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)

Oxidative damage to alpha 1-proteinase inhibitor (alpha 1-PI) may be important in the pathogenesis of emphysema. We have studied the ability of 2 enzymes (catalase and methionine-S-oxide reductase) to prevent and reverse oxidation of alpha 1-PI by hydrogen peroxide. Pre-incubation of catalase with H2O2 protected alpha 1-PI from oxidation, but the enzyme could not reverse prior oxidation of alpha 1-PI. In contrast, methionine-S-oxide reductase fully restored activity to H2O2-oxidised alpha 1-PI. Sputum sol-phase from smokers and non-smokers contained alpha 1-PI that was only about 30% active. Functional activity increased in both smokers (p less than 0.025) and non-smokers (p less than 0.05) approximately 2-fold following incubation with the reductase. Western blotting of the samples showed that about 20% of the alpha 1-PI was present as an enzyme-inhibitor complex and 20% was proteolytically cleaved. These observations suggest proteolysis, complexing with enzyme and oxidation are mechanisms of inactivation of alpha 1-PI in lung secretions.
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PMID:The effect of catalase and methionine-S-oxide reductase on oxidised alpha 1-proteinase inhibitor. 352 23

The effect of elastin peptides (Kappa-elastin) was investigated on human monocytes. The data presented here indicate that elastin peptides increase the intracellular Ca2+ level measured by Quin 2 fluorescence and mediate the release of beta glucuronidase and elastase. The O2 consumption and H2O2 release were stimulated in a dose-dependent manner. The early rise of cAMP was followed by a return to the original level at 30 min and by a concomitant increase of cGMP level. The action of elastin peptides on intracellular calcium level and cGMP levels may well be related to its previously demonstrated chemotactic activity. These activities may well play a role in the modifications of the extracellular matrix following elastin degradation as observed in atherosclerosis, emphysema and aging.
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PMID:Effect of elastin peptides on human monocytes: Ca2+ mobilization, stimulation of respiratory burst and enzyme secretion. 364 24

We have examined the effect of the myeloperoxidase-hydrogen peroxide-halide system and of activated human neutrophils on the ability of serum alpha 1-protease inhibitor (alpha 1-PI) to bind and inhibit porcine pancreatic elastase. Exposure to the isolated myeloperoxidase system resulted in nearly complete inactivation of alpha 1-PI. Inactivation was rapid (10 to 20 s); required active myeloperoxidase, micromolar concentrations of H2O2 (or glucose oxidase as a peroxide generator), and a halide cofactor (Cl- or I-); and was blocked by azide, cyanide, and catalase. Intact neutrophils similarly inactivated alpha 1-PI over the course of 5 to 10 min. Inactivation required the neutrophils, a halide (Cl-), and a phorbol ester to activate secretory and metabolic activity. It was inhibited by azide, cyanide, and catalase, but not by superoxide dismutase. Neutrophils with absent myeloperoxidase or impaired oxidative metabolism (chronic granulomatous disease) failed to inactivate alpha 1-PI, and these defects were specifically corrected by the addition of myeloperoxidase or H2O2, respectively. Thus, stimulated neutrophils secrete myeloperoxidase and H2O2 which combine with a halide to inactivate alpha 1-PI. We suggest that leukocyte-derived oxidants, especially the myeloperoxidase system, may contribute to proteolytic tissue injury, for example in elastase-induced pulmonary emphysema, by oxidative inactivation of protective antiproteases.
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PMID:Myeloperoxidase-catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils. 616 45

It has been suggested that oxidants from pulmonary inflammatory cells may contribute to the development of emphysema by (i) direct tissue toxicity and (ii) inhibition of alpha 1-antitrypsin, thus diminishing protection of the lung from proteolytic damage. The extracellular release of hydrogen peroxide (H2O2) by human alveolar macrophages (AM) has been measured. AM were obtained by bronchoalveolar lavage and adherence from 24 smokers and 17 non-smokers. Smokers' AM released significantly more H2O2 (3.83 nmol h-1 micrograms-1 of DNA; SEM 0.44) than those of non-smokers' (2.33 nmol h-1 microgram-1 of DNA; SEM 0.40) (P less than 0.05). AM from donors with a recent lower respiratory tract infection released increased quantities of H2O2 (5.22 nmol h-1 microgram-1 of DNA; SEM 0.72; P less than 0.01) even when allowance was made for smoking habits. These findings are consistent with the hypothesis that H2O2 of AM origin contributes to the development of emphysema in smokers.
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PMID:Extracellular release of hydrogen peroxide by human alveolar macrophages: the relationship to cigarette smoking and lower respiratory tract infections. 662 51

