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)

Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.
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PMID:Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression. 1249 23

Cocaine produces hepatotoxicity by a mechanism that remains undefined but has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, and exposure to noninjurious doses of LPS increases the toxicity of certain hepatotoxins. Previously it was demonstrated that exposure to noninjurious doses of LPS dramatically increases cocaine-mediated hepatotoxicity (CMH). This study was conducted to investigate whether pretreatment with N-acetylcysteine (NAC), a glutathione (GSH) precursor and an antioxidant agent, inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily oral NAC (200 mg/kg) or sterile saline followed an hour later by cocaine (20 mg/kg) or sterile saline. Four hours following the last cocaine or saline treatment, the mice were administered 12 x 10(6) EU LPS/kg or sterile saline. For the cocaine alone and cocaine and LPS groups, NAC pretreatment significantly decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities with absence of necrotic hepatic lesions, indicating a reduction of liver injury. In addition, in all groups pretreated with NAC, hepatic GSH concentration was significantly increased, as were hepatic and blood glutathione peroxidase (GPx) and catalase (CAT) activities. In conclusion, the results demonstrate that NAC pretreatment exerted a protective effect against LPS potentia-tion of CMH.
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PMID:N-acetylcysteine pretreatment decreases cocaine and endotoxin-induced hepatotoxicity. 1252 69

Trypanosoma cruzi-infected mice display increased susceptibility to shock induced by injection of lipopolysaccharide (LPS), anti-CD3, or resulting from interleukin (IL)-10-defective response to the parasite itself, but the basis of such susceptibility remains unknown. Herein, we tested the susceptibility of mice inoculated with virulent and avirulent T. cruzi to staphylococcal enterotoxins (SE), potent inducers of inflammatory cytokine secretion. Mice infected with T. cruzi CL-strain or inoculated with the avirulent clone CL-14, a clone that does not induce disease or polyclonal lymphocyte activation, succumb suddenly to low doses of staphylococcal enterotoxin B (SEB), but not to staphylococcal enterotoxin A (SEA). High plasma levels of TNF, IFN-gamma, and liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found in these mice, indicating lethal toxic shock. Sensitization to shock required inoculation of live avirulent trypomastigotes and a time interval before challenge with SEB. We found no prior skewing of T cell receptor (TCR) Vbeta-repertoire in CL-14-inoculated mice that could be responsible for sensitization. Splenocytes from CL-14-inoculated mice proliferated more under anti-Vbeta8 than anti-TCRbeta stimulation when compared with normal mice, but were suppressed to SEB stimulation. Both SEB and anti-Vbeta8 antibodies stimulated splenocytes from T. cruzi-inoculated mice to secrete higher levels of inflammatory cytokines than normal controls. Taken together, our results show that T. cruzi inoculation can sensitize mice to lethal SEB-induced shock even in the absence of tissue damage, polyclonal lymphocyte activation, or previously increased levels of inflammatory cytokines, and they suggest that altered reactivity of Vbeta8 lymphocytes may be involved in the phenomenon.
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PMID:Trypanosoma cruzi sensitizes mice to fulminant SEB-induced shock: overrelease of inflammatory cytokines and independence of Chagas' disease or TCR Vbeta-usage. 1257 26

Aflatoxin B(1) (AFB(1)) is a fungal toxin that causes both acute hepatotoxicity and liver carcinoma in exposed humans and animals. Previous studies have shown that exposure of rats to nontoxic doses of bacterial lipopolysaccharide (LPS) augments AFB(1) acute hepatotoxicity, resulting in enhanced injury to hepatic parenchymal cells and bile ducts. At larger doses, LPS causes damage to sinusoidal endothelial cells (SECs) and activation of the coagulation system. Accordingly, we tested the hypothesis that treatment of rats with AFB(1) and LPS damages SECs and activates the coagulation system, which is critical for potentiation of AFB(1) hepatotoxicity by LPS. Male, Sprague-Dawley rats were given 1 mg/kg AFB(1) (ip), then 4 hours later 7.4 x 10(6) EU/kg LPS was administered (iv). A time-dependent injury to SECs and parenchymal cells was observed in AFB(1)/LPS-cotreated animals that became significant by 12 h, as estimated by increases in plasma hyaluronic acid (HA) and alanine aminotransferase (ALT) activities, respectively. Immunohistochemical analysis revealed that endothelial cell immunostaining was decreased in both centrilobular and periportal regions after AFB(1)/LPS treatment. Immunohistochemical evidence of fibrin deposition was found in both centrilobular and periportal regions by 12 h, but these deposits persisted only in periportal regions by 24 h. Administration of the anticoagulant heparin to AFB(1)/LPS-cotreated animals markedly attenuated increases in markers of hepatic parenchymal cell injury but provided only minimal amelioration of bile duct injury. These results suggest that AFB(1)/LPS coexposure results in SEC injury and activation of the coagulation system, and that the coagulation system is required for the development of hepatic parenchymal cell injury but not bile duct injury in this model.
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PMID:Augmentation of aflatoxin B1 hepatotoxicity by endotoxin: involvement of endothelium and the coagulation system. 1260 47

