Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro effects of the Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) on neutrophil elastase release and myeloperoxidase-induced inactivation of alpha-1-protease inhibitor (alpha 1-PI) were investigated. 1-hp (6-25 microM), but not pyocyanin, caused a dose-dependent enhancement of elastase release by FMLP:cytochalasin B (CB)-activated human neutrophils. 1-hp (0.78-6.25 microM) also increased the oxidative inactivation of the elastase inhibitory capacity of alpha 1-PI exposed to FMLP:CB-activated neutrophils. Methionine, a scavenger of hypochlorous acid, completely protected alpha 1-PI from inactivation by stimulated neutrophils in the presence or absence of 1-hp. Similar protective effects were observed with sodium azide, an inhibitor of myeloperoxidase. P. aeruginosa-derived 1-hp may promote an elastase-antielastase imbalance in vivo by increasing the release of neutrophil elastase and by enhancing the oxidative inactivation of alpha 1-PI, thereby contributing to the development of tissue destruction in P. aeruginosa-infected patients.
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PMID:Enhanced release of elastase and oxidative inactivation of alpha-1-protease inhibitor by stimulated human neutrophils exposed to Pseudomonas aeruginosa pigment 1-hydroxyphenazine. 132 22

IgG is split by neutrophil elastase into Fc and Fab fragments. These IgG fragments influence the functions of stimulated neutrophils such as chemotaxis, oxidative burst, and enzyme release. FMLP stimulated leukocyte chemotaxis is specifically inhibited by the elastase generated Fc fragments. Seven nmol Fc/10(6) PMN totally inhibit the chemotaxis stimulated by 16 to 125 nM FMLP. Native IgG and Fab fragments show no effect. FMLP-stimulated superoxide anion generation is specifically inhibited by Fc fragments with half maximal inhibition by 1.2 nmol/10(6) PMN. The generation of hydrogen peroxide is concomitantly stimulated, resulting in a superoxide dismutase-like effect. FMLP-stimulated elastase and myeloperoxidase release are enhanced by Fab fragments (10 nmol/10(6) PMN) to 206 and 155%, respectively, of reference values by 25 nM FMLP, while Fc and native IgG stimulate to a less extent. Consequently, elastase-generated Fc fragments have an inhibitory effect on inflammation by reducing chemotaxis and oxidative burst of stimulated neutrophils. The release stimulating activity of Fab fragments results in an up-regulation of elastase induced IgG degradation.
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PMID:Regulation of neutrophil functions by elastase-generated IgG fragments. 133 54

The human chromosomal gene for the granulocyte CSF (G-CSF) receptor was molecularly cloned from a human gene library. The gene is about 16.5 kb long, and present in a single copy per haploid human genome. The human G-CSF receptor gene consists of 17 exons, and the sequences of exons are completely identical to those of cDNAs isolated from human U-937 myeloid leukemia or placenta cDNA libraries. The G-CSF receptor can be subdivided into several regions: an Ig-like domain, a cytokine receptor homologous domain, three fibronectin type III domains, a transmembrane domain, and a cytoplasmic region. Exons 3-17 code for the G-CSF receptor protein, and each subdomain of the receptor is encoded by a set of exons. Primer extension analysis of the G-CSF receptor mRNA identified major and minor transcription start sites. There is no canonical "TATA" box upstream of the CAP site. About 110 nucleotides upstream of the transcription initiation site of the gene, there is an element of 18 nucleotides that is homologous to the sequences found in the promoter of human myeloperoxidase and neutrophil elastase genes.
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PMID:Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor. 153 Jul 96

When neutrophils are recruited to tissue sites and exposed to phagocytosable targets, they release oxidants which may be responsible for the local inactivation of alpha-1-proteinase inhibitor (A1PI). Consequently, A1PI becomes incapable of inhibiting the proteolytic activity of elastase, released at the same time by neutrophils as a result of leakage from phagocytic vacuoles. In the present paper we show that phagocytosing neutrophils inactivate A1PI via a process inhibitable by chemical agents known to interfere with the hypochlorous acid (HOCl)-generating myeloperoxidase pathway. The anti-inflammatory drug nimesulide (NMS), which is able to efficiently limit the extracellular availability of HOCl in the neutrophil surroundings, was found to prevent the inactivation of A1PI by neutrophils. The results provide evidence for a possible way to control neutrophil elastase activity by rescuing its natural inhibitor (A1PI) at inflamed tissue sites during infectious and noninfectious processes.
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PMID:The anti-inflammatory drug nimesulide rescues alpha-1-proteinase inhibitor from oxidative inactivation by phagocytosing neutrophils. 157 12

