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)

In this study, we investigated the influence of D-galactosamine (GalN), indomethacin, and dexamethasone on the pharmacokinetics of injected or induced tumor necrosis factor (TNF) and interleukin-6 (IL-6) after a bolus injection of murine TNF (mTNF) or lipopolysaccharide (LPS). It is well known that GalN treatment renders mice much more vulnerable to TNF or LPS lethality. Nevertheless, GalN had no influence on TNF clearance or IL-6 induction after mTNF injection; however, the induced TNF and IL-6 levels were considerably augmented by the GalN cotreatment when a high dose of LPS was injected (GalN was given as a single injection together with TNF or LPS). Indomethacin and dexamethasone, either of which shows a clear protection against TNF/LPS lethality in normal mice, did not change the clearance of injected mTNF, but both reduced the TNF-induced IL-6 levels. Indomethacin did not affect the level and clearance of LPS-induced TNF, whereas the induced IL-6 levels were significantly lower than in the control mice. The circulating TNF and IL-6 concentrations after LPS injection in mice pretreated with dexamethasone were very considerably reduced. Furthermore, neither agent had an influence on the number of TNF binding sites on hepatocytes. We conclude that the strongly enhanced sensitivity of GalN-treated mice towards mTNF-induced or LPS-induced lethality was not reflected in circulating TNF or IL-6 levels, and that dexamethasone and indomethacin both reduce circulating IL-6 concentrations in mice treated with TNF and LPS.
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PMID:The influence of modulating substances on tumor necrosis factor and interleukin-6 levels after injection of murine tumor necrosis factor or lipopolysaccharide in mice. 165 27

The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.
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PMID:Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. 165 17

Lead markedly augments the lethality of endotoxin lipopolysaccharide (LPS) in rats. In this model of LPS toxicity, the liver is severely injured. Much of the tissue injury produced by LPS is thought to be mediated by the cytokine tumor necrosis factor (TNF). Tumor necrosis factor recently has been speculated to be a mediator of several models of liver injury such as that produced by galactosamine. To investigate the possible role of TNF in the lead-enhanced LPS toxicity model, we administered doses of lead acetate (15 mg/kg), LPS (100 micrograms/kg), or TNF (6.25 x 10(6) U/kg) that produced minimal changes in liver enzymes. However, when lead was administered simultaneously with either LPS or TNF, serum aspartate transaminase, alanine transaminase, alkaline phosphatase, glutamyl transpeptidase, and plasma triglyceride levels were markedly increased. Lead + LPS treatment increased both peak serum TNF concentrations and TNF "area under the curve" as compared with LPS alone. We conclude that lead not only enhances LPS lethality but also LPS liver injury. Furthermore, lead enhances TNF liver injury and increases LPS-stimulated serum TNF levels. These data suggest that the lead-enhanced LPS model offers a system for studying TNF-induced liver injury.
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PMID:Lead enhances lipopolysaccharide and tumor necrosis factor liver injury. 167 39

Mice were fed diets with three different ratios of alpha-linolenate (18:3n-3) to linoleate (18:2n-6), and the severity of hepatitis during endotoxic shock was compared. Dietary enrichment with alpha-linolenate increased the severity of hepatitis and the mortality induced by lipopolysaccharide (LPS) in combination with D-galactosamine (GalN). Differences in the dietary alpha-linolenate/linoleate balance were mainly reflected in the levels of arachidonate and eicosapenatenoate in liver phospholipids. Pretreatment of mice with indomethacin was found to also enhance the severity of GalN/LPS-hepatitis. This indicated that cyclooxygenase products of arachidonate may suppress the development of GalN/LPS-hepatitis. The enhancement by high alpha-linolenate diets was not observed when a lethal dose of LPS in the absence of GalN was given. Our results indicate that there are pathophysiological conditions of endotoxin-induced hepatitis under which cyclooxygenase products of arachidonate play protective roles.
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PMID:Effect of dietary alpha-linolenate/linoleate balance on endotoxin-induced hepatitis in mice. 167 89

Specific endotoxic lipopolysaccharide (LPS) binding sites on the cell membranes of murine lymphocytes and macrophages that may serve as functional receptors for LPS have recently been identified using photoactivatable cross-linking LPS derivatives. A monoclonal antibody (Mab 5D3) with specificity for this 80-kDa protein has also been generated and characterized. The capacity of MAb 5D3 to protect mice against the lethal effects of endotoxin was investigated. Pretreatment of CF1 mice with as little as 15 micrograms of MAb 5D3 provided virtually complete protection against a dose of endotoxin 10-fold greater than that required to kill all mice in an untreated control group using the galactosamine sensitization model. Significant protection was also afforded normal mice given MAb 5D3 relative to saline. Several lines of evidence suggest that MAb 5D3-mediated protection is due to the agonist properties of this antibody rather than a receptor blockade mechanism.
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PMID:Monoclonal antibody to mouse lipopolysaccharide receptor protects mice against the lethal effects of endotoxin. 170 23

