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)

Fever was induced in rabbits by i.v. administration of lipopolysaccharide (LPS) or administration of interleukin-1 beta (IL-1 beta) into the organum vasculosum laminae terminalis (OVLT). Intra-OVLT injection of IL-1 receptor antagonist (IL-lra), 1 h before LPS or IL-1 beta injection, inhibited the LPS- or IL-1 beta-induced fever. Dexamethasone (a potent inhibitor of the transcription of inducible nitric oxide synthase, iNOS), L-N5-(1-iminoethyl)ornithine (an irreversible NOS inhibitor), aminoguanidine (a specific iNOS inhibitor), or indomethacin (an inhibitor of cyclo-oxygenase, COX) also inhibited IL-1 beta-induced fever when injected into the OVLT 1 h before IL-1 beta injection. These results suggest that iNOS or COX pathways in the OVLT mediate the IL-1 beta-induced fever in rabbits.
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PMID:Inhibition of nitric oxide synthase or cyclo-oxygenase pathways in organum vasculosum laminae terminalis attenuates interleukin-1 beta fever in rabbits. 873 93

1. Male (350-450 g) Long Evans rats were chronically instrumented to permit regional haemodynamics to be monitored in the conscious state. In the first experiment, either saline (0.4 ml h-1) or dexamethasone (3 mg kg-1, 125 micrograms kg-1 h-1) was infused continuously for 24 h, before co-infusion of lipopolysaccharide of (LPS, 150 micrograms kg-1 h-1) for 24 h. Dexamethasone prevented the delayed (5-24 h) fall in mean arterial blood pressure (MAP) and the renal and hindquarters vasodilatation seen with LPS infusion alone, but not the initial (about 2 h) fall in MAP or renal vasodilatation. However, at this dose, dexamethasone itself caused a significant rise in MAP and regional vasoconstrictions. 2. In the second experiment, dexamethasone at a lower dose (12.5 micrograms kg-1 h-1) had only slight pressor and vasoconstrictor effects. However, in its presence, infusion of LPS caused a substantial and progressive rise in MAP (maximum at 8 h, +32 +/- 3 mmHg) together with persistent mesenteric and hindquarters vasoconstriction and a transient renal vasodilatation. 3. In the third experiment, the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 h-1), blocked the slight pressor and regional vasoconstrictor effects of the lower dose of dexamethasone. Furthermore, in the presence of dexamethasone and SB 209670, infusion of LPS caused marked, but transient hypotension (nadir at 5 h, -24 +/- 2 mmHg) and renal and mesenteric vasodilatation. 4. At the end of all experimental protocols, sequential administration of the AT1-receptor antagonist, losartan, followed by the V1-receptor antagonist, (+)-(CH2)5-O-Me-Tyr, vasopressin, caused effects indicating a variable involvement of angiotensin and vasopressin in the maintenance of cardiovascular status. 5. Collectively, the results indicate that, in the conscious rat, dexamethasone interacts with vasoconstrictor and vasodilator mechanisms, and hence its influence on the haemodynamic responses to LPS cannot be attributed, simply, to inhibition of the activity of inducible nitric oxide synthase and/or cyclo-oxygenase-2.
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PMID:Effects of dexamethasone and SB 209670 on the regional haemodynamic responses to lipopolysaccharide in conscious rats. 873 87

1. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001-10 micrograms) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. 2. The LPS-induced febrile response was mimicked by intra-OVLT injection of the nitric oxide (NO) donors, S-nitroso-acetylpenicillamine (SNAP, 1-10 micrograms), sodium nitroprusside (SNP, 50 micrograms), or hydroxylamine (10 micrograms), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10-100 micrograms), or prostaglandin E2 (PGE2, 0.2 micrograms). 3. Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 micrograms), anisomycin (a protein synthesis inhibitor, 100 micrograms), L-N5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10-200 micrograms), aminoguanidine (a specific iNOS inhibitor, 1000 micrograms), or NG-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 micrograms of NG-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. 4. Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1-10 micrograms), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 micrograms), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 micrograms) attenuated the fever induced by intra-OVLT injection of SNAP. 5. The PGE2-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 micrograms), L-NMMA (100 micrograms) or L-NIO (200 micrograms). 6. These results suggest that iNOS-COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.
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PMID:Nitric oxide synthase-cyclo-oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits. 873 93

