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)

There is increasing evidence that diseases caused by organic dusts are mainly of an inflammatory nature. Among the many agents present in organic dusts, bacterial endotoxin is a major candidate for the inflammatory reaction. The purpose of this paper was to review the inflammatory response in humans after inhalation of bacterial endotoxin (lipopolysaccharide, LPS) in order to improve the understanding of symptoms and reactions found among persons exposed to endotoxin-containing organic dusts. It has been reported that inhalation of LPS causes changes in forced expiratory volume in one second (FEV1), and forced vital capacity (FVC). At the alveolar level, inhalation of LPS can induce changes in the diffusion capacity. Activation and migration of neutrophils are major effects of acute LPS inhalation. Changes in mediators of inflammation, such as eosinophilic cationic protein (ECP), myeloperoxidase (MPO), interleukin-8 (IL-8), IL-1beta, tumor necrosis factor alpha (TNFalpha) and C-reactive protein (CRP) in the airways and/or blood, have also been found. Inhalation of 30-40 microg LPS seems to be a threshold level for inducing clinical symptoms and lung function changes in healthy subjects. The threshold dose for inducing changes in blood neutrophils may be less than 0.5 microg LPS. In conclusion, available data regarding the responses to LPS inhalation challenges demonstrate a local and a systemic inflammatory response at lower doses of LPS, while higher inhaled doses are required to elicit significant clinical and lung function responses. Future inhalation studies on LPS need to focus on relevant diagnostic tools for the inflammatory reaction among persons exposed to endotoxin-containing organic dusts and to evaluate whether the large variation between individuals in the response to organic dusts or endotoxin could be due to differences in the molecular mechanisms responsible for the toxicity of the agent.
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PMID:The inflammatory response in humans after inhalation of bacterial endotoxin: a review. 1140 88

Human peripheral blood (PB) CD14(lo)/HLA-DR(+) cells were initially described as a subset of mature monocytes. Recently, it has been suggested that these represent a part of a new subset of dendritic cells (DC), characterized by the coexpression of MDC-8/HLA-DR/CD16. The aim of the present paper was to analyze the morphological, cytochemical, phenotypical, and functional characteristics of PB CD16(+)/HLA-DR(+) cells compared to both PB CD14(+) monocytes and CD16(-) DC. In contrast to CD14(+) monocytes, purified CD16(+)/HLA-DR(+) cells displayed cytoplasmic veils and lacked cytoplasmic myeloperoxidase and alpha-naphthyl acetate esterase. Normal human PB CD16(+)/HLA-DR(+) cells also displayed phenotypic characteristics different from those of CD14(+) monocytes: they lacked the CD64 Fcgamma receptor, showed lower levels of CD32, and expressed higher amounts of CD16 compared to CD14(+) monocytes. They also displayed a different pattern of expression of other antigens, including CD14, HLA-DR, CD45RA, CD45RO, complement receptors and complement regulatory surface proteins, adhesion and costimulatory molecules, and cytokine receptors, among others. When compared to CD16(-) DC, CD16(+)/HLA-DR(+) cells showed reactivity for CD16, dim positivity for CD14, higher expression of both Ig- and complement-receptors and lower reactivity for HLA-DR, adhesion, and costimulatory molecules (with the exception of CD86). The CD16(+)/HLA-DR(+) cell subset displayed a higher Ig/complement-mediated phagocytic/oxidative activity than CD16(-) DC, although this activity was significantly lower than that of mature monocytes. Regarding cytokine production at the single cell level, LPS plus IFN-gamma-stimulated PB CD16(+)/HLA-DR(+) cells produced significant amounts of IL1beta, IL6, IL12, TNFalpha, and IL8; however, the percentage of cytokine-producing cells and the amount of cytokine/cell were lower in CD16(+)/HLA-DR(+) cells than in CD14(+) monocytes. In addition, upon comparing CD16(+)/HLA-DR(+) cells with CD33(+++)/CD16(-) DC, we found that the percentage of cytokine-producing cells and the amount of cytokine/cell were significantly different in both cell subsets. In summary, our results show that CD16(+)/HLA-DR(+) cells clearly display different morphologic, cytochemical, immunophenotypical, and functional characteristics compared to both mature monocytes and CD16(-) DC. Interestingly, these cells are more frequent than other DC in normal human adult PB and cord blood samples, while they are less represented in normal bone marrow.
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PMID:Comparative analysis of the morphological, cytochemical, immunophenotypical, and functional characteristics of normal human peripheral blood lineage(-)/CD16(+)/HLA-DR(+)/CD14(-/lo) cells, CD14(+) monocytes, and CD16(-) dendritic cells. 1151 46

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.
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PMID:Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response. 1171 Sep 94

