Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is a vasoconstrictive peptide released by ischemic/injured endothelium which increases intracellular ionized calcium [Ca2+]i in vascular smooth muscle. Previous work from this lab has shown that ET-1 also increases human peripheral blood monocyte [Ca2+]i, and that 24 h incubation of monocytes with 10(-9) M ET-1 causes production of prostaglandin E2 and interleukin-6. In these studies, ET-1-stimulated monocyte supernatants were evaluated for their effect on neutrophil superoxide production. While ET-1 alone had no direct effect, incubation of neutrophils for 20 min in ET-1-stimulated monocyte supernatants resulted in a 10-fold increase in superoxide production over basal levels, 44% as much superoxide production as induced by peptide N-formyl-methionyl-leucyl-phenylalanine (N = 6, p < .001). Monocyte supernatants were analyzed for interleukin-8 (IL-8 or neutrophil activation protein) content by radioimmunoassay. ET-1-stimulation resulted in production of 54% as much IL-8 as lipopolysaccharide controls (N = 6, p < .001). While a number of monokines can activate neutrophils, IL-8 has been shown to be a potent neutrophil activator as well as a superoxide primer. Therefore, ET-1-treated monocytes probably upregulate neutrophil superoxide production via a mechanism which includes IL-8.
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PMID:Endothelin-stimulated monocyte supernatants enhance neutrophil superoxide production. 773 49

Endothelin-1 (ET-1) is known to be involved in a variety of pathophysiologic conditions, especially of the pulmonary vasculature. The aim of this study was to investigate physiologic mediators potentially involved in the pathogenesis of pulmonary hypertension, for their effects on ET-1 gene expression at both the transcriptional and translational level. Rat microvascular and pulmonary artery endothelial cells grown in culture were exposed to vasoactive mediators (thrombin or an anoxic gas mixture) and inflammatory mediators (lipopolysaccharide, interleukin 1 alpha, interleukin 1 beta, or tumor necrosis factor alpha) for various time periods. The change in prepro-ET-1 (ppET-1) mRNA levels in these cells in response to stimuli was a time-dependent phenomenon. The inflammatory mediators caused an acute rise in ppET-1 mRNA levels whereby peak induction occurred after 1 h with a rapid decline to control levels by 4 h. The vasoactive mediators elicited a more sustained response whereby a significant elevation in ppET-1 mRNA expression occurred quickly and remained elevated through 4 h. The pattern of induction was more rapid for thrombin than for anoxic gas exposure. Radioimmunoassay analysis demonstrated a similar response for thrombin and the inflammatory mediators in ET-1 mature peptide release, whereas the effect of anoxic gas exposure was divergent. Significant elevations were noted after 6 h for thrombin as well as each of the inflammatory mediators except IL-1 alpha. In response to the anoxic gas exposure, however, a significant rise in ET-1 peptide release was not evident until after 24 h. To determine the level at which ppET-1 mRNA induction is regulated, cells were cotreated with each of the stimuli and actinomycin D or cycloheximide. Results indicate that the induction of ppET-1 mRNA levels is likely due to de novo transcription, as well as mRNA stabilization. In summary, inflammatory and vasoactive agents are important regulators of ET-1 gene expression in rat pulmonary endothelial cells; most important, we observed a differential response at the mRNA or peptide level depending on the mediator involved.
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PMID:Effects of vasoactive and inflammatory mediators on endothelin-1 expression in pulmonary endothelial cells. 774 14

Endothelin-1 (ET-1) is a vasoconstrictor and proinflammatory peptide, but its role in the vascular response to sepsis is unknown. After intraperitoneal injection of male Wistar rats (300 g) with 20 mg/kg of Salmonella enteritidis lipopolysaccharide (LPS), the expression of ET-1 mRNA was significantly increased in pulmonary artery and aorta within 1 h and arterial ET-1 concentration was elevated. Despite this increase in ET-1 production, there was no difference in baseline systemic or pulmonary arterial pressures between control and endotoxin-treated rats, and, furthermore, combined ETA/ETB receptor antagonism using bosentan produced reductions in systemic and pulmonary arterial pressures that were not greater than the modest fall seen in controls. However, bosentan completely antagonized the hemodynamic effects of exogenous ET-1 in controls but only weakly antagonized its effects in LPS animals. After LPS the initial (ETB-mediated) systemic hypotensive responses to ET-1 were attenuated, but the subsequent systemic pressor responses were not. By contrast, the increases in pulmonary arterial pressure in response to ET-1 and the ETB receptor agonist sarafotoxin S6c were significantly reduced in LPS animals. Vascular ET-1 mRNA expression and arterial ET-1 concentration are elevated after LPS treatment in rats, but the functional activity of ET-1 cannot be exposed by combined ETA/ETB receptor antagonism, possibly because of an alteration in the functional status of ET receptors.
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PMID:Endothelin-1 in rat endotoxemia: mRNA expression and vasoreactivity in pulmonary and systemic circulations. 917 5