The potency of dexamethasone has been determined as an inhibitor of intratracheally administered platelet activating factor- (PAF), or interleukin (IL)-5-induced eosinophilia, and of lipopolysaccharide-(LPS), tumour necrosis factor alpha-(TNF alpha) or cytokine-induced neutrophil chemoattractant- (CINC) induced neutrophilia in guinea-pig lungs. Dexamethasone was a potent inhibitor of PAF- induced eosinophil accumulation, but higher doses of dexamethasone were required to inhibit IL-5-induced eosinophilia. LPS-induced neutrophilia was less sensitive to the inhibitory effects of dexamethasone, than PAF-induced eosinophilia. Both LPS- and TNF alpha-induced neutrophilia were inhibited by the same doses of dexamethasone. In contrast, higher doses of dexamethasone were required to inhibit CINC-induced neutrophilia. Since data in the literature show that PAF-induced eosinophilia in guinea-pig lungs is dependent on the generation of IL-5, it is concluded that inhibition of this response, by dexamethasone, is due to inhibition of release of IL-5. Similarly, although data in the literature show that LPS-induced neutrophilia is dependent on the generation of TNF alpha, it is concluded that inhibition of this response, by glucocorticoids, is due to an action on an event which occurs after the release of TNF alpha, possibly through inhibition of chemokine release.
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PMID:Inhibition of PAF-, LPS-, and cytokine-induced granulocyte accumulation in guinea pig lung by dexamethasone: evidence that inhibition of IL-5 release is responsible for the selective inhibition of eosinophilia by glucocorticoids in guinea-pigs. 874 Oct 5

Regulation by dexamethasone of intercellular adhesion molecule-1 (ICAM-1) in cultured monolayers of the human umbilical vein endothelial cell line EAhy926 was investigated. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in combination or lipopolysaccharide (LPS) alone gave time- and dose-dependent increases in ICAM-1. Sustained expression of ICAM-1 was observed after short exposure (30 min) to TNF-alpha + IFN-gamma, but not to LPS. LPS-induced ICAM-1 expression was not inhibited by interleukin-1 (IL-1) receptor antagonist (0.01-100 micrograms/ml). Dexamethasone (1,000 nM) did not inhibit TNF-alpha + IFN-gamma-induced ICAM-1 expression or mRNA induction. In contrast, dexamethasone dose dependently (0.1-1,000 nM) inhibited LPS-induced ICAM-1 expression; however, its effect on mRNA was not established, because ICAM-1 mRNA induced by LPS was not detected at the time points investigated in this study (3 and 20 h). Adhesion of unstimulated human neutrophils to EAhy926 monolayers activated with TNF-alpha + IFN-gamma or LPS was increased in the presence of dexamethasone at low doses, whereas neutrophil adhesion to LPS- but not cytokine-stimulated endothelial cells was significantly reduced (P < 0.05) in the presence of a high dose of dexamethasone (1,000 nM). In conclusion, dexamethasone was demonstrated to regulate the expression and function of ICAM-1 in a stimulus-dependent manner.
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PMID:Regulation of ICAM-1 by dexamethasone in a human vascular endothelial cell line EAhy926. 877 19