Taurine protects lung tissue from oxidant-induced damage in a variety of models that involve inflammation as a pathogenic feature. The mechanism of taurine protection is thought to be related to the formation and subsequent action of taurine chloramine (Tau-Cl). Tau-Cl results from the activity of a halide-dependent myeloperoxidase system associated with neutrophils. Since chemokines are secreted by activated alveolar macrophages and are prominently involved in propagating the inflammatory response in lung, we determined the effects of Tau-Cl on MCP-1 and MIP-2 production in NR8383, a cloned cell line derived from rat alveolar macrophages. Activation of NR8383 cells with LPS and IFN-gamma resulted in accumulation of MCP-1 and MIP-2 in the conditioned media over the following 24-h and this was inhibited by Tau-Cl in a concentration dependent fashion. Northern blot analyses of MCP-1 and MIP-2 mRNA expression revealed concentration dependent inhibition by Tau-Cl. Expression of MCP-1 transcripts was more potently inhibited by Tau-Cl relative to that of MIP-2. Since the promoter regions of these chemokine genes are regulated by NF-kappaB, nuclear protein extracts were evaluated for NF-kappaB binding to its sequence specific recognition site (EMSA). Tau-Cl treated cells expressed reduced nuclear NF-kappaB binding relative to the activated control cells. The composition of the NF-kappaB dimer contained predominately p50 and p65 subunits, but some c-Rel was also present. These results suggest that Tau-Cl inhibits production of chemokines by activated NR8383 cells through a mechanism that involves, in part, the NF-kappaB signaling pathway.
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PMID:Chemokine production by rat alveolar macrophages is inhibited by taurine chloramine. 1171 62

We investigated the effect of alpha-melanocyte stimulating hormone (alpha-MSH) on endotoxin-induced intestinal inflammation and the role of nitric oxide and prostaglandins in this response. alpha-MSH treatment (25 microg/rat, intraperitoneally (i.p.); twice daily) reduced the severity of the lesions macroscopically and microscopically. This protective effect was found to be confined mainly to the distal ileum. These lesions were reversed by pretreatment with the non-selective COX inhibitor indomethacin (10 mg/kg, subcutaneously (s.c.)) but not by the selective COX-2 inhibitor nimesulide (3 mg/kg, s.c.), the NO donor sodium nitroprusside (4 mg/kg, i.v.) or the iNOS inhibitor dexamethasone (3 mg./kg, i.p.) at macroscopic level and reversed by Indo or Dex at microscopic level. Increased peroxidase activity -index of tissue neutrophil infiltration- in the distal ileum of LPS-treated rats was decreased by alpha-MSH and this effect was reversed by pretreatment with Indo. In conclusion, the neuropeptide alpha-MSH has a beneficial effect on endotoxin-induced distal intestinal lesions by a mechanism which probably involves nitric oxide and COX-1 derived prostaglandins.
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PMID:The effect of alpha-melanocyte stimulating hormone on endotoxin-induced intestinal injury. 1178 93

1. TNF-alpha converting enzyme (TACE) and matrix metalloproteinases (MMPs) are believed to play a role in various airway inflammatory disorders. Therefore we have tested the effect of two new inhibitors of TACE/MMPs (PKF242-484, PKF241-466) in models of airway inflammation. 2. PKF242-484 and PKF241-466 inhibited purified MMP-1, -2, -3, -9, -13 and rat collagenase at low nanomolar range. Both compounds inhibited the TNF-alpha release from activated human peripheral blood mononuclear cells with IC(50) values of 56+/-28 and 141+/-100 nM, respectively and had no significant effect on the activation of other human leukocytes, as neither neutrophils and eosinophils oxidative burst nor proliferation or cytokines production by T cells were inhibited in vitro. 3. PKF242-484 and PKF241-466 had beneficial effects in two different murine models of acute lung inflammation in vivo. The influx of neutrophils and lymphocytes into the airways was reduced 3 and 24 h after intranasal LPS challenge. This was accompanied by reduced levels of myeloperoxidase and elastase activities in the bronchoalveolar lavage. Furthermore, a complete inhibition of TNF-alpha release into the airways was observed. In addition, PKF242-484 effectively reduced the influx of neutrophils, eosinophils and lymphocytes in a model of acute allergic lung inflammation. 4. PKF242-484 and PKF241-466 are two novel and potent dual inhibitors of TACE and MMPs, which show activity in in vivo models of lung inflammation. Such compounds could have beneficial effects in airway inflammatory conditions such as asthma and chronic obstructive pulmonary disease.
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PMID:Pharmacological profile of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in models of airway inflammation. 1193 5

