinase inhibitor (alpha 1 PI) is the major component of the antielastase screen of the lower respiratory tract of healthy subjects. Bronchoalveolar lavage was performed in 8 nonsmokers (27.8 +/- 3.8 years) and 9 smokers (25 +/- 0.96 years). The lavage fluids were tested for leukocyte and pancreatic elastase inhibitory capacity (LEIC and PEIC) and immunoreactive alpha 1 PI and bronchial inhibitor (brI) content. The mean +/- s.e.m. levels of LEIC, PEIC, alpha 1 PI and brI were 0.16 +/- 0.039, 0.042 +/- 0.006, 0.09 +/- 0.007 and 0.013 +/- 0.002 mol/mol albumin, respectively. Thus, on the average, the molar concentration of brI was about 14% that of alpha 1 PI. The difference between LEIC and alpha 1 PI did not reach statistical significance (P = 0.0503). The PEIC was however significantly lower than the alpha 1 PI levels (P less than 0.05), indicating that the lavage fluids contained both active and inactive alpha 1 PI. Nonsmokers and smokers did not differ in their LEIC, PEIC, alpha 1 PI and brI levels. When the data were examined on an individual basis, the subjects could be divided into 2 groups: group I (n = 9; 3 nonsmokers, 6 smokers) whose LEIC/alpha 1 PI molar ratios were higher than unity and group II (n = 8; 5 nonsmokers, 3 smokers) whose LEIC/alpha 1 PI molar ratios were equal or lower than unity. Group I subjects had significantly higher LEIC values (0.26 +/- 0.05 mol elastase inhibited/mol albumin) than group II individuals (0.055 +/- 0.006; P less than 0.001) but the two groups had similar levels of immunoreactive alpha 1 PI (0.09 and 0.08 mol alpha 1 PI/mol albumin for group I and II, respectively), functionally active alpha 1 PI (percentage of active alpha 1 PI: 53% and 37% for group I and II, respectively) and immunoreactive brI (0.016 and 0.010 mol brI/mol albumin for group I and II, respectively). These results suggested that the lavage fluids from group I contained significant amounts of undefined leukocyte elastase inhibitor(s). Gel filtration of a lavage fluid from group I showed that the undefined elastase inhibitor(s) co-eluted with brI. Most of the lavage fluids were still able to inhibit leukocyte elastase following removal of alpha 1 PI by perchloric acid precipitation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The elastase inhibitory capacity and the alpha 1-proteinase inhibitor and bronchial inhibitor content of bronchoalveolar lavage fluids from healthy subjects. 331 Oct 75

A highly effective, reversible elastase inhibitor, MeOSuc-Ala-Ala-Pro-boroVal-OH, was tested for its ability to prevent emphysema induced by intratracheally administered elastase in hamsters. Anesthetized hamsters were given elastase intratracheally with or without the inhibitor or were given elastase intratracheally and the inhibitor intraperitoneally. Two weeks after administration, lungs were removed, and static air pressure volume curves were performed followed by intratracheal fixation and morphometric determination of mean linear intercepts. The results indicate significant preservation of structure and function whether the inhibitor is given intratracheally or intraperitoneally and suggest that this inhibitor may be useful in controlling diseases arising from aberrant proteolysis by elastolytic enzymes.
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PMID:A new peptide boronic acid inhibitor of elastase-induced lung injury in hamsters. 363 81

The primary function of alpha 1-antitrypsin (alpha 1-AT), an antiprotease produced by the liver, is the inhibition of neutrophil elastase, a protease capable of hydrolysing most connective tissue components. The importance of alpha 1-AT is demonstrated by the high incidence of early-onset emphysema in individuals with hereditary alpha 1-AT deficiency (Type PiZZ), in whom serum levels of alpha 1-AT are 10-20% of normal. Oxidants in tobacco smoke can inactivate alpha 1-AT in vitro, and studies have shown that alpha 1-AT from the lungs of individuals who smoke cigarettes may also be partially inactivated, perhaps explaining the high incidence of emphysema associated with cigarette smoking. Oxidative inactivation is probably due to modification of the Met residue (Met358) at the P1 subsite position of the elastase binding site of the protein. To study the possibility of modulating the biological properties of alpha 1-AT, we have introduced selected sequence modifications at the reactive site by in vitro mutation of a cloned alpha 1-AT complementary DNA. We describe here the characterization of two alpha 1-AT analogues produced in Escherichia coli. The first, alpha 1-AT(Met385----Val), is not only fully active as an elastase inhibitor but is also resistant to oxidative inactivation. The other, alpha 1-AT(Met358----Arg), no longer inhibits elastase but is an efficient thrombin inhibitor. The active site of the latter is identical to that of the alpha 1-AT (Pittsburgh) variant, which was associated with a fatal bleeding disorder.
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PMID:Synthesis in E. coli of alpha 1-antitrypsin variants of therapeutic potential for emphysema and thrombosis. 388 Aug 73

