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)

Given the pivotal role suggested for IFN-gamma in immune diseases of the vascular wall, we investigated the effects of IFN-gamma on nitric oxide (NO) and endothelin-1 (ET-1) expression in bovine aortic endothelial cells (BAEC). We have previously reported that TNF-alpha enhanced NO synthase activity in BAEC as assessed by quantifying release of bioactive NO with reporter monolayers and measuring conversion of L-[14C]arginine to L-[14C] citrulline. In murine macrophages IFN-gamma synergizes with TNF-alpha or lipopolysaccharide to induce robust increases in calcium-independent NO synthase activity. In this study we have found that IFN-gamma alone failed to have a significant effect on NO synthase activity in BAEC. In contrast to murine macrophages, IFN-gamma inhibited TNF-alpha-stimulated induction of endothelial NO synthase activity in a concentration-dependent manner. This observation suggests that there is major difference in the response of BAEC and murine macrophages to IFN-gamma. A second major aim of this study was to determine the effect of IFN-gamma on preproET-1 mRNA expression and ET-1 secretion rates in BAEC. IFN-gamma alone had little or no effect on ET-1 mRNA levels and basal ET release when measured for 8 h. However, cotreatment with IFN-gamma potentiated the stimulatory effect of TNF-alpha on BAEC ET-1 mRNA transcript levels and ET release. In contrast, pretreatment of cells with IFN-gamma for 16-24 h blunted the stimulatory effect of TNF-alpha. These findings suggest that endothelial cell expression of vasoactive mediators is modified by the temporal interplay of at least two immune mediators, IFN-gamma and TNF-alpha.
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PMID:Effects of interferon-gamma on nitric oxide synthase activity and endothelin-1 production by vascular endothelial cells. 138 25

Observations that primary rat astrocytes express high-affinity binding sites for endothelins and, in addition, are capable of producing not only endothelin-3 but also endothelin-1 prompted the investigation of a possible relation between endothelin peptides and receptors in these cells. Sarafotoxin S6b, an endothelin receptor agonist, was used as a tool to study endothelin receptor-mediated changes in the secretion of endothelin-1 and -3. The effects of sarafotoxin S6b and endothelin-1 in stimulating inositolphospholipid turnover as well as in inducing AP1 in primary astrocyte cultures were found to be similar. A low cross-reactivity of sarafotoxin S6b with endothelin-1 and -3 in the endothelin radioimmunoassays used here, along with a distinctly different elution position in high-performance liquid chromatography, allowed a clear discrimination between sarafotoxin and endothelins in the culture media. Stimulation of primary rat astrocytes with 10(-7) M sarafotoxin S6b for 1 hour resulted in a substantial increase in endothelin-1 immunoreactivity in the medium. This immunoreactivity reached a peak at 3 hours and showed no further increase after 8 and 24 hours. Treatment of our cultures with phorbol myristate acetate, lipopolysaccharide, tumor necrosis factor alpha, and norepinephrine for 24 hours led to only a moderate elevation of endothelin-1 immunoreactivity. Immunoreactive endothelin-3 was not affected by any of the treatments tested. Thus, our data suggest that endothelins in primary rat astrocytes are subject to selective autoregulation, as demonstrated by the potentiation of endothelin-1 secretion after activation of glial endothelin receptors.
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PMID:Selective autoregulation of endothelins in primary astrocyte cultures: endothelin receptor-mediated potentiation of endothelin-1 secretion. 164 83

The effect of endotoxin on the release of endothelin, a novel potent vasoconstrictor peptide, was examined in anesthetized dogs and in cultured endothelial cells. Administration of 2.63 mg lipopolysaccharide, E. coli 0111:B4/kg body weight caused shock in the animals and produced a long-lasting increase in the plasma immunoreactive endothelin-1 level that remained higher than the basal level (1.83 pg/ml as mean level) from 30 to 120 min after the injection, with a peak at 90 min (8.15 pg/ml as mean level). In vitro immunoreactive endothelin-1 in a culture medium, in which calf pulmonary artery endothelial cells were incubated in the presence of 10% fetal bovine serum, increased dose dependently with the concentration of added lipopolysaccharide between 0.01 and 10 micrograms/ml. These data indicate that plasma endothelin increases during endotoxin shock and that stimulation by endotoxin, per se, in the presence of serum participates at least partially in the mechanism for its release.
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PMID:Elevation of plasma endothelin concentrations during endotoxin shock in dogs. 166 11