In smoking subjects with obvious emphysema, the interaction between neutrophil-derived MPO and H2O2 produced by alveolar inflammatory cells (alveolar macrophages (AM) and polymorphonuclear neutrophils (PMN)) has the ability to spontaneously inactivate, in vitro, the alpha 1 proteinase inhibitor (alpha 1PI). This inactivation can induce a desequilibrium of the protease-antiprotease balance in the lungs. In this study, we investigated the ability of glutathione to protect alpha 1PI. In a cellular model of alpha 1PI inactivation mimicking the effects of alveolar inflammatory cells present in the lower respiratory tract of smoking patients with emphysema, we demonstrated that glutathione can protect alpha 1PI against the oxidative inactivation by these activated cells. This protection has been computed in a cellular experimentation (AM and MPO-system) with a 50% inhibitory concentration of 62 microM. Moreover, glutathione has an important inhibitory effect directly on H2O2 released by PMA-stimulated AM (IC50 = 30 microM) or PMA stimulated PMN (IC50 = 70 microM). The mechanism, which governs glutathione may be a result of a scavenging effect on H2O2 as demonstrated in a free cellular experiment. With this in vitro demonstrated effectiveness, glutathione as a therapeutic antioxidant, via the aerosol, has been proposed, in order to prevent tissue damage, inflicted by an excess of activated phagocytic cells, in some lung diseases such as smoking patients with emphysema.
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PMID:Protective role of glutathione on alpha 1 proteinase inhibitor inactivation by the myeloperoxidase system. Hypothetic study for therapeutic strategy in the management of smokers' emphysema. 772 Dec 28

Chronic inhalation of coal dust can cause several lung disorders, including simple coal workers pneumoconiosis (CWP), progressive massive fibrosis (PMF), chronic bronchitis, lung function loss, and emphysema. This review focuses on the cellular actions and interactions of key inflammatory cells and target cells in coal dust toxicity and related lung disorders, i.e. macrophages and neutrophils, epithelial cells, and fibroblasts. Factors released from or affecting these cells are outlined in separate sections, i.e. (1) reactive oxygen species (ROS) and related antioxidant protection mechanisms, and (2) cytokines, growth factors and related proteins. Furthermore, (3) components of the extracellular matrix (ECM), including the modifying role of ROS, cytokines, proteases and antiproteases are discussed in relation to tissue damage and remodelling in the respiratory tract. It is recognised that inhaled coal dust particles are important non-cellular and cellular sources of ROS in the lung, and may be significantly involved in the damage of lung target cells as well as important macromolecules including alpha-1-antitrypsin and DNA. In vitro and in vivo studies with coal dusts showed the up-regulation of important leukocyte recruiting factors, e.g. Leukotriene-B4 (LTB4), Platelet Derived Growth Factor (PDGF), Monocyte Chemotactic Protein-1 (MCP-1), and Tumor Necrosis Factor-alpha (TNF alpha), as well as the neutrophil adhesion factor Intercellular Adhesion Molecule-1 (ICAM-1). Coal dust particles are also known to stimulate the (macrophage) production of various factors with potential capacity to modulate lung cells and/or extracellular matrix, including O2-., H2O2, and NO, fibroblast chemoattractants (e.g. Transforming Growth Factor-beta (TGF beta), PDGF, and fibronectin) and a number of factors that have been shown to stimulate and/or inhibit fibroblast growth or collagen production such as (TNF alpha, TGF beta, PDGF, Insulin Like Growth Factor, and Prostaglandin-E2). Further studies are needed to clarify the in vivo kinetics and relative impact of these factors.
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PMID:Mechanisms and mediators in coal dust induced toxicity: a review. 1002 91