There has been a widespread impression that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mediate the toxicity of high doses of lipopolysaccharide (LPS, endotoxin) and are key factors in septic shock. However, the clinical efficacy of treatment with antagonists of TNF-alpha and IL-1beta is still controversial, suggesting that mediators other than TNF-alpha and IL-1beta might contribute causally to endotoxin-induced death. Recent studies implicated high mobility group-1 (HMG-1) protein as a late mediator of endotoxin lethality in mice. However, the role of HMG-1 in mediating multiple organ damage-associating trauma has not been studied. This study was designed to investigate changes in HMG-1 gene expression in vital organs, and its potential role in mediating multiple organ damage following major burns. Wistar rats were subjected to a 35 percent full-thickness thermal injury, and randomly divided into three groups as follows: normal controls (n = 7), thermal injury (n = 24), and recombinant bactericidal/permeability-increasing protein (rBPI21) treatment (n = 12). Tissue samples from liver and lungs were collected to measure tissue endotoxin levels and HMG-1 mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. Our data demonstrated a significant increase in HMG-1 gene expression in tissues at 24 h postburn, which remained markedly elevated up to 72 h after thermal injury (P< 0.05-0.01). Treatment with rBPI21 could significantly decrease tissue HMG-1 mRNA expression in the liver and lung (P < 0.01). In addition, there were high positive correlations between hepatic HMG-1 mRNA and serum aminoleucine transferase (ALT) and aspartate aminotransferase (AST) levels, and also between pulmonary HMG-1 mRNA and myeloperoxidase activities (P < 0.05-0.01). Taken together, these findings indicate that thermal injury per se can markedly enhance HMG-1 gene expression in various organs. Up-regulation of HMG-1 expression may be involved in the pathogenesis of endogenous endotoxin-mediated multiple organ damage secondary to major burns.
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PMID:The significance of changes in high mobility group-1 protein mRNA expression in rats after thermal injury. 1195 36

We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine. In vehicle-challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg-1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid. The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad-spectrum adenosine receptor antagonist, 8-SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively. Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine.
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PMID:Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats. 1197 75

Nitric oxide (NO) is an endogenous vasodilator and modulator of inflammation. During endotoxemia, the beneficial effects of NO are overwhelmed by the inflammatory cascade, resulting in a functional depletion of NO. S-nitroso-albumin (S-NO-alb) exists as a novel and highly stable NO thiol complex that slowly releases NO into the vascular micro-environment. Using a porcine model, we examined the ability of intravenous S-NO-alb to modulate cardiopulmonary dysfunction characteristic of endotoxemia. Pigs were anesthetized, instrumented for standard cardiopulmonary function measurements, and randomly assigned to receive: (i) albumin + saline; (ii) albumin + LPS; or (iii) S-NO-alb + LPS. Cardiopulmonary parameters were evaluated every 30 min and ex vivo phorbol myristate acetate (PMA)-stimulated superoxide release was serially determined as a marker of in vivo neutrophil priming. Lung myeloperoxidase (MPO) activity was measured as a marker of neutrophil migration into the lung. LPS-induced cardiopulmonary dysfunction was characterized by a sustained elevation in mean pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure, as well as a reduction in cardiac index, stroke volume index and PaO(2) over 6 h. Pretreatment with S-NO-alb attenuated LPS-induced cardiopulmonary dysfunction without adversely affecting systemic hemodynamics. Moreover, S-NO-alb blunted the LPS-induced hypoxemic response and reduced neutrophil activation. S-NO-alb did not, however, attenuate LPS-induced increases in lung MPO. Our results suggest that S-NO-alb can selectively modulate endotoxin-induced pulmonary dysfunction, attenuate neutrophil priming and block the early mortality (40%) in this model.
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PMID:Modulation of endotoxin-induced cardiopulmonary dysfunction by S-nitroso-albumin. 1198 42

We postulated that the seleno-organic compound ebselen would attenuate neutrophil recruitment and activation after aerosolized challenge with endotoxin (LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given ebselen (1-100 mg/kg i.p.) followed by aerosolized LPS exposure (0.3 mg/ml for 30 min). Airway inflammatory indices were measured 4 h postchallenge. Bronchoalveolar lavage (BAL) fluid cellularity and myeloperoxidase activity were used as a measure of neutrophil recruitment and activation. RT-PCR analysis was performed in lung tissue to assess gene expression of TNF-alpha, cytokine-induced neutrophil chemoattractant-1 (CINC-1), macrophage-inflammatory protein-2 (MIP-2), ICAM-1, IL-10, and inducible NO synthase. Protein levels in lung and BAL were also determined by ELISA. Ebselen pretreatment inhibited neutrophil influx and activation as assessed by BAL fluid cellularity and myeloperoxidase activity in cell-free BAL and BAL cell homogenates. This protective effect was accompanied by a significant reduction in lung and BAL fluid TNF-alpha and IL-1 beta protein and/or mRNA levels. Ebselen pretreatment also prevented lung ICAM-1 mRNA up-regulation in response to airway challenge with LPS. This was not a global effect of ebselen on LPS-induced gene expression, because the rise in lung and BAL CINC-1 and MIP-2 protein levels were unaffected as were lung mRNA expressions for CINC-1, MIP-2, IL-10, and inducible NO synthase. These data suggest that the anti-inflammatory properties of ebselen are achieved through an inhibition of lung ICAM-1 expression possibly through an inhibition of TNF-alpha and IL-1 beta, which are potent neutrophil recruiting mediators and effective inducers of ICAM-1 expression.
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PMID:Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. 1209 4


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