Injury to hepatocytes most likely occurs via disturbances in the microcirculation. The role of vasoconstriction due to the effect of endogenous endothelin-1 (ET-1) in the development of galactosamine (GalN)- and lipopolysaccharide (LPS)-induced liver injury was investigated. Using the multiple indicator dilution technique, we measured the volume of the hepatic sinusoids and the apparent Disse space as indicators of overall hepatic microcirculation. Serum purine nucleoside phosphorylase activity as a marker of damage to nonparenchymal cells increased and the volume of the sinusoids and the Disse space decreased prior to hepatocyte damage in rats treated intraperitoneally with GalN and LPS. Moreover, the amount of ET-1 release was elevated. When livers from untreated rats were perfused with ET-1 in a recirculating system, hepatocyte damage was observed similar to experiments with GalN and LPS. A monoclonal anti-endothelin antibody, AwETN40, diminished the extent of liver injury caused by GalN and LPS in isolated perfused rat liver. The present study suggests that vasoconstriction is an early event in GalN- and LPS-induced liver injury and that the development of hepatocyte damage is mediated via microcirculatory disturbances due to endogenous ET-1.
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PMID:Endogenous ET-1 contributes to liver injury induced by galactosamine and endotoxin in isolated perfused rat liver. 761 21

In the lung, endothelin-1 (ET-1) is synthesized by several cell types and acts locally to cause vasoconstriction and bronchoconstriction, activate alveolar macrophages, and stimulate chloride secretion. We report ET-1 production, binding, and signal transduction by a previously unrecognized site, the alveolar epithelial cell. L2 cells, a cloned rat alveolar epithelial cell line, secreted ET-1 and contained ET-1 mRNA. Exposure of L2 cells to lipopolysaccharide, tumor necrosis factor-alpha, interleukin-1, or transforming growth factor-beta stimulated ET-1 release, whereas interferon-gamma or platelet-derived growth factor decreased ET-1 secretion. 125I-ET-1 binding to L2 cells revealed a single binding site with a maximal binding capacity of 22.4 fmol/mg protein and a dissociation constant of 4.03 nM. 125I-ET-1 binding was completely inhibited by ET receptor A (ETA) blockade and by unlabeled ET-1 >> ET-3 = sarafotoxin 6c, consistent with the presence of ETA. Exogenous ET-1 increased, whereas blockade of endogenous ET-1 decreased prostaglandin E2 (PGE2) production by L2 cells; exogenous ET-1 also increased adenosine 3',5'-cyclic monophosphate (cAMP) production. We conclude that 1) cloned rat alveolar epithelial cells synthesize ET-1; 2) inflammatory mediators modulate ET-1 production; 3) L2 cells express ETA; 4) ET-1 increases PGE2 and cAMP levels in these cells; and 5) BQ-123, an ETA antagonist, decreases their basal PGE2 production. These studies suggest that ET-1 may function as an autocrine factor in alveolar epithelial cells.
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PMID:Endothelin-1 synthesis, receptors, and signal transduction in alveolar epithelium: evidence for an autocrine role. 786 40

Nitric oxide (10 ppm) inhaled by pigs before or during endotoxin shock induced by an infusion of E. coli lipopolysaccharide. Nitric oxide inhalation selectively attenuated pulmonary hypertension during endotoxin infusion without influencing mean arterial blood pressure and cardiac output. Upon cessation of nitric oxide inhalation, pulmonary artery pressure rapidly increased to levels seen in endotoxin-treated controls. The oxygenation and pH of arterial blood were significantly higher in the animals receiving nitric oxide. A marked increase in arterial plasma noradrenaline and neuropeptide Y was seen in endotoxin-treated control pigs while in the nitric oxide-treated pigs this increase was markedly reduced. The increase in arterial plasma endothelin-1 was not influenced by nitric oxide inhalation. Infusion of L-arginine (substrate for nitric oxide synthesis) also attenuated the pulmonary hypertension but was not selective for the pulmonary vasculature. L-Nitro-arginine (a nitric oxide synthesis inhibitor) initiated a rapid but brief elevation of arterial blood pressure and of pulmonary artery pressure as well as a reduction in cardiac output. Nitric oxide inhalation selectively reduces pulmonary hypertension in porcine endotoxin shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic activation.
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PMID:Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxin shock. 847 50

An immortalized human endothelial cell line was obtained by transfecting umbilical vein endothelial cells in primary culture with plasmid pMK16 containing SV40 replicated origin defective gene. The essential functional properties demonstrated in these immortalized human endothelial cells also retaining the classical phenotypical characteristics of endothelial cells in primary culture are: (1) endothelin-1 secretion; (2) capacity to convert big endothelin-1 into endothelin-1; (3) the capacity to secrete IL1 beta and IL6 interleukins both spontaneously and after lipopolysaccharide (LPS) stimulation; (4) arginine transfer from the extracellular to the intracellular medium. Such stable cell line could facilitate studies of regulation of endothelin-1 production; (5) No-synthase activity; (6) binding and metabolisation of acetylated low-density lipoproteins.
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PMID:[Functional properties of a new line of immortalized human endothelial cells]. 852 Oct 79

