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)

Somatostatin infusion causes hyperkalemia in healthy subjects and in some animal models. The purpose of this investigation was to determine what effect octreotide has on potassium homeostasis during serious illness and if there is a dose-response relationship. Sixty-six male Sprague-Dawley rats (185-225 g) were randomized to receive parenteral nutrition (PN) only, PN plus continuous infusion of Escherichia coli lipopolysaccharide (LPS), or PN plus LPS plus octreotide 10, 100, or 1000 micrograms/kg/day for 48 hours. Before randomization all animals received isocaloric, isonitrogenous, isokalemic PN. A 24-hour urine was collected and a blood sample was taken at the end of the study immediately before euthanization. Data were analyzed by ANOVA and Duncan's multiple range test. Nonhemolyzed serum samples from 50 rats were available for study. Serum potassium concentrations were in the normal range for rats and did not differ significantly among the groups: 5.97 +/- 0.86, 5.96 +/- 1.58, 5.78 +/- 1.48, 5.79 +/- 1.67, 5.35 +/- 0.78 mEq/L, respectively. No differences among groups were found for fractional excretion of potassium or serum creatinine concentration. Octreotide administration in escalating dosages does not cause hyperkalemia in endotoxemic rats given intravenous potassium at a constant rate by PN.
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PMID:Octreotide and potassium homeostasis. 916 58

In vitro pretreatment of human monocytes (MO) with low-dose lipopolysaccharide (LPSp) inhibits TNF release in response to subsequent LPSa activation. Septic patients are often indistinguishable from patients with systemic inflammatory response syndrome (SIRS). We hypothesized that in vivo exposure to "septic" stimuli impairs subsequent LPSa-stimulated MO TNF production in vitro. Human peripheral MO were obtained after informed consent from controls or patients with sepsis, SIRS, or posttrauma [ACCP/SCCM definitions]. Cells were plated in vitro, incubated 24 hr, and then stimulated with 0-1000 ng/ml LPSa for 4 hr. Parallel control MO were incubated in vitro with 100 ng/ml LPSp for 24 hr and then stimulated with 1000 ng/ml LPSa for 4 hr. Supernatant TNF (mean U/ml +/- SEM) was measured by bioassay. ANOVA was used to determine statistical significance. In vitro LPSp pretreatment markedly inhibited subsequent LPSa-stimulated TNF release. In vitro LPSa-stimulated TNF release was likewise significantly inhibited with MO from septic patients compared to controls. Inhibition was more profound in septic patients with shock (not shown). No impaired TNF release was seen with MO from SIRS or trauma patients. In conclusion, in vivo preexposure to inflammatory stimuli in septic patients alters monocyte regulation in a manner similar to in vitro endotoxin tolerance. Provocative in vitro monocyte LPS stimulation may distinguish patients with sepsis and SIRS.
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PMID:In vivo endotoxin tolerance: impaired LPS-stimulated TNF release of monocytes from patients with sepsis, but not SIRS. 920 54

Ischemia-reperfusion (IR) lung injury occurs after various clinical procedures, including cardiopulmonary bypass. It is not clear whether endogenous nitric oxide (NO) is protective or injurious in lungs subjected to IR. Thus, in this study we examined the contribution of endogenous NO to IR injury in isolated, blood-perfused rat lungs. Lungs of male Wistar rats (300 g) were subjected to 30 min ischemia and 180 min reperfusion (I30R180). Lungs were sampled for inducible nitric oxide synthase (i-NOS) mRNA expression (each n = 3) and NOS enzyme activity (each n = 4) at different time points. NOS inhibitors NG-nitro-L-arginine-methyl ester (10[-4] M) and aminoguanidine (10[-4] M) were used to study the contribution of NO to IR injury in lungs subjected to I30R30 and I30R180. The contribution of i-NOS to IR lung injury was studied by inducing i-NOS enzyme with Salmonella lipopolysaccharide, followed by I30R30. We found that ischemia-reperfusion alone can upregulate i-NOS mRNA and i-NOS enzyme activity (p < 0.05, ANOVA), but downregulate constitutive NOS enzyme activity over 180 min reperfusion. Endogenously produced NO is protective against lung injury in I30R180 in normal rats and lung injury in I30R30 in septic rats. NO is also pivotal in maintaining pulmonary vascular homeostasis in septic rat lungs undergoing IR.
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PMID:The role of endogenous nitric oxide in modulating ischemia-reperfusion injury in the isolated, blood-perfused rat lung. 944 9

