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)

Gentiopicroside (GPS), a main bitter secoiridoid constituent of roots of Gentiana macrophylla Pall., was tested for therapeutic effects on the two hepatic injury models, the CCl4-induced and lipopolysaccharide (LPS)/bacillus Calmette-Guerin (BCG)-induced hepatitides. An increase in serum level of hepatic aminotransferases (GOT: EC 2.6.1.1. and GPT: EC 2.6.1.2.) induced by a p.o. treatment of CCl4 was suppressed by pretreatment with GPS at 30-60 mg/kg/day for 5 consecutive days. An increase of these enzymes triggered by an i.v. treatment with LPS in mice primed with bacillus Calmette-Guerin (BCG) was also inhibited by GPS pretreatment at the same dose of GPS. In the BCG/LPS model, tumor necrosis factor (TNF), a major inflammatory mediator, was increased in serum with a peak at 90-120 min, followed by an increase of serum transaminase activities. GPS treatment significantly suppressed the increase of TNF in serum at the therapeutic doses, suggesting that GPS protected against hepatitis by inhibiting the production of TNF.
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PMID:Suppression of chemically and immunologically induced hepatic injuries by gentiopicroside in mice. 799 67

Massive hepatic cell necrosis can be induced by Corynebacterium parvum and lipopolysaccharide (LPS) in rats. In this model, serum LDH, GOT and GPT activities are significantly increased in vivo within several hours after LPS injection. An in vitro experimental acute liver injury animal model was produced by using multicellular spheroids composed of rat parenchymal and non-parenchymal liver cells. These multicellular spheroids were prepared by detaching the confluent monolayer on the collagen-conjugated thermo-responsive polymer coated culture dish at a temperature below the lower critical solution temperature and culturing it on the non-adhesive substratum. LPS caused clear elevations of GOT, GPT and LDH activities from these spheroids into the medium. However, the increase of LDH activity was only observed in the monolayer culture system. These results suggest that the multicellular spheroids of liver cells are useful models as an alternative to animal tests for hepatotoxicity.
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PMID:An experimental model of acute liver injury using multicellular spheroids composed of rat parenchymal and non-parenchymal liver cells. 812 32

The changes in plasma concentrations of reduced glutathione were investigated in rats with endotoxin hepatitis. An increase in serum alanine aminotransferase activity and in serum total bilirubin concentration was observed 12 hr after the intraperitoneal co-administration of small doses of Escherichia coli lipopolysaccharide and D-galactosamine in starved rats. At the same time, an increase in the plasma concentration of reduced glutathione was also observed. The increase in reduced glutathione from 14 +/- 2 to 20 +/- 9 microM (n = 11, P < 0.05) correlated well with that in serum alanine aminotransferase activity. Ulinastatin, a potent inhibitor of polymorphonuclear leukocyte elastase, partially counteracted all of these changes. Ulinastatin also reduced histological liver damage induced by endotoxin. We conclude that the increase in the plasma concentration of reduced glutathione reflects hepatocellular damage associated with endotoxin hepatitis. The partial reversal of the damage by ulinastatin is consistent with the proposal that the activation of polymorphonuclear leukocytes is involved in endotoxin hepatitis.
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PMID:Increase in the plasma concentration of reduced glutathione observed in rats with liver damage induced by lipopolysaccharide/D-galactosamine: effects of ulinastatin, a urinary trypsin inhibitor. 814 54

The bisbenzylisoquinoline (BBI) alkaloids chondocurine, cycleanine, tetrandrine and berbamine were tested for their capacity to suppress hepatic injury and production of tumor necrosis factor (TNF) induced by lipopolysaccharide (LPS) in mice primed with bacillus Calmette-Guerin (BCG). When administered for three consecutive days before LPS injection, chondocurine, cycleanine and tetrandrine (10 mg/kg/day) strongly suppressed serum alanine aminotransferase (EC 2.6.1.1.) and aspartate aminotransferase (EC 2.6.1.2.); however, berbamine gave only slight protection. Chondocurine, cycleanine and tetrandrine but not berbamine significantly reduced the level of TNF which peaked 2 hr after LPS injection. This study shows that BBI alkaloids prevent BCG/LPS-induced hepatitis at least in part by suppressing TNF production.
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PMID:Suppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated mice. 825 Sep 73

Lipopolysaccharide binding protein (LBP) is a serum glycoprotein that complexes with lipopolysaccharide (LPS) to facilitate macrophage response to endotoxin. To determine the conditions that stimulate LBP production in vivo, we measured the induction of LBP in models of inflammation produced by LPS, Corynebacterium parvum, and turpentine injection. Plasma aspartate aminotransferase and alanine aminotransferase concentrations and hepatocyte fibrinogen synthesis were elevated in all models. Northern blot analysis revealed 17-, 14-, and 20-fold upregulation of hepatocyte LBP mRNA following treatment with LPS, C parvum, and turpentine, respectively. Peritoneal macrophage interleukin 6 and tumor necrosis factor production following endotoxin stimulation was augmented by cultured hepatocyte supernatants, suggesting increased LBP synthesis in these groups. The results show that LBP mRNA is induced during hepatic inflammation and suggest that LBP is an acute-phase protein important in regulating the in vivo response to endotoxin.
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PMID:Induction of hepatocyte lipopolysaccharide binding protein in models of sepsis and the acute-phase response. 841 76

Multiple organ dysfunction (MOD) is the leading cause of mortality in septic patients with circulatory shock. Recent evidence suggests that the overproduction of the cytokine, tumor necrosis factor-alpha(TNF), and oxygen free radical molecules may mediate the progression of sepsis to MOD and death. In this study, we have examined the ability of MDL 101,002, a free radical scavenger, to reduce organ dysfunction and cytokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 ng/kg, i.p.) 30 min prior to an LPS challenge resulted in a dose-dependent reduction in several markers indicative of organ dysfunction and mortality. MDL 101,002 markedly decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or urea and creatinine, respectively. MDL 101,002 also prevented LPS-induced pulmonary edema, but did not prevent leukopenia and only partially reduced thrombocytopenia. Associated with these improvements in organ dysfunction and survival was a modest decrease in LPS-stimulated interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) secretion and a marked ( > 90%) inhibition of TNF secretion by MDL 101,002. The data are consistent with a role for oxygen free radicals in the development of endotoxin-induced organ dysfunction and shock and suggest that free radical scavengers could reduce the mortality consequent to sepsis by decreasing organ dysfunction, at least in part, through a reduction in free radical stimulated cytokine secretion.
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PMID:Reduction in endotoxin-induced organ dysfunction and cytokine secretion by a cyclic nitrone antioxidant. 858 85

1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.
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PMID:The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. 868 Jul 15

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

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.
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PMID:The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat. 876 73

After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.
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PMID:Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls. 879 52


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