Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cell-eosinophil interactions in allergy have not yet been completely defined. To determine whether mast cells influence eosinophil survival, human peripheral blood eosinophils were incubated with rat peritoneal mast cell sonicate. After 3 days, viable eosinophils in medium were 21.3% compared with 44% with mast cell sonicate. Like sonicate, supernatants of compound 48/80-activated mast cells enhanced eosinophil survival, demonstrating that the factor(s) involved is stored preformed and rapidly released. Increased eosinophil survival was due to an inhibition of apoptosis (morphologic analysis; annexin V/PI). Neutralizing Abs to granulocyte-macrophage CSF (GM-CSF), but not to IL-3 or IL-5, decreased by 61.7% the enhancing effect on eosinophil viability. Eosinophils are the source of GM-CSF since its release in the culture medium was inhibited by their incubation with the mast cell sonicate together with dexamethasone. In addition, eosinophils incubated with the sonicate expressed mRNA for GM-CSF. To partially characterize the mast cell-derived factor(s) increasing eosinophil survival, the sonicate was heated (56 degrees C/30 min or 100 degrees C/10 min) or preincubated with antihistamines or with anti-TNF-alpha-neutralizing Abs. Most of the activity was heat labile. TNF-alpha was found to be predominantly (70%) responsible, while histamine had no role. Mast cell sonicate also caused eosinophils to release eosinophil peroxidase and to display morphologic signs of activation. In conclusion, we have demonstrated that mast cells enhance eosinophil survival in part through their activation to produce and release the autocrine survival cytokine GM-CSF.
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PMID:Mast cells enhance eosinophil survival in vitro: role of TNF-alpha and granulocyte-macrophage colony-stimulating factor. 960 60

To identify tumour necrosis factor (TNF)-alpha immunopositive cells, third trimester human placental bed biopsies were selected from nine normotensive control women, 16 severely pre-eclamptic patients and seven patients with pre-existing hypertension with superimposed pre-eclampsia. In addition, five first and early second trimester specimens were included in the study. Immunostaining was performed with a mouse IgG1 monoclonal antibody (J1D9) reactive specifically with human TNF-alpha (1:300 ascitic fluid), using a biotin-streptavidin-peroxidase technique. Variable staining of stromal cells was noted in all biopsies. Specimens of early pregnancy showed marked immunostaining for TNF-alpha on proliferating tips of anchoring villi, invasive interstitial cytotrophoblast (but not the multinuclear giant cells), and endovascular trophoblast invading the spiral arteries. At term, weak staining was found in trophoblast incorporated within spiral artery walls. In biopsies from pre-eclamptic patients, spiral arteries without physiological change showed very little staining except in atherotic vessels where the infiltrated lipophages often showed intense immunolabelling. The marked presence of TNF-alpha in extravillous cytotrophoblast of young specimens is suggestive of a role in early invasion. Immunostaining of foam cells in non-invaded spiral arteries in pre-eclampsia at or near-term indicates a potential role of this cytokine in the development of atherotic lesions.
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PMID:Immunolocalization of tumour necrosis factor-alpha (TNF-alpha) in the placental bed of normotensive and hypertensive human pregnancies. 963 18

Bronchopulmonary hyperreactivity (BHR), an increased responsiveness to nonspecific bronchoconstrictor agents, is a well-known characteristic of bronchial asthma. It has been recently suggested that the severity of this disease is related to the endotoxin content of house dust. In the present report, it is shown that the i.p. administration of bacterial LPS to mice is followed by a marked early dose-dependent BHR in response to methacholine. The microscopic examination showed no ultrastructural lesions of the lungs or of the airways, but a marked neutrophil accumulation in the capillaries, as confirmed by an increase of the lung content in the neutrophil enzyme marker myeloperoxidase. In parallel, high levels of TNF-alpha were found in plasma as well as its transcripts in the lung tissues. Using immunologic (anti-TNF-alpha and anti-granulocyte Abs), and pharmacologic (dexamethasone and vinblastine) tools, it is demonstrated that BHR is apparently neither related to the presence of neutrophils in the pulmonary microvasculature nor to the synthesis of TNF-alpha.
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PMID:Systemic administration of endotoxin induces bronchopulmonary hyperreactivity dissociated from TNF-alpha formation and neutrophil sequestration into the murine lungs. 964 58