Ischaemia in wounds may modulate the expression of tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The release of these and other cytokines by stimulated macrophages influences wound healing. Our aim was to examine the separate and combined effects of hypoxia and glucose deprivation on TNF-alpha and GM-CSF mRNA levels in human monocytes isolated from peripheral blood by density gradient centrifugation and purified by adherence. Cells were incubated for a 16-hour period in a hypoxic (3% O2) or normoxic (21% O2) environment in the presence or absence of glucose followed by a further 4 h under normoxic conditions in the presence or absence of lipopolysaccharide (LPS, 100 pg/ml). These different incubation conditions had no effect on cell viability, cell number, lactate dehydrogenase release or superoxide anion generation (n = 5, p > 0.05, paired t test). However, Northern hybridisation showed that hypoxia decreased the expression of GM-CSF mRNA in LPS-stimulated human monocytes by 46% (n = 9, p < 0.05, paired t test) and increased the expression of TNF-alpha by 102% (n = 7, p < 0.05, paired t test). The increase in the level of immunoreactive TNF-alpha in the cell supernatants paralleled the increase in TNF-alpha mRNA. The combination of glucose deprivation and hypoxia decreased the expression of both GM-CSF and TNF-alpha mRNA in LPS-stimulated human monocytes. Similarly, a decrease in the level of TNF-alpha in the cell supernatants was observed (n = 3-5, p < 0.05, two-way ANOVA). These data suggest that incubation conditions simulating ischaemia reduce LPS-induced cytokine expression.
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PMID:Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor expression in human cultured monocytes. 954 21

Interleukin (IL)-10 inhibits the synthesis of proinflammatory cytokines implicated in fever, including IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. We hypothesized that IL-10 functions as an antipyretic in the regulation of fevers to lipopolysaccharide (LPS) and turpentine. Body temperature was measured by biotelemetry. Swiss Webster (SW) mice treated with recombinant murine IL-10 were resistant to fever induced by a low dose of LPS (100 microgram/kg ip) and to the hypothermic and febrile effects of a high (septiclike) dose of LPS (2.5 mg/kg ip). IL-10 knockout mice developed an exacerbated and prolonged fever in response to a low dose of LPS (50 microgram/kg ip) compared with their wild-type counterparts. At 4 h after injection of the low dose of LPS, plasma levels of IL-6, but not TNF-alpha, were significantly elevated in the IL-10 knockout mice compared with their wild-type controls (ANOVA, P < 0.05). After injection of the same high dose of LPS injected into SW mice, wild-type mice developed a fever at 24 h whereas IL-10 knockout mice immediately developed a profound hypothermia that lasted through 41 h (ANOVA, P < 0.05). Body weight and food intake were more significantly depressed in response to the high dose of LPS in the knockout mice compared with their wild-type controls. Only 30% of the IL-10 knockout mice survived compared with 100% of the wild-type mice (Fisher's exact test, P < 0.05). Fever in response to the injection of turpentine (100 microliter/mouse sc) did not differ between wild-type and IL-10 knockout mice. These data support the hypotheses that 1) IL-10 functions as an endogenous antipyretic following exposure to LPS, 2) a putative mechanism of the early antipyretic action of IL-10 is through the inhibition of plasma levels of IL-6, 3) IL-10 has a protective role in the lethal effects of exposure to high levels of LPS, and 4) endogenous IL-10 does not have a role in fever induced by turpentine.
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PMID:An antipyretic role for interleukin-10 in LPS fever in mice. 988 80