The effect of a synthetic elastase inhibitor was studied in experimental emphysema. The development of emphysema was totally prevented by this material. In the authors' opinion the administration of synthetic elastase inhibitors can be considered as a new possibility in the treatment of pulmonary emphysema.
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PMID:Prevention of elastase-induced emphysema by aerosol administration of a specific synthetic elastase inhibitor. 655 2

Purified human neutrophil elastase (HNE) and a crude extract of human neutrophils (EXT) were administered intratracheally to hamsters, and their effects were determined 21 and 56 days later by measurement of lung statics and dynamics and by light microscopy and morphometry of the lungs. A dose of 450 micrograms of HNE (HNE 450) produced focal emphysema of moderate severity. The combination of HNE 450 and EXT (HNE 450 + EXT) produced no more severe emphysema than HNE 450 alone; EXT alone did not produce emphysema. The HNE 450, HNE 450 + EXT, and EXT all produced persistent secretory cell metaplasia in large intrapulmonary airways. In a second experiment, 40 micrograms of HNE (elastolytic activity equivalent to that in EXT), designated HNE 40, did not produce secretory cell metaplasia. Neither EXT nor EXT treated with the elastase inhibitor suc-ala-ala-pro-val chloromethyl ketone (EXT + CMK), which had a residual elastolytic activity equivalent to 15 micrograms of HNE, produced emphysema; both preparations caused bronchial secretory cell metaplasia 21 days after treatment. Values of maximal expiratory flow, measured 21 days after treatment, were reduced at points between 20 and 50% of vital capacity for HNE 450 and between 30 and 80% of vital capacity for HNE 450 + EXT; maximal expiratory flows were not significantly different from saline controls for HNE 40, EXT, or EXT + CMK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. 656 Oct 16

The inhibitory effect of synthetic elastase inhibitor was studied in experimental emphysema. The development of emphysema was totally prevented by this substance. According to the authors' opinion the administration of synthetic elastase inhibitors can be considered as a new possibility in the treatment of pulmonary emphysema.
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PMID:Protective effect of specific elastase inhibitor in experimental pulmonary emphysema. 656 60

Elastase/elastase inhibitor imbalance in the lung has been implicated in the pathogenesis of pulmonary emphysema. In light of this, it may be significant that the activity of two major elastase inhibitors, alpha 1-proteinase inhibitor (alpha 1-antitrypsin, alpha 1Pi) and bronchial mucous proteinase inhibitor, can be decreased by oxidizing agents. The effect can be observed with ozone, substances present in cigarette smoke, and oxygen metabolites generated by lung macrophages as well as peroxidative systems released by other phagocytic cells. Thus alpha 1Pi recovered from lung washings of cigarette smokers has only half the predicted normal activity per mg inhibitor and contains 4 moles of methionine sulfoxide (oxidized methionine) per mole of inactive inhibitor. By contrast, alpha 1Pi purified from nonsmokers' lung washings is fully active and contains only native methionine. At the same time, lung washes from some smokers show significantly greater hydrolytic activity against a specific synthetic elastase substrate than do lung washes of nonsmokers. These findings suggest that some smokers may develop an acquired imbalance between elastase and elastase inhibitor in their lungs, favoring activity of the enzyme. In addition to the potential effect of cigarette smoking on lung elastase/elastase inhibitor balance, smoking also may interfere with elastin repair mechanisms. Specifically, acidic water-soluble gas phase components of cigarette smoke prevent synthesis of desmosine cross-links during elastinogenesis in vitro. This report will attempt to correlate the foregoing information on biochemical changes in the lung induced by cigarette smoking with the development of emphysema in the smoker.
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PMID:The role of oxidative processes in emphysema. 660 Aug 89


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