Thyroid-associated ophthalmopathy (TAO) has a major effect on the two compartments of the retro-orbital (RO) space, leading to enlargement of the extraocular muscles and other RO tissues. T lymphocyte infiltration of RO tissue is a characteristic feature of TAO and there is current interest in whether these T cells are specifically and selectively reactive to RO tissue itself. We recently established 18 T cell lines (TCL) from RO adipose/connective tissue of six patients with severe TAO by using IL-2, anti-CD3 antibodies and irradiated autologous peripheral blood mononuclear cells (PBMC) to maintain the growth of T cells reactive to autologous RO tissue protein fractions. Here we report on the phenotype characteristics and cytokine gene expression profiles of these orbital TCL and on their immunoreactivity to the organ-specific thyroid antigens thyrotropin receptor (TSH-R), thyroidal peroxidase (TPO) and thyroglobulin (TG). Flow cytometry revealed that 10 TCL were predominantly of CD4+ phenotype, three being mostly CD8+ and five neither CD4+ nor CD8+. Analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) of cytokine gene expression revealed both Th1- and Th2-like products in all TCL: IL-2 product (in 17 TCL), interferon-gamma (IFN-gamma) (n = 10), tumour necrosis factor-beta (TNF-beta) (n = 15), IL-4 (n = 12), IL-5 (n = 17), IL-6 (n = 13), TNF-alpha (n = 12) and IL-10 (n = 4). Reactivity to thyroid antigens was observed only in two TCL, the other 16 being uniformly unreactive. Although 10 out of 18 RO tissue-reactive TCL were predominantly CD4+ there were no significant relationships between TCL phenotype, cytokine gene profile, magnitude of reactivity to RO tissue protein or the (rare) occurrence of thyroid reactivity. The findings of both Th1- and Th2-like cytokine gene expression in all RO tissue-reactive TCL support the concept that TAO is a tissue-specific autoimmune disease, distinct immunologically from the thyroid, and involving both T cell and B cell autoimmune mechanisms in disease pathogenesis.
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PMID:Analysis of orbital T cells in thyroid-associated ophthalmopathy. 964 11

Based on the assumption that glutathione peroxidase (GPx) activity might be limiting in preventing peroxide-induced impairment of endothelial regulatory functions, we studied the effect of a series of new selenium-containing GPx mimics on endothelial cells exposed to an inflammatory stress. The two compounds that have the highest GPx activity, BXT-51072 and BXT-51077, were shown to be the most efficient inhibitors of leukocyte recruitment by human umbilical vein endothelial cells (HUVEC), upon incubation with neutrophils (10-fold excess over HUVEC) and with 1 ng/ml TNF-alpha for 1 or 3.5 h. When HUVEC were pre- and cotreated with 10 microM of either compound, neutrophil adhesion and endothelial alteration were markedly inhibited, as assessed by immunoassays of myeloperoxidase and von Willebrand factor, respectively. These two GPx mimics were also found to be the most efficient inhibitors of the TNFalpha-induced endothelial expression of P- and E-selectin and of the TNFalpha- or interleukin1-induced endothelial release of interleukin-8. Our results demonstrate that GPx mimics such as BXT-51072 behave as potent antagonists of TNF-alpha and interleukin-1 through the downregulation of endothelial proinflammatory responses.
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PMID:Glutathione peroxidase mimics prevent TNFalpha- and neutrophil-induced endothelial alterations. 968 Jan 72

1. The toxic effects of nonsteroidal anti-inflammatory drugs for the lower gastrointestinal tract share certain features with inflammatory processes, suggesting that the release of inflammation cytokines such as TNF-alpha may damage the intestine. 2. Rats received a s.c. injection of indomethacin. Then, jejunum-ileum was taken up for the quantification of ulcerations, production of TNF-alpha, nitrites and PGE2 ex vivo and activity of calcium-independent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential effectors of TNF-alpha. 3. Jejunum-ileum from rats having received indomethacin (10 mg kg(-1)) produced TNF-alpha ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase. 4. Similar intestinal ulcerations and upregulation of TNF-alpha were obtained with flurbiprofen (30 mg kg(-1)), chemically unrelated to indomethacin. 5. TNF-alpha production was proportional to the indomethacin dose (from 3-20 mg kg(-1)) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration. 6. Pretreatment of rats with RO 20-1724, a type-IV phosphodiesterase inhibitor which inhibits TNF-alpha synthesis, substantially reduced jejunum-ileum ulcerations, TNF-alpha and nitrite production and tissue enzyme activities. 7. These findings provide evidence that TNF-alpha is increased in indomethacin-induced intestinal ulcerations and support suggestions that TNF-alpha is involved at an early stage of nonsteroidal anti-inflammatory drug toxicity for the small intestine.
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PMID:Increase in tumor necrosis factor-alpha production linked to the toxicity of indomethacin for the rat small intestine. 972 49