The proteinase-proteinase inhibitor balance plays an important role in mediating inflammation-associated tissue destruction. alpha 2-Macroglobulin (alpha 2M) is a high-affinity, broad-spectrum proteinase inhibitor found abundantly in plasma and interstitial fluids. Increased levels of alpha 2M and proteinase-alpha 2M complexes can be demonstrated in patients with sepsis, emphysema, peridontitis, rheumatoid arthritis, and other inflammatory diseases. Despite these increased levels, proteolysis remains a significant problem. We hypothesized that a mechanism for inactivating alpha 2M-mediated proteinase inhibition must exist and recently demonstrated that alpha 2M isolated from human rheumatoid arthritis synovial fluid is oxidized and has decreased functional activity. The oxidant responsible for alpha 2M inactivation and the mechanism of such destruction were not studied. We now report that while hypochlorite and hydroxyl radical both modify amino acid residues on alpha 2M, only hypochlorite can abolish the ability of alpha 2M to inhibit proteinases. Hydrogen peroxide, on the other hand, has no effect on alpha 2M structure or function. Protein unfolding with increased susceptibility to proteolytic cleavage appears to be involved in alpha 2M inactivation by oxidation. The in vivo relevance of this mechanism is supported by the presence of multiple cleavage fragments of alpha 2M in synovial fluid from patients with rheumatoid arthritis, where significant tissue destruction occurs, but not in patients with osteoarthritis. These results provide strong evidence that hypochlorite oxidation contributes to enhanced tissue destruction during inflammation by inactivating alpha 2M.
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PMID:Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin. 1052 45

Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE). Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung. A (GT)n dinucleotide repeat in the 5'-flanking region of human HO-1 gene shows length polymorphism and could modulate the level of gene transcription. To investigate the correlation between the length of the (GT)n repeat and susceptibility to the development of CPE, we screened the frequencies of alleles with varying numbers of (GT)n repeats in the HO-1 gene in 101 smokers with CPE and in 100 smokers without CPE. Polymorphisms of the (GT)n repeat were grouped into three classes: class S alleles (<25 repeats), class M alleles (25-29 repeats), and class L alleles (>/=30 repeats). The proportion of allele frequencies in class L, as well as the proportion of genotypic frequencies in the group with class L alleles (L/L, L/M, and L/S), was significantly higher in the smokers with CPE than in smokers without CPE. Moreover, we analyzed the promoter activities of the HO-1 gene carrying different (GT)n repeats (n=16, 20, 29, and 38), by transient-transfection assay in cultured cell lines. H2O2 exposure up-regulated the transcriptional activity of the HO-1 promoter/luciferase fusion genes with (GT)16 or (GT)20 but did not do so with (GT)29 or (GT)38. These findings suggest that the large size of a (GT)n repeat in the HO-1 gene promoter may reduce HO-1 inducibility by reactive oxygen species in cigarette smoke, thereby resulting in the development of CPE.
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PMID:Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. 1063 Nov 50

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.
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PMID:Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. 1080 80

Hydrogen peroxide is widely used in products such as rocket fuel, bleaching preparations and topical disinfectants. Contact of hydrogen peroxide with the skin can cause severe skin damage. In this report, we describe a case of skin injury induced by hydrogen peroxide. The patient was a 34-year-old man working in a dry cleaning shop. While he was pouring 35% hydrogen peroxide, some of it accidentally splashed over his left shoulder and back, and then an erythema, purpura and vacuolar eruption, similar to bubble wrap, appeared on his left shoulder and down the left side of his back. Histologically, numerous vacuolar structures were observed in the epidermis, dermis and subcutaneous tissue. Coupled with the clinical features, these vacuolar structures were considered as 'oxygen bubbles'. Subcutaneous emphysema was detected by chest X-ray examination. All skin eruptions rapidly healed without scarring by using a steroid ointment. As far as we know, this is the first time such clinical and histological features have been described
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PMID:Occupational skin injury by hydrogen peroxide. 1097 Oct 65


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