UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide is known to stimulate production of nitrite via expression of inducible nitric oxide (NO) synthase in not only macrophages but also glial cells. We found that in glial cell cultures lipopolysaccharide-stimulated inducible NO synthase expression and nitrite accumulation were synergistically enhanced by pretreatment with endothelin, whereas endothelin itself did not induce these responses. Pretreatment with endothelin-1, endothelin-3, and the selective endothelin type B (ETB) receptor agonist IRL 1620 caused the same effect with similar potencies, suggesting that the synergism was mediated via the endothelin ETB receptor. A protein kinase C inhibitor, calphostin C, suppressed endothelin-3-enhanced inducible NO synthase expression. Pretreatment with either endothelin-3 or phorbol ester enhanced lipopolysaccharide-induced production of tumor necrosis factor-alpha (TNF-alpha). Simultaneous addition of TNF-alpha increased lipopolysaccharide-stimulated inducible NO synthase expression. These results suggest that the increase in inducible NO synthase expression by endothelin was due to the elevated TNF-alpha production via protein kinase C. Our findings present the possibility that endothelin is implicated in neurotoxicity via enhancement of inducible NO synthase expression.
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PMID:Endothelin enhances lipopolysaccharide-induced expression of inducible nitric oxide synthase in rat glial cells. 947 43

Adrenomedullin (AM) is a potent vasorelaxant peptide recently identified in extracts of pheochromocytoma. We have found that AM is actively secreted from endothelial cell (EC) and vascular smooth muscle cell (VSMC). To elucidate the function of AM secreted from EC, the effects of 43 substances on secretion of AM from cultured rat EC were examined in this study. We first confirmed that synthesized AM was not stored but constitutively secreted from EC, indicating that the amount secreted could be used as an index of AM synthesis in EC. EC secreted AM at a rate 5.8 times higher than VSMC, and AM gene transcription in EC significantly contributed to the total aortic AM messenger RNA. Tumor necrosis factor, interleukin-1, and lipopolysaccharide augmented AM secretion from EC, showing cooperative effects, which suggests that AM secreted from EC participates in the induction of hypotension in septic shock. Transforming growth factor beta1 and FCS suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion. Thrombin potently stimulated AM secretion from EC but suppressed it from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1 secretion but to a lesser extent. Interferon-gamma inhibited AM secretion from EC, whereas oxidized LDL stimulated it. Regulation of AM production in EC is found to be similar to that of VSMC with several exceptions, but AM and ET-1 production in EC are deduced to be controlled independently and by different mechanisms. AM stimulates cAMP production in EC, though receptors expressed on cultured rat EC are not specific to AM but to calcitonin gene-related peptide. Based on these findings, AM production in EC is thought to be regulated by a variety of substances coming from blood and neighboring cells, and the secreted AM is deduced to dilate blood vessels as an endothelium-derived relaxing factor competing with ET-1.
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PMID:Regulation of adrenomedullin production in rat endothelial cells. 949 11

To elucidate the pathologic role of endothelin-1 (ET-1) in septic shock, we measured plasma ET-1 concentrations after bacterial lipopolysaccharide (LPS) administration in dogs and determined systemic, pulmonary, and renal hemodynamics and blood gas parameters with or without the nonselective ET receptor antagonist TAK-044. Plasma ET-1 concentrations increased significantly after LPS administration, which correlated positively with mean arterial pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, and central venous pressure. LPS infusion induced hypotension, metabolic acidosis, hypoxemia, and renal dysfunction. TAK-044 prevented LPS-induced metabolic acidosis, hypoxemia, and renal dysfunction, but not hypotension. These findings suggest that increased circulating ET-1 plays a compensatory role in the reversal of systemic vasodilatation in septic shock, but exerts deleterious effects on renal and pulmonary circulation.
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PMID:Pathologic role of endothelin-1 in septic shock. 959 46

Many pathologic conditions are associated with elevations in the production of endothelin-1 (ET-1) in the blood vessel wall. Because many of these conditions are cytokine-driven we examined the effects of a mixture of cytokines and lipopolysaccharide on ET-1 production in human vascular smooth-muscle (VSMC) cells derived from the internal mammary artery (IMA) and saphenous vein (SV). Incubation of VSMCs from IMA and SV with a combination of tumor necrosis factor-alpha (10 ng/ml), interferon-gamma (1,000 U/ml), interleukin-1 beta (500 U/ml) and lipopolysaccharide (10 micrograms/ml) for up to 48 h markedly elevated the expression of mRNA for ET-1 and the release of ET-1 into the culture medium. We conclude that low levels of ET-1 mRNA and peptide production in human VSMCs are markedly increased by exposure to cytokines and LPS. This suggests that during inflammatory states the VSMC, as well as the endothelium, may be a site of significant ET-1 production in the blood vessel wall.
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PMID:Cytokine and lipopolysaccharide stimulation of endothelin-1 release from human internal mammary artery and saphenous vein smooth-muscle cells. 959 78