The aim of the present study was to determine the efficacy of a new combination regimen including antioxidant, proton pump inhibitor, and antibiotics against Helicobacter pylori and to document the changes of oxidative stress and cytokines involved in H. pylori-associated gastritis. From each of 57 patients with endoscopically diagnosed gastric and/or duodenal ulcers associated with H. pylori infection, five gastric antral biopsy specimens were taken for the diagnosis of H. pylori and for experimental measures. The patients were then treated either with lansoprozole 30 mg + amoxicillin 1.5 g (LA group; 21 patients) or lansoprazole 30 mg + amoxicillin 1.5 g + rebamipide 300 mg (LAM group; 36 patients) for two weeks. Four weeks after the initiation of treatment, the patients were endoscoped again and biopsy specimens were obtained. Mucosal malondialdehyde (MDA) levels; myeloperoxidase (MPO) activities; superoxide dismutase; catalase; glutathione peroxidase; cytokines IL-1, IL-6, TNF-alpha; and chemokines IL-8, GRO-alpha, RANTES (regulated on activation normal T expressed and secreted) were measured. Using paraffin-embedded tissue sections, in situ terminal deoxyribonucleotide transferase (TdT) -mediated dUTP nick end labeling (TUNEL) for apoptosis and immunohistochemical staining for inducible nitric oxide synthase (iNOS) were performed. Two weeks of treatment with the LA regimen resulted in 57.4% eradication rates of H. pylori, whereas two weeks of treatment with the LAM regimen resulted in 75.0% eradication rates. Eradication rates between these two groups were statistically significantly different (P < 0.05). Mucosal MDA levels and MPO activities were significantly lower in the LAM group than the LA group. Mucosal levels of cytokines IL-1, IL-6, and TNF-alpha and of chemokines IL-8, GRO-alpha, and RANTES were all significantly decreased after the treatment of H. pylori, especially in the LAM-treated group. The apoptotic index and iNOS score were significantly reduced after the eradication of H. pylori. The addition of the antioxidative drug rebamipide to the eradication regimen against H. pylori has quantitative and qualitative advantages such as either augmenting the eradication rates of H. pylori or decreasing oxidative stress and cytokines levels generated by H. pylori infection.
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PMID:Quantitative and qualitative usefulness of rebamipide in eradication regimen of Helicobacter pylori. 975 49

We previously reported that taurine chloramine (TauCl), a product of activated neutrophils, inhibits the generation of macrophage inflammatory mediators such as nitric oxide (NO), TNF-alpha, and PGE2. Taurine, the most abundant free amino acid in the cytosol of neutrophils, is chlorinated to form TauCl by the halide-dependent myeloperoxidase (MPO) system. Under physiological conditions, TauCl reduces HOCl toxicity. In this study, we investigated the influence of TauCl on generation of oxygen free radicals, cytokines and eicosanoids by activated murine peritoneal neutrophils. We found that TauCl, but not taurine alone, inhibited the production of NO, prostaglandin E2, interleukin-6 and tumor necrosis factor-alpha, in a dose-dependent manner. In contrast, the products of the respiratory burst, as measured by luminol-dependent chemiluminescence (LCL), were reduced by both taurine and TauCl. However, taurine affected LCL at higher concentrations and to a lesser extent than TauCl. The results of these studies suggest that TauCl decreases production of tissue-damaging inflammatory mediators and may regulate the balance between protective, microbicidal and toxic effect of neutrophils.
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PMID:Taurine chloramine down-regulates the generation of murine neutrophil inflammatory mediators. 977 76

The increased production of pro-inflammatory cytokines and nitric oxide have been postulated to contribute to the deleterious sequella of LPS administration. To date, clinical strategies to control these responses using individual specific inhibitors have been disappointing. The aim of the present study was to determine whether a tetravalent guanylhydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected intravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCl) 60 min prior to the injection of LPS (100 microg/100 g body weight). LPS produced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-alpha levels as well as in tissue content of TNF-alpha, IL-1beta, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidase (MPO) activities as well as with an increase in lung and spleen nitric oxide end products (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-alpha levels. CNI-1493 attenuated the LPS-induced increase in tissue cytokine (TNF-alpha, IL-1beta, and IL-6) content in lung and spleen but did not alter that of liver or gut. CNI-1493 pretreatment protected both lung and gut from LPS-induced apoptosis and in addition attenuated the rise in MPO activity in the gut. These results suggest diverse effects of CNI-1493 that are tissue specific and that confer protection against the hemodynamic and inflammatory responses to LPS.
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PMID:CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS. 984 Jun 47

Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).
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PMID:Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. 985 50


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