Human neutrophil elastase (NE), a 29-Kd potent serine protease stored in azurophilic granules of mature neutrophils, is coded for by the NE gene, a single copy gene with 5 exons spanning a 6-kb segment of chromosome 11 at q14. With the knowledge that the NE gene expression is limited to early myeloid cell differentiation, mechanisms modulating expression of the NE gene were evaluated in the HL-60 promyelocytic leukemia cell line, a model of early bone marrow precursor cells. Consistent with the presence of NE messenger RNA (mRNA) transcripts in undifferentiated HL-60 cells, nuclear transcription run-on analyses showed that HL-60 cells actively transcribed the NE gene. However, the transcription rate of the NE gene was relatively low, only 40% of the myeloperoxidase gene, a gene expressed in parallel with NE. When induced toward the mononuclear phagocytic lineage with phorbol 12-myristate 13-acetate (PMA), HL-60 cells exhibited marked suppression of NE gene transcription, declining to 17% of the resting rate within 2 days. Induction toward mononuclear phagocytic lineage differentiation caused no change in NE mRNA transcript half-life (T1/2), but mRNA levels decreased markedly over time, with levels undetectable 1.5 days after PMA stimulation. In contrast, when induced toward the myelocytic lineage with dimethyl sulfoxide, the rate of NE gene transcription increased 1.9-fold within 5 days. Interestingly, the mRNA transcript levels increased 2.5-fold by 5 days despite the fact that induction toward myelocytic lineage differentiation was accompanied by a marked reduction of NE mRNA transcript T1/2. Together, these observations suggest that the NE gene expression during bone marrow differentiation is modulated mainly at the transcriptional level, with some posttranscriptional modulation contributing, particularly during myelocytic lineage differentiation.
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PMID:Transcriptional and posttranscriptional modulation of human neutrophil elastase gene expression. 158 20

Guinea pig neutrophils contain the antimicrobial cationic peptides GNCP-1 and GNCP-2 in the granules. In this study, the GNCP gene was isolated, and the structure was characterized. Using cDNA probes, one phage clone was isolated from a guinea pig genomic library. The gene spanned greater than 3 kb, and comprised three exons and two introns. Sequence analysis revealed that the gene encoded GNCP-2. Exon 1 mainly coded for the 5' untranslated region, exon 2 coded for the prepro-peptide region of GNCP-2, and exon 3 coded for the mature peptide region of GNCP-2 and the 3' untranslated region. Primer extension analysis indicated that the transcription initiation site was located to a thymidine residue, 93 bp upstream of the ATG initiation codon of GNCP-2 mRNA. A possible TATA box was located 24 bp upstream of the transcription start site. Interestingly, the pyrimidine-rich sequences identified in the promoter regions of the human neutrophil elastase and myeloperoxidase genes were also found in the 5' flanking region of the GNCP-2 gene.
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PMID:Structure of the guinea pig neutrophil cationic peptide gene. 159 12

Exposure to silica can induce fibrosis and/or emphysema. Various factors such as proteases, other hydrolases and oxidants may be involved in the destruction of lung parenchyma. On the other hand, antiproteases play an important role in the protection of lung parenchyma against the action of proteases. We have developed an animal model of silicosis in monkey Macacus cynomolgus and followed these factors by bronchoalveolar lavage (BAL). We have studied glycosidases activities, elastase-like activity, immunoreactive alpha 1-protease inhibitor (alpha 1PI), neutrophil elastase inhibitory capacity (NEIC) and myeloperoxidase. Bronchoalveolar cells in serial BAL were also studied. Six monkeys were exposed to quartz aerosols (100 mg.m-3) for 18 wks. They were followed until they developed X-ray changes, which occurred between 21-64 wks after the end of the dust exposure. Cellular "silicotic nodules" were observed in lung biopsies. A control animal underwent serial BAL. Changes were seen in the differential cell count. The release of superoxide anion by bronchoalveolar cells obtained during the experiment was increased. Separation on a gradient of Percoll showed the presence of young macrophages, which exhibited enhanced release of superoxide anion as compared to the totality of bronchoalveolar cells. The biochemical analysis of BAL fluids obtained during and after the period of dust exposure showed an increase in glycosidases, alpha 1PI and NEIC. Some free elastase-like activity was simultaneously detected in BAL fluids from exposed animals but not from the control. This elastase-like activity was very low compared to NEIC. The increase in enzymatic and antiprotease activities occurred at different points in time for each animal, suggesting large differences in individual responses to dust, but occurred before the chest X-ray abnormalities.
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PMID:An attempt to evaluate lung aggression in monkey silicosis: hydrolases, peroxidase and antiproteases activities in serial bronchoalveolar lavages. 164 17