In vitro pharmacologic measures of drug specificity are well established, i.e. drug interaction with a specific target such as an enzyme, receptor, or ion channel. However, in vitro measures of drug selectivity, defined as effects on secondary targets, are lacking. Two-dimensional gel electrophoresis (2-D gel) was examined as a measure of drug selectivity by comparing the effects of three drugs, tenidap, piroxicam, and dexamethasone, on the synthesis of intracellular proteins in lipopolysaccharide (LPS)-stimulated murine macrophages. A set of 902 35S-methionine-labeled proteins were separated consistently, identified by their coordinates of apparent isoelectric point and molecular weight, and quantified. LPS altered the concentrations of 45 proteins. Tenidap, at 10 microM, affected a total of five proteins (suppressed three; stimulated two), whereas piroxicam, at 10 microM, suppressed two proteins. Dexamethasone at 0.01 microM suppressed eight proteins and stimulated one. Thus, none of the drugs reversed the LPS-induced changes. Two of the eight proteins suppressed by dexamethasone were also suppressed by tenidap and were identified as proIL-1 alpha and proIL-1 beta. Since the subset of affected proteins provided a unique protein "fingerprint" for each drug, the three drugs were mechanistically differentiated by 2-D gel analysis. Compared to LPS (5% affected proteins), all three drugs were selective (< or = 1% affected) with piroxicam > tenidap > dexamethasone. With identification of affected proteins, this technique can provide a useful in vitro assessment of drug selectivity.
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PMID:Determining selectivity of drugs by quantitative two-dimensional gel analysis. A study of tenidap, piroxicam, and dexamethasone. 878 11

1. The isoprostane 8-epi-prostaglandin (PG)F2 alpha is produced by free radical-catalyzed peroxidation of arachidonic acid. It may also be formed as a minor product of the cyclo-oxygenase activity of platelet PGH synthase (PGHS)-1. We investigated 8-epi-PGF2 alpha production associated with induction of the human monocyte PGHS-2 and its pharmacological modulation. 2. Heparinized whole blood samples were drawn from healthy volunteers, 48 h following oral dosing with aspirin 300 mg to suppress platelet cyclo-oxygenase activity. One ml aliquots were incubated with lipopolysaccharide (LPS: 0.1-50 micrograms ml-1) for 0-24 h at 37 degrees C. PGE2 and 8-epi-PGF2 alpha were measured in separated plasma by radioimmunoassay and enzyme immunoassay techniques. 3. Levels of both eicosanoids were undetectable (i.e. < 60 pg ml-1) at time 0. LPS induced the formation of PGE2 and 8-epi-PGF2 alpha in a time- and concentration-dependent fashion, coincident with the induction of PGHS-2 detected by Western blot analysis of monocyte lysates. After 24 h at 10 micrograms ml-1 LPS, immunoreactive PGE2 and 8-epi-PGF2 alpha averaged 10,480 +/- 4,643 and 295 +/- 140 pg ml-1 (mean +/- s.d., n = 6), respectively. 4. Dexamethasone and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), a selective inhibitor of the cyclo-oxygenase activity of PGHS-2, reduced PGE2 and 8-epi-PGF2 alpha production in response to LPS. 5. Isolated monocytes produced PGE2 and 8-epi-PGE2 alpha in response to LPS (10 micrograms ml-1) in a time-dependent fashion. Monocyte PGE2 and 8-epi-PGF2 alpha production was largely prevented by dexamethasone (2 microM) and cycloheximide (10 micrograms ml-1) in association with suppression of PGHS-2 but not of PGHS-1 expression. 6. We conclude that the induction of PGHS-2 in human monocytes is associated with cyclo-oxygenase-dependent generation of the vasoconstrictor and platelet-agonist 8-epi-PGF2 alpha.
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PMID:Induction of prostaglandin endoperoxide synthase-2 in human monocytes associated with cyclo-oxygenase-dependent F2-isoprostane formation. 881 55