Endothelin-1 (ET-1) mRNA expression and protein production were examined in primary rat articular chondrocyte (AC) cultures by RT-PCR and radioimmunoassay, respectively. We found that serum-starved rat AC express ET-1 mRNA and produce the peptide constitutively. Treatment of cells with 10% FCS resulted in a marked increase in ET-1 levels with a peak at 48 h (5.6-fold). A similar concentration-dependent effect was also obtained in the presence of interleukin 1beta (3.1-fold), tumour necrosis factor alpha (3. 5-fold), lipopolysaccharide (2.7-fold), transforming growth factor beta1 (3.5-fold), epidermal growth factor (5.0-fold) and insulin-like growth factor-I (4.4-fold). In addition, ET-1 was found to induce, over a period of 24 h, a potent concentration-dependent stimulation of DNA synthesis in rat AC. These findings demonstrate for the first time the constitutive expression and production of ET-1 by rat AC which could be modulated by several cytokines and growth factors, suggesting a possible role for ET-1 in autocrine regulation of chondrocyte function.
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PMID:Constitutive and inducible expression of endothelin-1 in primary rat articular chondrocyte culture. 924 82

Endothelin-1, unlike the selective endothelin ETB receptor agonist sarafotoxin S6c, causes nociception in the rat when injected intraarticularly into the naive knee-joint. By using selective antagonists, the present study further characterizes the receptors underlying the articular nociceptive actions of endothelin-1, as well as the possible contribution of endogenous endothelins towards nociception induced by carrageenan or E. coli lipopolysaccharide (LPS) in this tissue. Nociception was evaluated by placing the animal for 1 min each hour on a revolving (3 rpm) cylinder and measuring the increase in time the hindpaw of the limb affected by the intra-articular (i.a.) injection of the nociceptive agent, failed to touch its metallic surface (i.e. paw elevation time, PET). In naive joints, endothelin-1 (120 pmol) increased the area under the PET curve (AUC 0-6 h, in arbitrary units) from 61+/-3 (control) to 156+/-12. This nociceptive effect was reduced by prior intravenous (i.v.) injection of the mixed ET(A)/ET(B)receptor antagonist bosentan (by 54 and 73% with 10 and 30 mg/kg) or i.a. administration of the selective ETA receptor antagonist BQ-123 (cyclo [D-Asp-Pro-D-Val-Leu]; by approximately/= 45% with 10 or 30 nmol), but was unaffected by the selective ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methoxycarbonyl- tryptophanil-D-norleucine; 10 nmol). Prior joint challenge with carrageenan (300 microg) 72 h beforehand (i.e. priming) rendered the joint more sensitive to nociception induced by either endothelin-1 or sarafotoxin S6c (15, 30 and 60 pmol). Responses elicited by endothelin (30 pmol) in the primed joint were sensitive to inhibition by either BQ-123 or BQ-788 (each causing approximately/= 80% inhibition at 10 nmol). Priming also enhanced PET responses to carrageenan itself and to LPS (1 microg) markedly and persistently, increasing the area under the curve (AUC 0-12 h, in arbitrary units) from 241+/-19 to 409+/-50 and from 312+/-40 to 466+/-25, respectively (P < 0.05), without changing that measured following vehicle injection (from 121+/-3 to 117+/-4). Bosentan (up to 30 mg/kg, i.v.) failed to modify nociception caused by carrageenan or LPS in naive joints, by carrageenan in the primed joint, or control PET responses. LPS-induced nociception in the primed joint, however, was inhibited by 52 to 56% by bosentan (3 or 10 mg/kg) or 59% by local injection of the selective endothelin ET(B) receptor antagonist BQ-788 (10 nmol, i.a.), but was unaffected by the selective endothelin ETA receptor antagonist BQ-123. Thus, nociception induced by endothelin-1 in the naive joint is mediated largely via endothelin ETA receptors, whereas both ET(A)and ET(B) receptors contribute to its action in the carrageenan-primed joint. Furthermore, LPS-induced nociception in the primed joint is mediated to a large extent via endothelin release and activation of ET(B) receptors within the joint itself. These findings may be relevant to the etiology of pain underlying chronic arthritic disease in humans.
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PMID:Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints in the rat: inhibition by endothelin receptor antagonists. 980 51