1. Inflammatory disease states predispose to myocardial infarction. Here we have investigated the effects of a systemic inflammatory response syndrome, i.e. lipopolysaccharide (LPS)-induced circulatory shock in rats, on coronary vascular tone. 2. Anaesthetized rats were given LPS (10 mg kg-1, i.v.) and the hearts excised 180 min later for isolated perfusion at constant flow by the Langendorff technique. Once the ex vivo perfusion was started, the perfusion pressure strongly increased in these hearts compared to hearts from control rats (130 +/- 3 vs. 49 +/- 3 mmHg after 10 min). This increase in coronary resistance was not associated with a reduction in endothelial cell function, for the vasodilator responses to bradykinin were unchanged. 3. When hearts were removed 30 min after the injection of LPS, the LPS-induced rise in perfusion pressure was delayed. No changes in perfusion pressure were seen when the hearts were removed 15 min after the injection of LPS. Pre-treatment with cycloheximide or an anti-tumour necrosis factor-alpha (TNF-alpha) antibody or continuous infusion in vivo and in vitro of the endothelin ETA receptor selective antagonist FR 139317, greatly decreased the increase in coronary vascular resistance induced by LPS. 4. These data suggest that TNF-alpha may induce the release of endothelin-1 (ET-1) and that this mediates at least part of the coronary vasoconstriction. This hypothesis is supported by the demonstration that LPS administration increased the circulating levels of both TNF-alpha and ET-1. 5. We conclude, therefore, that in inflammatory disease states, such as LPS-induced septic shock, there is the sequential release of TNF-alpha and endothelin-1 which leads to an increase in coronary vascular tone and so a predisposition to myocardial ischaemia. Inactivation of TNF-alpha by an antibody as well as ETA receptor blockade by a selective antagonist may effectively interfere with this pathway.
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PMID:The contribution of tumour necrosis factor-alpha and endothelin-1 to the increase of coronary resistance in hearts from rats treated with endotoxin. 871 12

1. This study investigates the effects of the non-selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid-base balance and survival in a rat model of endotoxic shock. 2. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.) resulted in increases in the serum levels of tumour necrosis factor-alpha (TNF-alpha, maximum 60 min after LPS), endothelin-1, (ET-1; maximum 120 min after LPS), and interferon-gamma (IFN-gamma, maximum 180 min after LPS). 3. Injection of LPS also resulted in a fall in blood pressure from 113 +/- 3 mmHg (time = 0) to 84 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg-1, i.v. bolus + 100 micrograms kg-1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia. 4. Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h-survival from 71% (control) to 30% and 13%, respectively. 5. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilation (fall in PaCO2). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS. 6. Thus, the non-selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS-rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET-1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.
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PMID:Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. 873 96

1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. Pulmonary and systemic haemodynamics as well as splenic, renal and intestinal blood flows were measured continuously. Release and synthesis of ET-1 and Big ET-1 were also measured. 2. Only three of the six pigs in the control group survived 3 h of LPS infusion while in the bosentantreated group all six pigs were alive at that time. A biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) was seen in control pigs. Pretreatment with bosentan did not influence the first peak but markedly attenuated the second, more prolonged increase in MPAP and PVR. The second dose of bosentan completely restored these parameters to pre-LPS levels. The LPS-induced changes in mean arterial blood pressure, heart rate and systemic vascular resistance were similar in both groups, while cardiac output (CO) was significantly higher in the bosentan-treated group. The second bosentan dose increased CO and splenic and intestinal blood flow without further lowering of blood pressure. 3. Bosentan caused an increase of the basal arterial plasma levels of ET-1-like immunoreactivity (LI), from 16.8 +/- 1.3 pM to 49.6 +/- 10.0 pM (n = 6, P < 0.01). However, the rate of the increase of ET-1 levels during the LPS infusion was not affected by bosentan. Repeated administration of bosentan during LPS infusion caused an additional increase of ET-1-LI levels. Neither the basal levels of Big ET-LI nor the LPS induced 8 fold increase in Big ET-LI were changed by bosentan. The level of preproET-1 mRNA in the lung was increased about 3 fold after 4.5 h of LPS treatment. This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.
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PMID:Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. 876 86


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