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 healthy or previously damaged pulp responds to most of the drugs currently applied to the dentin with an inflammatory reaction. By means of a standardized biological screening test, the modes of action of hydrogen peroxide and of Falikain preparations are demonstrated on the pulp of the rat incisor. Hydrogen peroxide produces an emphysema of the pulp tissue associated with a slowing of the circulation and partly irreversible capillary stases, whereas Falicain compound preparations (Falicid, Myrex) cause, by way of haemolysis, injuries involving entire areas of the pulp. For this reason, hydrogen peroxide should not be used for cleaning cavities. Myrex is well suited for symptomatic treatment to relieve pain, if removal of the inflamed pulp ensues.
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PMID:[Reactions of the pulp-dentin system to drugs]. 106 48

The oxidative inactivation of the alpha-1-proteinase inhibitor (alpha 1PI) is one of the mechanisms responsible for creating the elastase/antielastase imbalance during inflammation in the lower respiratory tract. Chronic supremacy of elastase may cause degradation of elastin fibers leading to the pulmonary emphysema. In this study we have investigated the effect of erythrocytes (RBC, concentrations 0.125 to 1.5%) on the oxidative inactivation of alpha 1PI by the phorbol myristate acetate-stimulated polymorphonuclear leukocytes (PMNL) and PMNL myeloperoxidase-H2O2-halide system. During exposure of alpha 1PI to both systems in the presence of RBC the significant protection (p less than 0.001) of alpha 1PI was found for all RBC concentrations, e.g. at RBC concentration of 1% the elastase inhibitory capacity (EIC) of alpha 1PI increased from 0 to 60 +/- 6 and 88 +/- 9% of the control value (untreated alpha 1PI), n = 5, respectively. The preincubation of RBC with chloramine-T (1 mM), inhibition of RBC catalase or depletion of RBC reduced glutathione alone did not diminish the capacity of RBC to protect alpha 1PI. However, these treatments together completely deprived RBC of their protective properties. Moreover, we have compared the decrease in the EIC of human blood and its plasma after incubation with H2O2 (0.1 mM to 0.1 M) or chloramine-T (1 microM to 1 mM). For the incubation with H2O2 no decrease in blood EIC was found whereas in plasma the loss of EIC was already visible at a H2O2 concentration of 0.1 mM. Also for the incubation with chloramine-T the EIC of blood was more resistant to oxidant damage than EIC of plasma. It is suggested that RBC contaminations present in the phagocyte inflammatory infiltration in the lower airways may protect alpha 1PI from oxidative inactivation and thus indirectly diminish proteolytic lung injury related to inflammation.
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PMID:Erythrocytes protect alpha-1-proteinase inhibitor from oxidative inactivation induced by chemicals, the myeloperoxidase-H2O2-halide system and stimulated polymorphonuclear leukocytes. 165 55

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

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

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.
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PMID:Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. 228 87

Current concepts relating to the pathogenesis of emphysema associated with cigarette smoking is that an imbalance exists within the lower respiratory tract between neutrophil elastase and the local anti-neutrophil elastase screen, enabling uninhibited neutrophil elastase to destroy the alveolar structures over time. The possible role of alveolar macrophages in contributing to this imbalance was investigated by evaluating the ability of cigarette smokers' alveolar macrophages to inactivate alpha 1-antitrypsin (alpha 1AT), the major anti-neutrophil elastase of the human lower respiratory tract. In vitro, alveolar macrophages of smokers spontaneously released 2.5-fold more superoxide anion and eightfold more H2O2 than macrophages of nonsmokers (P less than 0.01, both comparisons). Using a model system that reproduced the relative amounts of alveolar macrophages and alpha 1AT found in the epithelial lining fluid of the lower respiratory tract, we observed that smokers' macrophages caused a 60 +/- 5% reduction in the ability of alpha 1AT to inhibit neutrophil elastase. In marked contrast, under the same conditions, nonsmokers' macrophages had no effect upon the anti-neutrophil elastase function of alpha 1AT. Addition of superoxide dismutase, catalase, mannitol, and methionine prevented inactivation of alpha 1AT by smokers' macrophages, implying that the release of oxidants mediated the inactivation of alpha 1AT. In addition, by utilizing a recombinant DNA produced modified form of alpha 1AT containing an active site substitution (met358----val), the inactivation of alpha 1AT by smokers' alveolar macrophages was prevented, suggesting that the smokers' macrophages inactivate alpha 1AT by oxidizing the active site of the alpha 1AT molecule. These results suggest that in cigarette smokers, the alveolar macrophage can modulate the activity of alpha 1AT as an inhibitor of neutrophil elastase and thus play a role in the pathogenesis of emphysema associated with cigarette smoking.
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PMID:Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of alpha 1-antitrypsin, rendering it ineffective as an inhibitor of neutrophil elastase. 282 59