Septic shock is a life-threatening disorder caused by lipopolysaccharide (LPS) and other bacterial products. Accumulating evidence indicates a role for vasoactive substances and cytokines in this disease process. In this study we examined the effect of LPS on the gene expression of endothelin-1 (ET-1) and adrenomedullin (AM), two major vasoactive peptides predominantly produced by vascular endothelial cells, to investigate their role in the pathophysiology of septic shock. LPS induced ET-1 and AM gene expression in the heart, lung, kidney, liver, and aorta within 6 h. In the liver, whereas basal ET-1 and AM mRNA were hardly detectable, ET-1 and AM gene expression and peptide production were markedly increased by LPS. This LPS-induced upregulation of ET-1 and AM expression is greatly potentiated by D-galactosamine (D-GalN), although D-GalN alone could not induce ET-1 and AM gene expression. These results, together with the previous findings that liver injury induced by LPS and D-GalN is mainly mediated by tumor necrosis factor-alpha (TNF-alpha), suggest that the LPS-cytokine pathway may cause upregulation of ET-1 and AM production, leading to dysregulation of systemic and regional vascular tone.
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PMID:Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. 959 37

Circulating endothelin-1 (ET-1) concentration increases significantly in animal models of sepsis. The main mechanism responsible for this rise in ET-1 levels is believed to be upregulation of ET-1 synthesis in various organs, such as the lungs and heart. In this study we investigated whether ET-1 is synthesized in the ventilatory muscles and whether this synthesis is regulated in septic shock. Conscious rats were injected with Escherichia coli endotoxin (lipopolysaccharide [LPS]) and killed 6, 12, and 24 h later. A fourth group of rats was injected with normal saline and served as a control. The diaphragm was excised at the end of the experiment and quickly frozen. Diaphragmatic ET-1 level was measured with radioimmunoassay, and messenger RNA (mRNA) expression of ET-1 precursor prohormone (preproET-1), preproET-3, and endothelin-converting enzyme was measured with reverse transcription-polymerase chain reaction. LPS injection elicited an early (within 6 h) and prolonged rise in diaphragmatic ET-1 concentration. In addition, mRNA levels of preproET-1 and preproET-3 rose by about 4- and 3-fold within 6 to 12 h of LPS injection, whereas mRNA of endothelin-converting enzyme increased by more than 10-fold and peaked within 24 h of LPS injection. Immunostaining with anti-ET-1 antibody revealed positive ET-1 staining in the endothelium and somatic muscle fibers of septic diaphragms. These results indicate that diaphragmatic muscle fibers synthesize significant amounts of ET-1 in septic shock and that the rise in ET-1 production is due to upregulation of ET precursors and the converting enzyme.
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PMID:Production of endothelins by the ventilatory muscles in septic shock. 973 Aug 75

Macrophages have been shown to produce endothelin and to play a role in the pathogenesis of neural damage after cerebral ischemia or vasospasm after subarachnoid hemorrhage. Cyclooxygenase 2 is induced during inflammation following brain insult and participates in inflammation-mediated neurotoxicity. However, it has not yet been established how endothelin-1 acts on cyclooxygenase 2 expression in macrophages. In the present study, we examined the effects of endothelin-1 on cyclooxygenase 2 expression and prostaglandin E2 production, and the effects of endothelin ET(A) and ET(B) receptor antagonists. Stimulation by endothelin-1 ranging from 10(-11) to 10(-9) M time and dose dependently increased the production of prostaglandin E2 and the expression of cyclooxygenase 2 protein without changing that of cyclooxygenase 1 protein, an effect which was inhibited by dexamethasone, nonsteroidal anti-inflammatory drugs and the selective endothelin ET(B) receptor antagonist, BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-L-me thoxycarbonyl-tryptophanyl-D-norleucine). The selective endothelin ET(A) receptor antagonist, BQ123 [cyclo (D-Trp-D-Asp-Pro-D-Val-Leu)] also inhibited these reactions, but its potency was less than that of the selective endothelin ET(B) receptor antagonist. Endothelin ET(A) and ET(B) receptor antagonists had no effects on cyclooxygenase 2 protein expression and prostaglandin E2 production in lipopolysaccharide-stimulated macrophages. We conclude that endothelin-1 increases cyclooxygenase 2 protein expression and prostaglandin E2 production via mainly endothelin ET(B) receptors and partly endothelin ET(A) receptors in macrophages; however, lipopolysaccharide increases both cyclooxygenase 2 protein expression and prostaglandin E2 production in pacrophages without involving endothelin ET(A) or ET(B) receptor-mediated processes.
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PMID:Cyclooxygenase 2 expression by endothelin-1-stimulated mouse resident peritoneal macrophages in vitro. 976 26