Despite the fact that septic shock is characterized by a decrease in systemic vascular resistance, the main cause of death is due to multiple organ failure. The organ dysfunction is usually attributed to cell death caused by overproduction of free radicals derived from inflammation. In the host infected by endotoxin (lipopolysaccharide, LPS), the expression and release of proinflammatory tumor necrosis factor-alpha (TNF-alpha) rapidly increases, and the formation of free radicals (e.g., superoxide anion [O2*-] and nitric oxide [NO*] in the present study) are inevitably overproduced. In this study, we present evidence that overall treatment of LPS rats with terbutaline, a beta2-adrenoceptor agonist, attenuates the delayed hypotension and ameliorates the tachycardia. Overproduction of TNF-alpha and NO* (produced by inducible NO synthase [iNOS] examined by Western blot analysis in the lung and the liver) is inhibited by treatment of LPS rats with terbutaline. In addition, treatment of endotoxemic rats with terbutaline also reduces the O2*- levels in the lung and the liver. Terbutaline also improves the liver (assessed by aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin/globulin) and kidney (assessed by creatinine and uric acid) dysfunction induced by endotoxin. These findings suggest that the amelioration of circulatory failure and organs injury by terbutaline is associated with its suppression in TNF-alpha, O2*- and NO (via iNOS) production in animals with endotoxic shock.
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PMID:Inhibition by terbutaline of nitric oxide and superoxide anion levels of endotoxin-induced organs injury in the anesthetized rat. 1263 May 30

Drug idiosyncrasy is an adverse event of unknown etiology that occurs in a small fraction of people taking a drug. Some idiosyncratic drug reactions may occur from episodic decreases in the threshold for drug hepatotoxicity. Previous studies in rats have shown that modest underlying inflammation triggered by bacterial lipopolysaccharide (LPS) can decrease the threshold for xenobiotic hepatotoxicity. The histamine-2 (H2)-receptor antagonist ranitidine (RAN) causes idiosyncratic reactions in people, with liver as a usual target. We tested the hypothesis that RAN could be rendered hepatotoxic in animals undergoing a modest inflammatory response. Male rats were treated with a nonhepatotoxic dose of LPS (44 x 10(6) endotoxin units/kg i.v.) or its vehicle and then 2 h later with a nonhepatotoxic dose of RAN (30 mg/kg i.v.) or its vehicle. Liver injury was evident only in animals treated with both RAN and LPS as estimated by increases in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase activities within 6 h after RAN administration. LPS/RAN cotreatment resulted in midzonal liver lesions characterized by acute necrosuppurative hepatitis. Famotidine (FAM) is an H2-antagonist for which the propensity for idiosyncratic reactions is far less than RAN. Rats given LPS and FAM at a dose pharmacologically equipotent to that of RAN did not develop liver injury. In vitro, RAN sensitized hepatocytes to killing by cytotoxic products from activated neutrophils, whereas FAM lacked this ability. The results indicate that a response resembling human RAN idiosyncrasy can be reproduced in animals by RAN exposure during modest inflammation.
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PMID:Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. 1289 37

The aim of this study was to evaluate the effect of insulin-like growth factor-I (IGF-I) on lethality and liver function in experimental acute liver failure. Intravenous co-administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) to rats induced high mortality and marked increases in aspartate aminotransferase, alanine aminotransferase and total bilirubin, associated with hypoglycemia. One-hour pre-treatment with IGF-I significantly prevented lethality and blood parameter changes in rats. Histological examination also showed that massive hepatocellular hemorrhagic necrosis and inflammatory cell infiltration around peri-central veins in the liver, as well as shrinkage of cytoplasm and nuclear condensation, were induced by GalN plus LPS injection, but these all were improved by pre-treatment with IGF-I. Overall, this study showed that IGF-I treatment resulted in effective prevention of lethal acute liver failure in rats induced by GalN plus LPS, suggesting a therapeutic potential for IGF-I in the prevention of acute liver failure.
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PMID:Insulin-like growth factor-I prevents lethal acute liver failure induced by D-galactosamine and lipopolysaccharide in rats. 1292 83