The aim of this study was to establish the effect of bacterial endotoxin lipopolysaccharide (LPS) on the release of Type II phospholipase-A2 (PLA2) and prostaglandin E2 (PGE2) from late-pregnant human placental tissue incubated in vitro. Under basal conditions, immunoreactive Type II PLA2 and PGE2 were released from tissue explants in a time-dependent manner (up to 24 h, ANOVA, P<0. 0001, n=6). The release of these mediators was not associated with a loss of cell membrane integrity, as indicated by concentrations of the intracellular enzyme, lactate dehydrogenase (LDH), in the incubation medium. Incubation of explants in the presence of LPS (0. 001-100 microg LPS/ml) significantly decreased PLA2 tissue content (P<0.02, n=6) and increased the accumulation of PLA2 and PGE2 in the incubation medium (P<0.0001, n=6). The data obtained in this study indicated that Type II PLA2 and PGE2 are released from term placenta under basal conditions and that LPS stimulated their release. The associated decrease in PLA2 tissue content is consistent with the hypothesis that LPS induces the release of stored PLA2. This study identifies one pathway by which products of bacterial infection may induce the release of a pro-inflammatory, extracellularly active PLA2 from intrauterine tissues that may promote the formation of phospholipid metabolites involved in the process of labour and delivery (e.g. the prostaglandins).
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PMID:Effect of bacterial endotoxin on the in vitro release of Type II phospholipase-A2 and prostaglandin E2 from human placenta. 992 99

Besides its central role in coagulatory pathways, thrombin is known to be a key mediator of macrophage and granulocyte activation in vitro. During recent years the concept of thrombin inhibition by the specific thrombin inhibitor, hirudin, has been established to treat septic disorders. Since basic mechanisms of sepsis include leukocyte/endothelial cell interaction and deterioration of capillary perfusion, we hypothesized that hirudin modulates leukocyte activation and microvascular injury. Severe endotoxemia was induced in Syrian hamsters by intravenous administration of endotoxin (lipopolysaccharide [LPS], E. coli, 2mg/kg) at 0 h. Hirudin (0.25 mg/kg/h) was substituted intravenously during the 4 h after the induction of endotoxemia (n = 7, hirudin). In control animals (n = 6, control) LPS was given without hirudin substitution. In skinfold chamber preparations leukocyte/endothelial cell interaction and functional capillary density (FCD, measure of capillary perfusion) were analyzed during a 24-h period after LPS injection using intravital fluorescence microscopy. Hirudin effectively normalized thromboplastin time and antithrombin activity when compared to controls (P < 0.05, ANOVA). However, hirudin did not attenuate LPS-induced arteriolar and venular leukocyte adherence, and even tended to increase leukocyte adherence after 24 h (P > 0.05, MANOVA). In parallel, addition of hirudin led to a significant deterioration of FCD over time when compared to controls (hirudin: baseline = 171 +/- 19 cm(-1) versus 16 +/- 9 at 24 h; control: baseline = 150 +/- 20 cm(-1) versus 62 +/- 18 at 24 h; P < 0.05). The fall in FCD in hirudin animals was associated with a significant increase of wet-to-dry weight ratios in lung, kidney, muscle, and small intestine (P < 0.05 versus control, ANOVA). Thus our study does not indicate a protective effect of hirudin on microcirculation during endotoxemia, despite an improvement of coagulatory parameters. This result may at least in part explain the lack of efficacy of hirudin on lethality during endotoxemia and sepsis.
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PMID:The thrombin antagonist hirudin fails to inhibit endotoxin-induced leukocyte/endothelial cell interaction and microvascular perfusion failure. 1109 85