Injection of bacterial lipopolysaccharide (LPS) into animals results in a transient increase in serum tumor necrosis factor (TNF). Maximal increases in TNF were detected by 1 h and 3-4 h serum TNF was no longer apparent. These animals were LPS tolerant and a repetitive LPS stimulus did not result in an additional peak in TNF. Regulation of TNF expression in LPS-tolerant animals was at the transcriptional level as TNF mRNA was not apparent in spleen or peritoneal macrophages following a second LPS stimulus. Adrenalectomized (adrex) mice, in contrast, did not become LPS tolerant and sera from these animals demonstrated an additional peak in TNF 1 h following a second LPS stimulus. Concomitant with the secondary rise in serum TNF in adrex mice was an increase in splenic TNF mRNA. The ability of adrex mice to become LPS tolerant was restored by exogenous glucocorticoids. LPS tolerance was also investigated in the galactosamine LPS model which like the adrex model is characterized by a thousandfold increase in the sensitivity of these animals to the lethal effects of LPS. Consistent with the absence of LPS tolerance in adrex mice, galactosamine-sensitized mice were also responsive to a second LPS stimulus and did not become LPS tolerant. While LPS-treated adrex mice had no significant increases in serum corticosterone, corticosterone levels in LPS-treated galactosamine-sensitized mice were comparable to LPS-stimulated normals suggesting that LPS tolerance involves both glucocorticoid-dependent and -independent components. Finally, prophylactic administration of a monoclonal antibody against murine TNF protected normal and galactosamine-sensitized mice from a lethal dose of LPS and yet had no protective effect in adrex animals.
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PMID:Glucocorticoid-dependent and -independent mechanisms involved in lipopolysaccharide tolerance. 171 5

D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-alpha. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-alpha-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-alpha production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-alpha. Thus we suggest that the acute-phase response protects against death in D-galactosamine-sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-alpha release.
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PMID:The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-alpha. 172 88

The possible involvement of interleukin-1 alpha (IL-1 alpha) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. The injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1 alpha antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-alpha (TNF) antiserum significantly protected mice from liver injury. The use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-1 alpha could not substitute for LPS. However, recombinant murine IL-1 alpha enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-1 alpha acts synergistically with TNF in this hepatitis model.
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PMID:Interleukin-1 alpha enhances hepatotoxicity of tumor necrosis factor-alpha in galactosamine-sensitized mice. 177 33

Although the shock syndrome is recognized as a form of "mediator poisoning", a plethora of details is hardly converging into a coherent concept of chronological and molecular order. As a model for organ failure in septic shock, three alternative experimental approaches with a common pathology are presented: When galactosamine-sensitized mice receive either lipopolysaccharide or leukotriene D4 or tumor necrosis factor alpha they develop fulminant hepatitis within few hours with a lethal outcome within one day. Detailed pharmacological intervention studies allow to conclude that endotoxin-induced leukotriene D4 release induces a transient ischemia by the known vasoconstrictive action of this eicosanoid. A following reperfusion/reoxygenation phase gives rise to superoxide formation which inactivates alpha 1 proteinase inhibitor. Thus a serine protease becomes active which is responsible for the processing of a monocytic tumor necrosis factor alpha precursor to be released into the circulation after proteolytic cleavage. By this sequence the final central mediator of shock and sepsis becomes systematically abundant. The concept arising from these studies reconciles previously known findings and provides a link between the role of reactive oxygen species in inflammation, the balance of proteases and antiproteases in the extracellular space and the release of the cytokine tumor necrosis factor in sepsis and shock.
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PMID:Reactive oxygen species, antiproteases, and cytokines in sepsis. 179 93

Hepatoprotective effects of KF-14363 were investigated in the following experimental models. KF-14363 inhibited the increase in serum glutamate pyruvate transaminase (GPT) dose-dependently, and a significant inhibition was noted at a dose of 30 mg/kg or more. KF-14363 significantly inhibited the D-galactosamine (D-gal)-induced increase in serum transaminase by oral administration at 250 mg/kg x 1 and 250 mg/kg x 2 doses. The D-gal-induced decrease in total protein levels was inhibited at doses of 100 mg/kg x 2 and 250 mg/kg x 2. KF-14363 (100 mg/kg or more) significantly inhibited the increase in liver triglyceride levels induced by DL-ethionine (250 mg/kg x 3). KF-14363 (300 mg/kg) significantly inhibited the D-gal plus lipopolysaccharide-induced increase in GPT. At 100 mg/kg or less, however, an inhibiting tendency was noted, which was not significant as the values varied widely. KF-14363 (100 mg/kg) significantly inhibited Propionibacterium acnes plus lipopolysaccharide-induced mortality at 7 and 8 hr, and it showed an inhibitory tendency at 24 hr. These results demonstrate that KF-14363 is a compound that has a protective effect against the damage induced in various experimental liver injury models with different mechanisms.
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PMID:Hepatoprotective effects of 1-[(2-thiazolin-2-yl)-amino]acetyl-4-(1,3-dithiol-2-ylidene)-2,3,4,5- tetrahydro-1H-1-benzazepin-3,5-dione hydrochloride (KF-14363) in various experimental liver injuries. 181 94


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