We postulated that a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; EDA), would attenuate inflammatory cytokine and chemokine expression in the liver after lipopolysaccharide (LPS) challenge through its antioxidant effect. Rats were administered EDA (0.3, 1.5, 3.0, 6.0, and 12.0 mg/kg) or the same volume of saline intravenously just after LPS (10 mg/kg) injection and then was continued intermittently every 2 h (five administrations in total). Survival was assessed for the next 24 h. In separate experiments, rats were sacrificed at 60 min, 90 min, 6 h, and 9 h after LPS injection. Serum and liver sections were collected for further analysis. Survival was improved by EDA in a dose-dependent manner up to 3 mg/kg, and maximum effects were observed at a dose of 3 mg/kg. After LPS injection, alanine aminotransferase levels increased significantly to about 1,250 IU/l in the vehicle-treated group, whereas values were blunted by about 80% by EDA. Furthermore, increases in 4-hydroxynonenal-modified proteins were also blunted in the liver by EDA. Moreover, mRNA expressions of macrophage infiltrating protein-2, monocyte chemoattractant protein (MCP)-1 and MCP-5 were attenuated by EDA. As a result, increases in the number of infiltrating inflammatory cells and mRNA expression of inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 were significantly blunted in the liver by EDA. This reduction was accompanied by a significant reduction of their serum levels. In conclusion, EDA prevented liver injury by both inhibition of recruitments of inflammatory cells and expression of inflammatory cytokine levels in the liver.
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PMID:Edaravone, a novel free radical scavenger, prevents liver injury and mortality in rats administered endotoxin. 1295 92

In normal mice, plasma histamine levels were 29.4+/-10.1 pmol/ml. When 0.1 microg of lipopolysaccharide (LPS) was intravenously injected into Propionibacterium acnes (P. acnes)-primed ICR mice, histamine levels increased remarkably to 61.2+/-15.9 pmol/ml (p<0.001). An increase was also observed in liver tissues. Oral administration of histidine at 200 mg/kg once daily for 5 d before intravenous LPS injection increased the plasma alanine aminotransferase (ALT) activity to 2936.5+/-356.3 IU/l, a significant change compared with the controls (2244.8+/-425.5 IU/l, p<0.05). The 24 h survival rate after LPS injection was 72.7% in the mice treated with 50 mg/kg of ranitidine, in contrast with 50% in the control group although the treatment did not significantly decrease the plasma ALT activity. On the other hand, 50 mg/kg of pyrilamine significantly reduced plasma ALT activity (p<0.001). The results suggested that histamine levels are related to hepatic damage in the P. acnes plus LPS induction of liver injury.
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PMID:Influence of histamine in a liver injury model induced by Propionibacterium acnes and lipopolysaccharide. 1451 42

Effects of endotoxemia-induced NO production on rat liver and hepatocytes in culture were investigated. Rats were treated intraperitoneally with saline, lipopolysaccharide (LPS, 10 mg/kg), L-nitroarginine methyl ester (L-NAME)+LPS, aminoguanidine (AG)+LPS, FK 506+LPS, S-nitroso-N-acetyl penicillamine (SNAP)+L-NAME+LPS and SNAP+FK 506+LPS. Mortality, hepatocyte viability and liver function test were estimated. Liver morphology was observed by light and electron microscopy. Hepatocyte cultures were treated with LPS, cytokine mixture (CM) with or without FK 506, L-NAME or AG. Hepatocyte function and inducible form of NOS (iNOS) expression were evaluated. Twenty-four hours after treatments with saline, LPS, L-NAME+LPS, AG+LPS, FK 506+LPS, SNAP+L-NAME+LPS and SNAP+FK 506+LPS, rat mortalities were 0%, 10%, 48%, 8%, 20%, 38% and 0%, and hepatocyte viabilities were 93+/-3%, 80+/-3%, 52+/-8%, 88+/-1%, 70+/-3%, 80+/-4% and 82+/-3%, respectively. AG+LPS or L-NAME+LPS administration was followed by excessive vacuolization of hepatocytes with lesions in the intermediary lobule zone characterized by features of secondary necrosis as a continuation of apoptotic processes. SNAP+L-NAME+LPS resulted in a well-preserved structure of central vein lobules with sparse signs of apoptosis. Treatment with LPS or CM increased iNOS expression in hepatocyte culture, which was inhibited by L-NAME, FK 506 or AG. AG reduced LPS-induced rise in alanine aminotransferase leakage. LPS-induced NO exerts cytoprotective effects in vivo, while LPS-induced NO in vitro appears to be toxic. Based on the data of this report, one cannot use in vitro results to predict in vivo responses to LPS-induced NO production. The pharmacological modulation of iNOS expression or NO production in vivo or in vitro, therefore, by the development of specific NO donors or inhibitors is promising for improvement of hepatocyte functions under the two experimental conditions, respectively.
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PMID:Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects. 1455 88


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