Endothelin-1 (ET-1) is a vasoactive peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1). We investigated gastric mucosal expression of ECE-1 during a 10-day course of inflammatory responses associated with acute gastritis elicited by Helicobacter pylori lipopolysaccharide. The ECE-1 activity was associated with microsomal fraction and the level of its expression reflected the extent of mucosal inflammatory involvement. The histologic pattern of inflammation reached a maximum on the 4th day following the lipopolysaccharide and was accompanied by a 4.1-fold enhancement in the expression of ECE-1 activity and a significant elevation in ET-1 (3.1-fold), TNF-alpha (8.8-fold), and apoptosis (11.6-fold). A 41.5% decrease in the severity of mucosal inflammation by the 10th day following the lipopolysaccharide was reflected in a 62.3% reduction in the mucosal expression of ECE-1 and a decline in TNF-alpha, ET-1, and apoptosis. Thus, H. pylori infection causes up-regulation of gastric mucosal ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that exacerbate the inflammatory process.
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PMID:Up-regulation of endothelin-converting enzyme-1 in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide. 1067 72

Endothelin-1 (ET-1) is a strong bronchoconstrictor which possesses pro-inflammatory properties and is claimed to be an important mediator in bronchial asthma. The present study was undertaken to investigate whether ET-1 synthesis, in an inflammation dominated by neutrophilic granulocytes, is as pronounced as previously demonstrated in an airway inflammation dominated by eosinophils. Moreover, the authors compared the production of ET-1 and tumour necrosis factor (TNF)-alpha in rat lungs following intratracheal instillation of either lipopolysaccharide (LPS) (neutrophilic inflammation) or Sephadex (SDX) (eosinophilic). The lung tissue ET-1 messenger ribonucleic acid (mRNA) expression was not increased in LPS treated animals whereas a six-fold increase was measured after 30 min in the SDX group (p<0.05). TNF-alpha mRNA signals increased early following LPS instillation, peaking at 2 h, whereas elevated TNF-alpha mRNA in the SDX model was observed at 24 h. The ET-1 concentrations in bronchoalveolar lavage fluid (BALF) rose slightly, but significantly, 3 h after both LPS and SDX exposure. At 24 h no further rise in ET-1 levels was observed in the LPS model, while a substantial increase in the ET-1 concentration was measured in the SDX group (p<0.05). The TNF-alpha concentrations in BALF rose considerably at 3 h in the LPS group, but was nearly abolished at 24 h. In SDX challenged animals however, an increase in BALF-TNF-alpha did not occur until 24 h postchallenge. In conclusion, intratracheal instillation of lipopolysaccharide, leading to a purely neutrophilic lung inflammation, does not induce synthesis of endothelin-1. This is in contrast to observations during an eosinophilic airway inflammation, indicating a specific role of endothelin-1 in lung inflammations dominated by eosinophils. In contrast to in vitro experiments, no evidence for induction of endothelin-1 synthesis was observed by high levels of tumour necrosis factor-alpha in vivo.
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PMID:Endothelin-1 production is associated with eosinophilic rather than neutrophilic airway inflammation. 1078 Jul 68

1. The aim of the present study was to evaluate the contribution of disturbance of coronary perfusion to myocardial depression in hearts isolated from lipopolysaccharide (LPS)-treated rats and to investigate the involvement of endothelin (ET)-1 and nitric oxide (NO). 2. Rats were treated with LPS (10 mg/kg, i.p.) and, 4 h later, plasma ET-1 concentrations were measured by radioimmunoassay and hearts were excised for perfusion at a constant perfusion flow. The selective ETA receptor antagonist BQ-123, in the absence or presence of aminoguanidine, a specific inhibitor of inducible NO synthase, was given 15 min before LPS challenge. Coronary perfusion pressure (CPP) and measures of myocardial contractile function were recorded. 3. In hearts isolated from LPS-treated rats, there was a marked increase in CPP that was abolished by pretreatment with BQ-123. In parallel, an increase in plasma ET-1 concentrations was seen in these rats. Lipopolysaccharide also induced decreases in left ventricular developed pressure (LVDP), the product of LVDP and heart rate and maximal rate of rise/fall of left ventricular pressure (+/- dP/dtmax). Single treatment with BQ-123 or aminoguanidine attenuated LPS-induced myocardial depression. However, when these two drugs were given simultaneously, myocardial depression elicited by LPS was blocked significantly. 4. Endothelin-1-mediated coronary vasoconstriction, together with NO, contributes to myocardial depression in hearts isolated from LPS-treated rats.
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PMID:Endothelin-1-mediated coronary vasoconstriction deteriorates myocardial depression in hearts isolated from lipopolysaccharide-treated rats: interaction with nitric oxide. 1547 62