1. The influence of endothelin receptor antagonists on febrile responses to E. coli lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) was assessed in conscious rats. 2. Intravenous (i.v.) LPS (5.0 microg kg(-1)) markedly increased rectal temperature to a peak of 1.30 degrees C over baseline at 2.5 h. Pretreatment with the mixed endothelin ET(A)/ET(B) receptor antagonist bosentan (10 mg kg(-1), i.v.) or the selective endothelin ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxycarboyl-D-norleucine; 3 pmol, into a lateral cerebral ventricle-i.c.v.) reduced the peak response to LPS to 0.90 and 0.75 degrees C, respectively. The selective endothelin ET(A) receptor antagonist BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]; 3 pmol, i.c.v.) was ineffective. 3. Increases in temperature caused by IL-1beta (180 fmol, i.c.v.), TNF-alpha (14.4 pmol, i.c.v.) or IL-1beta (150 pmol kg(-1), i.v.) were unaffected by BQ-788 (3 pmol, i.c.v.). 4. Central injection of endothelin-1 (0.1 to 3 fmol, i.c.v.) caused slowly-developing and long-lasting increases in rectal temperature (starting 2 h after administration and peaking at 4-6 h between 0.90 and 1.15 degrees C) which were not clearly dose-dependent. The response to endothelin-1 (1 fmol, i.c.v.) was prevented by BQ-788, but not by BQ-123 (each at 3 pmol, i.c.v.). Intraperitoneal pretreatment with the cyclo-oxygenase inhibitor indomethacin (2 mg kg(-1)), which partially reduced LPS-induced fever, did not modify the hyperthermic response to endothelin-1 (3 fmol, i.c.v.). 5. Therefore, central endothelin(s) participates importantly in the development of LPS-induced fever, via activation of a prostanoid-independent endothelin ET(B) receptor-mediated mechanism possibly not situated downstream from IL-1beta or TNF-alpha in the fever cascade.
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PMID:Essential role for endothelin ET(B) receptors in fever induced by LPS (E. coli) in rats. 980 38

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

Endotoxin-induced vascular hyporesponsiveness could potentially involve alterations of vascular smooth muscle (VSM) myoplasmic free calcium (Ca(m)) mobilization mechanisms. Contractile function and Ca(m)(fura-2 microfluorometry) regulation were evaluated in vitro using coronary (COR) and mesenteric (MES) artery preparations (100-250 microm inner diameter) isolated from guinea pigs 16 h after intraperitoneal (i.p.) injection of either saline (control; CON) or Escherichia coli endotoxin lipopolysaccharide (LPS; 4 mg/kg). Concentration-response relationships to K+ (5-100 mM) were significantly enhanced in both COR and MES arteries isolated from LPS-treated animals. In contrast, contractile responses to prostaglandin F2alpha (PGF2alpha; 1-100 microM) were markedly impaired in COR and MES arteries from LPS-treated animals, while endothelin-1 (ET; 1-100 nM)-mediated contractile responses of these arteries were enhanced at the maximal dose (100 nM). In COR arteries, PGF2alpha (1-100 microM) and ET (1-100 nM) produced biphasic increases in Ca(m) in both CON and LPS groups. No significant differences were observed in either the initial transient peak or secondary sustained Ca(m) responses between groups, suggesting a lack of effect of LPS upon intracellular Ca2+ release or Ca2+ influx mechanisms in COR arteries. Exposure of MES arteries to PGF2alpha and ET produced concentration-dependent increases in Ca(m) in both groups. However, Ca(m) responses of MES arteries lacked initial peak responses, suggesting potential differences in Ca(m) mobilization between COR and MES arteries. Ca(m) responses to K+ (80 mM) and PGF2alpha (1-100 microM) were similar in MES arteries from both groups; however, ET-mediated increases in Ca(m) were significantly blunted in LPS compared with CON MES arteries. Thus, endotoxemia produced differential effects upon depolarization (K4) and receptor (PGF2alpha, ET)-mediated contractile responses in both COR and MES arteries. Reductions in VSM Ca(m) mobilization appear unlikely as a mechanism for LPS-induced impairment of contractile function of COR and MES arteries; other mechanisms (i.e., decreased Ca2+ sensitivity of contractile proteins) may be involved in effects of LPS upon VSM function of COR and MES arteries.
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PMID:Contractile function and myoplasmic free Ca2+ (Cam) in coronary and mesenteric arteries of endotoxemic guinea pigs. 992 19

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