In vivo most extracellular iron is bound to transferrin or lactoferrin in such a way as to be unable to catalyze the formation of hydroxyl radical from superoxide (.O2-) and hydrogen peroxide (H2O2). At sites of Pseudomonas aeruginosa infection bacterial and neutrophil products could possibly modify transferrin and/or lactoferrin forming catalytic iron complexes. To examine this possibility, diferrictransferrin and diferriclactoferrin which had been incubated with pseudomonas elastase, pseudomonas alkaline protease, human neutrophil elastase, trypsin, or the myeloperoxidase product HOCl were added to a hypoxanthine/xanthine oxidase .O2-/H2O2 generating system. Hydroxyl radical formation was only detected with pseudomonas elastase treated diferrictransferrin and, to a much lesser extent, diferriclactoferrin. This effect was enhanced by the combination of pseudomonas elastase with other proteases, most prominently neutrophil elastase. Addition of pseudomonas elastase-treated diferrictransferrin to stimulated neutrophils also resulted in hydroxyl radical generation. Incubation of pseudomonas elastase with transferrin which had been selectively iron loaded at either the NH2- or COOH-terminal binding site yielded iron chelates with similar efficacy for hydroxyl radical catalysis. Pseudomonas elastase and HOCl treatment also decreased the ability of apotransferrin to inhibit hydroxyl radical formation by a Fe-NTA supplemented hypoxanthine/xanthine oxidase system. However, apotransferrin could be protected from the effects of HOCl if bicarbonate anion was present during the incubation. Apolactoferrin inhibition of hydroxyl radical generation was unaffected by any of the four proteases or HOCl. Alteration of transferrin by enzymes and oxidants present at sites of pseudomonas and other bacterial infections may increase the potential for local hydroxyl radical generation thereby contributing to tissue injury.
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PMID:Pseudomonas and neutrophil products modify transferrin and lactoferrin to create conditions that favor hydroxyl radical formation. 165 25

The aim of this work was to study the ability of human alveolar macrophages (AM) of 10 healthy smokers to inactivate alpha 1-proteinase inhibitor (alpha 1PI). Purified alpha 1PI was incubated for 45 min, with human alveolar macrophages before and after stimulation by phorbol myristate acetate (PMA) or opsonized zymosan. As a positive control, the same experiments were performed in parallel with blood human neutrophils (PMN). Results are expressed as percentage of inactivation of alpha 1PI as evaluated from its inhibitory activity against porcine pancreatic elastase. A strong correlation (r = 0.99) was shown when inhibitory activity of alpha 1PI was evaluated against porcine pancreatic elastase or human neutrophil elastase. Unstimulated AM (1.57 +/- 0.9%) as well as stimulated AM (PMA: 1 +/- 0.4%; zymosan: 3 +/- 0.6%) were unable to inactivate alpha 1PI. Gel electrophoresis of alpha 1PI demonstrated that AM before or after stimulation induced a slight proteolysis of alpha 1PI, whereas both cleaved and complexed alpha 1PI were found when alpha 1PI was incubated with activated PMN. Both unstimulated (22 +/- 2.6%) and activated PMN (PMA: 91.7 +/- 4.7%; zymosan: 90 +/- 5.5%) were responsible for a significant inactivation of alpha 1PI. Catalase, in contrast to superoxide dismutase, was responsible for a near complete protection of alpha 1PI inactivation by PMN. To better determine the role of PMN secretory products, especially myeloperoxidase (MPO), we also investigated the effect of zymosan-activated PMN supernatants or of purified MPO on the alpha 1PI-AM reaction. MPO assay in PMN supernatants demonstrated that activated neutrophils released significant amounts of MPO (16.8 +/- 4.1 U/ml), whereas MPO was undetectable in activated AM supernatants.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidative inactivation of alpha 1-proteinase inhibitor by alveolar macrophages from healthy smokers requires the presence of myeloperoxidase. 165 63

The neutrophil serine proteinases elastase and cathepsin G produce connective tissue injury, the extent of which depends on the balance between these enzymes and their inhibitors. The most important of these inhibitors is alpha 1-proteinase inhibitor, a member of a superfamily of homologous proteins known as serpins. Neutrophil cytosol inhibited the activities of human neutrophil elastase and cathepsin G in a dose-dependent fashion. To demonstrate formation of an enzyme-inhibitor complex, we combined 125I-elastase or 125I-cathepsin G with neutrophil cytosol or alpha 1-proteinase inhibitor and analyzed the products by polyacrylamide gel electrophoresis. Unbound elastase and cathepsin G each migrated to an apparent molecular weight of 25 kDa. In the presence of cytosol from neutrophils both radiolabeled enzymes migrated with a relative size of 68 kDa, whereas in the presence of alpha 1-proteinase inhibitor the relative size was 85 kDa. Enzyme-inhibitor complexes were stable in sodium dodecyl sulfate at 100 degrees C but were dissociated by hydrolysis in ammonium hydroxide (1.5 mol/L) at 37 degrees C. Formation of each complex was prevented by pretreatment of elastase or cathepsin G with diisopropylfluorophosphate, indicating that the inhibitor binds to the active site of the enzyme. Exposure of either alpha 1-proteinase inhibitor or neutrophil cytosol to the myeloperoxidase-H2O2-halide system prevented complex formation, suggesting the presence of an oxidizable amino acid at the binding site of the inhibitor. By electrophoretic analysis, the molecular weight of the cytosolic inhibitor was 43 kDa and neutrophils contained approximately 1 attomol of inhibitor per cell. The isoelectric points of the elastase and cathepsin G inhibitor were 5.5-5.9 and inhibitors of the two proteinases coeluted using size exclusion chromatography. These data demonstrate that human neutrophil cytosol contains a single serpinlike protein that inhibits elastase and cathepsin G. The inhibitor may be important in protecting the intracellular environment from proteolytic injury during degranulation.
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PMID:A cytosolic inhibitor of human neutrophil elastase and cathepsin G. 165 73


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