Endothelin-1 (ET-1) was originally characterized as a potent vasoconstrictor secreted by the endothelium and participating in the regulation of vascular tone. Subsequent analysis has revealed ET-1 to be a multifunctional peptide produced by a wide variety of cells and tissues under normal and pathologic conditions. The importance of macrophages as a source of ET-1 during infection and inflammation is supported by clinical observations in humans and in animal models of inflammation. We hypothesize that the production of ET-1 is part of the characteristic macrophage response to infection, and have begun to investigate the ability of various classes of microbes or microbial products to induce macrophage ET-1 production. We report the production of ET-1 by murine macrophages in response to stimulation with both gram-positive and gram-negative bacteria. Stimulation of macrophages with yeast (Candida albicans or Saccharomyces cerevisiae) or the protozoan parasite Leishmania major, elicited no significant release of ET-1. The production of ET-1 in response to lipopolysaccharide (LPS) was dose and time dependent, and required the expression of a functional toll-like receptor 4 (TLR4). Pharmacologic inhibition of the transcription factor, nuclear factor-kappaB (NF-kappaB) suppressed LPS-induced ET-1 production. Our findings complement the growing body of literature implicating a role for macrophage-derived ET-1 in inflammatory pathologies. The production of ET-1 by macrophages during infection and inflammation has the potential to affect tissue perfusion, leukocyte extravasation, and immune cell function.
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PMID:Murine macrophages produce endothelin-1 after microbial stimulation. 1617 33

Endothelin-1 (ET-1) is increasingly recognized as a proinflammatory mediator in various diseases, such as atherosclerosis and acute respiratory distress syndrome (ARDS). Angiopoietin-1 (Ang-1), a ligand of the endothelial receptor Tie2, inhibits endothelial apoptosis, reduces vascular leakage, and suppresses the induction of inflammatory markers, indicating that it has diverse vasoprotective, anti-inflammatory actions. Thus, we examined the effects of Ang-1 on ET-1 production in vitro and in vivo and investigated cell-based gene transfer of Ang-1 in a rat model of lipopolysaccharide (LPS)-induced ARDS. Cultured human endothelial cells were treated with recombinant Ang-1 with or without tumor necrosis factor-alpha (TNF-alpha) (100 U/ml). ET-1 release into the culture medium after 24 hrs was determined by enzyme-linked immunosorbent assay. Levels of preproendothelin-1 (ppET-1) mRNA were measured by quantitative reverse transcription-polymerase chain reaction. Fisher344 rats were subjected to cell-based gene transfer to the lung circulation by injecting syngeneic fibroblasts transfected with Ang-1 cDNA or a null plasmid vector. After 24 hrs, LPS (100 microg/kg body wt) was instilled intratracheally to induce pulmonary inflammation. Bronchoalveolar lavage was performed 6 hrs later, and lungs were harvested for histologic and molecular analyses. ET-1 release from cultured endothelial cells was dose-dependently reduced by Ang-1, which also prevented induction of ET-1 release by TNF-alpha (P < 0.05). RNA expression of ppET-1 was similarly reduced. In LPS-challenged lungs, ppET-1 RNA was induced 3.4-fold, and ET-1 protein in lavage fluid was increased 5.6-fold (P < 0.05). Ang-1 gene transfer attenuated the LPS-induced increases in ppET-1 RNA and lavage ET-1 protein by 34% and 33%, respectively (P < 0.05). The downregulation of ET-1 correlated with the amelioration of pulmonary inflammation, as indicated by reductions in leukocyte infiltration (by 43%) and intra-alveolar septal thickening (by 40%). These results show that ET-1 transcript and protein levels are downregulated by Ang-1 in both in vitro and in vivo systems and that cell-based Ang-1 gene transfer markedly ameliorated inflammation in vivo in an experimental model of ARDS. Thus, cell-based gene transfer of Ang-1 may provide a novel treatment strategy for ARDS by attenuating vascular inflammation via suppression of ET-1.
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PMID:Regulation of endothelin-1 by angiopoietin-1: implications for inflammation. 1674 Oct 35


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