Using radioactive tracers, we measured blood volume, albumin exchanges and blood leukocyte sequestration within lungs, following an intravenous injection of lipopolysaccharide (0.1-1 mg/kg). Neutrophil infiltration into the airways was followed in parallel experiments. Dexamethasone pretreatment (20 mg/kg, subcutaneous) failed to prevent early pulmonary changes induced by lipopolysaccharide as decreased blood volume, leukocyte sequestration, leukopenia or the increased trans-endothelial albumin exchanges. However, dexamethasone provided a significant protection against the later albumin leakage through the endothelial/epithelial barrier and the neutrophil accumulation in the airways observed in lipopolysaccharide-treated guinea-pigs. Our results indicate that the protective effect of dexamethasone in lipopolysaccharide-induced lung injury might derive from an initial reduction of leukocyte adhesion and a later decrease in alveolo-capillary permeability.
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PMID:Interference of dexamethasone with leukocyte blood volume and albumin movements in lungs from endotoxemic guinea-pigs. 881 84

1. Bacterial endotoxin (lipopolysaccharide derived from Escherichia coli) was injected intraperitoneally in conscious rats in doses ranging from 0.5 to 2.5 mg kg-1. At various times afterwards the animals were anaesthetized and subjected to a 30 min period of left coronary artery occlusion. 2. Under these conditions the severity of ventricular arrhythmias was markedly suppressed, in comparison with saline-injected controls, but this was particularly marked with the higher doses (1.5 and 2.5 mg kg-1); the number of ventricular premature beats was reduced from 1687 +/- 227 over the 0.5 h coronary artery occlusion period to 190 +/- 46 in those rats administered 2.5 mg kg-1 endotoxin 8 h previously (P < 0.05). The duration of ventricular tachycardia was also significantly reduced (138 +/- 26 s to 8.9 +/- 4.2 s; P < 0.01) and there was a reduction in the incidence of ventricular fibrillation (from 56% to 10%). 3. The time course of this protection was studied following the administration of a single dose of 2.5 mg kg-1 of endotoxin by anaesthetizing rats 4, 8 or 24 h later. Protection was apparent at each time but was particularly marked at 8 h. 4. No rat given the highest dose of endotoxin (32 in all) died as a result of ventricular fibrillation, or from any other cause, during an occlusion, in contrast to a 26% mortality in the controls (P < 0.01). 5. Infarct size, measured following a 30 min period of coronary artery occlusion followed by a 3 h reperfusion period, was reduced both 8 and 24 h after the administration of 2.5 mg kg-1 endotoxin (reductions of 24.3 and 23.1% respectively; P < 0.05). Endotoxin had no significant effect on the area at risk. 6. The beneficial effects of endotoxin on infarct size and on ventricular arrhythmias were markedly attenuated by the prior administration of dexamethasone, 3 mg kg-1 given 1 h prior to endotoxin administration. Dexamethasone itself reduced infarct size (P < 0.05) but had no direct effect on arrhythmia severity following coronary artery occlusion. 7. The mechanisms of this "cross-tolerance' induced by bacterial endotoxin against ischaemia-reperfusion injury remain to be elucidated but the most likely mechanisms appear to be the induction of protective enzymes or proteins (e.g. nitric oxide synthase, cyclo-oxygenase (COX) 2) probably mediated by cytokine release.
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PMID:Delayed protection against ischaemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin. 886 56

Interleukin-12 (IL-12) is a key inducer of differentiation of uncommitted T helper (TH) cells toward the TH1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses (i.e., humoral immunity). To examine the potential effects of stress on TH1/TH2 balance, we studied the ability of three prototype stress hormones-dexamethasone (a synthetic glucocorticoid) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccharide (LPS) in human whole blood. Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations; it had no effect on IL-10 secretion. The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor. Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-dependently increased the production of IL-10. The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol, a beta-adrenoreceptor antagonist, indicating that they were mediated by the beta-adrenergic receptor. These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and, hence, TH1/TH2 balance via the peripheral end-effectors of the stress system. Thus, stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH suppression. The TH1-to-TH2 shift may be responsible for the stress-induced susceptibility of the organism to certain infections. Through the same or a reciprocal mechanism, states associated with chronic hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune, allergic, infectious, or neoplastic diseases.
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PMID:Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. 890 82


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