While numerous studies have demonstrated that the myeloperoxidase system found in neutrophils can oxidize and functionally inactivate alpha 1-proteinase inhibitor in vitro, there is little direct evidence that this phenomenon is relevant in vivo. Using incubation with tritiated porcine pancreatic elastase followed by column chromatography to quantitate binding, we demonstrated recovery of microgram amounts of functional alpha 1-protease inhibitor from bronchoalveolar lavage of hamster lungs. When exposed to the myeloperoxidase system in vitro, hamster alpha 1-protease inhibitor was 97% inactivated. Functional alpha 1-protease inhibitor recovered by bronchoalveolar lavage 20 minutes after hamsters were given intratracheal injections with myeloperoxidase and either hydrogen peroxide or glucose plus glucose oxidase was only half that recovered from control animals. These studies suggest that the myeloperoxidase system is effective in oxidizing alpha 1-protease inhibitor in vivo. They support the concept that oxidation of alpha 1-protease inhibitor by myeloperoxidase from neutrophil granules in the presence of H2O2 and halide may produce elastase-antielastase imbalance in vivo and contribute to the development of acute lung injury and emphysema in humans.
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PMID:Myeloperoxidase-induced inactivation of alpha 1-antiprotease in hamsters. 298 79

Emphysema is a chronic pulmonary disorder characterized by a permanent enlargement of the air spaces distal to the terminal bronchioles consequent to destruction of the alveolar walls, including the epithelial and endothelial cells and the connective tissue matrix. There is increasing evidence that an imbalance of oxidants and antioxidants in the lower respiratory tract contributes to this process. Oxidants such as O2-., H2O2, OH, OCl- are generated in the lower respiratory tract as a result of normal biochemical processes, activation of inflammatory cells and inhaled toxic gases. Under normal circumstances, the parenchymal cells are protected by intracellular antioxidants and membrane radical scavengers. In addition, the fluid lining the epithelial surface contains a catalase-like antioxidant that protects the epithelial cells from oxidants. If the oxidant burden overcomes these defenses, the parenchymal cells may be injured, the connective tissue matrix may be partially degraded, the antiprotease screen that protects the lower respiratory tract from attack by neutrophil elastase may be rendered impotent. The alveolar wall then becomes highly vulnerable to elastolytic attack, with a complete destruction of the interstitial connective tissue matrix. In this regard, it is reasonable to hypothesize that reestablishment of the oxidant-antioxidant balance in favor of the antioxidants would be useful as a therapeutic strategy to suppress the emphysematous process.
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PMID:Oxidants, antioxidants and the pathogenesis of emphysema. 299 6

Oxidants derived from the atmosphere or from activated pulmonary phagocytes mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to these oxidants may cause emphysema. In this study we have investigated the effects of the antioxidants ascorbate, cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated PMNL in the presence of ascorbate and cysteine at concentrations of greater than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI to the antioxidants subsequent to PMNL-mediated oxidative inactivation was not associated with reactivation of elastase inhibitory capacity. Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection of alpha-1-PI did not affect degranulation or the binding of radiolabeled leukoattractant to PMNL. It is suggested that the protective effects of the antioxidants are related to their ability to scavenge superoxide and oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because the effects of ascorbate and especially those of dapsone were observed at concentrations of these agents that are attainable in vivo, our results may have clinical significance.
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PMID:Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro. 299 43

The oxidative inactivation of alpha 1-proteinase (alpha 1AP) inhibitor is a one of mechanisms that may lead to the pulmonary emphysema. This process is caused by oxidants derived from atmosphere and released from lung phagocytes. These cells produce various oxidants hydrogen peroxide (H2O2), hypochlorous acid (HClO), hydroxyl (OH.) and superoxide (O2-) radicals after inflammatory stimulation. In this study I have investigated the effects of H2O2 (1.5 x 10(-5) to 1.5 x 10(-2) M) alone or with addition of FeCl2 (50 microM) in order to generate OH., chloramine-T (1.5 x 10(-5) to 1.5 x 10(-3) M) which generates HClO, glucose 10 mg/ml-glucose oxidase (12.5 to 80 mU/ml)-H2O2 generating system, xanthine 0.2 mM-xanthine oxidase (12.5 to 80 mU/ml)-O2-2 generating system on the elastase inhibitory activity of alpha 1AP in vitro. H2O2 was weak in alpha 1AP inactivation--only concentration of H2O2 1.5 x 10(-2) caused severe loss of its activity to 23 +/- 8% inhibition of elastase. Addition of FeCl2 to H2O2 and following OH. generation did not enhance its alpha 1AP inactivation. O2-2 generating system inhibited moderately alpha 1AP. The % inhibition of elastase at concentration of xanthine oxidase 80 mU/ml was 65 +/- 7. HClO was most effective as an alpha 1AP inactivator. All used chloramine-T concentrations completely suppressed alpha 1AP activity. The obtained results and in vivo consumption of H2O2 by polymorphonuclear leukocyte myeloperoxidase for HClO production suggest that scavenging of these reactive oxygen species may be useful in prevention of emphysema.
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PMID:The comparative study of reactive oxygen species generated by polymorphonuclear leukocytes as alpha 1-proteinase inhibitor inactivators-possible application for antioxidant prevention of emphysema. 307 84


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