Information on the dose-response relationship is a prerequisite to defining the non-response threshold of exposure. We investigated whether nasal lipopolysaccharide (LPS) challenges induce an inflammatory response in a dose-dependent way. In three settings nasal lavage was performed before, and 20 min, 1, 6, 23, and 29 h after instillation of 0 microg, 10 microg, and 40 microg LPS for 10 s, in seven healthy subjects. Lavage fluids were analysed for concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor-alpha (TNF-alpha), histamine, and albumin. Symptoms were recorded by questionnaire and spirometric lung function was assessed after each lavage. The instillation of 40 microg LPS caused a small increase in nasal symptoms. TNF-alpha was below the detection limit (0.5 pg/ml) in most subjects and, like IL-8 and albumin, showed no relation to the LPS challenge. IL-6 increased over twofold with 10 microg LPS and over 13-fold with 40 microg LPS, with a peak at 6 h after LPS provocation, and the repeated design ANOVA was significant for dose and for time. Six hours after the 40 microg LPS challenge the histamine level significantly increased compared to the saline treatment. We conclude that short-lasting instillation of LPS causes a dose-dependent IL-6 release in the upper airways and minor nasal symptoms.
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PMID:Lipopolysaccharide-induced nasal cytokine response: a dose-response evaluation. 1119 30

Clinical studies demonstrate a better outcome of sepsis in females. Elevated estrogen levels and plasma cytokine imbalance occur in septic patients. We propose that gender-different cytokine secretion by the peripheral blood mononuclear cells (PBMCs) in sepsis determines the clinical outcome. A 2 x 10(6) PBMC sample from healthy volunteers (10 males and 10 females) was incubated with 1 ng/mL of lipopolysaccharide (LPS), estradiol (E2; 0, 0.03, 0.3, 3.0, 30 ng/mL), or 1 ng/mL of LPS + E2 (0, 0.03, 0.3, 3.0, 30 ng/ml), and supernatant cytokine levels were measured. Tumor necrosis factor alpha (TNF alpha) and interleukin (IL)-6 production by PBMCs from both sexes was time-dependently stimulated by LPS. At 6 h after LPS challenge, the TNF alpha level of male PBMCs was significantly higher but IL-6 secretion by female PBMCs was higher (two-way ANOVA: P < 0.05). E2 alone stimulated cytokine secretion by male PBMCs. Addition of the same E2 concentration as in sepsis patients' plasma modulated LPS-induced cytokine production. No significant sex differences in LPS-stimulated TNF alpha or IL-6 secretion by PBMCs were found, but IL-10 secretion by male PBMCs was significantly suppressed. This study demonstrated a gender difference in PBMCs responsiveness to LPS and E2 stimulation and E2-modulated cytokine secretion. In this PBMCs model of sepsis, only the supernatant IL-10 level was significantly lower in males. These ex vivo findings may partially explain the mechanism underlying the poorer outcome of male sepsis patients.
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PMID:Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. 1169 70

Advancement of cancer prevention and therapy requires clinical development of systemic biomarkers of pharmacological efficacy of the agent under scrutiny. Curcumin, a polyphenol derived from Curcuma spp., has shown wide-ranging chemopreventive activity in preclinical carcinogenic models, in which it inhibits cyclooxygenase (COX)-2 at the transcriptional level. COX-2 has been implicated in the development of many human cancers. To explore the inhibition of COX-2 activity as a systemic biomarker of drug efficacy, a biomarker of potential use in clinical trials of many chemopreventive drugs known to inhibit this enzyme, we measured COX-2 protein induction and prostaglandin E(2) (PGE(2)) production in human blood after incubation with lipopolysaccharide (LPS). When 1 microM curcumin was added in vitro to blood from healthy volunteers, LPS-induced COX-2 protein levels and concomitant PGE(2) production were reduced by 24% and 41%, respectively (P < 0.05 by ANOVA). To test whether effects on COX-2 activity could also be measured after oral dosing in humans, we conducted a dose-escalation pilot study of a standardized formulation of Curcuma extract in 15 patients with advanced colorectal cancer. Basal and LPS-mediated PGE(2) production was measured in blood, twice pretreatment and on days 1, 2, 8, and 29 of treatment. Analysis of basal and LPS-induced PGE(2) production during treatment demonstrated a trend toward dose-dependent inhibition (P < 0.005 by regression analysis), but there was no significant difference compared with values from pretreatment time points. Measurement of leukocyte COX-2 activity should be considered in clinical trials of other agents likely to inhibit this isozyme.
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PMID:Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents. 1175 48


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