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)

E-Selectin is an endothelial adhesion molecule involved in binding and targeting of neutrophils. Little is known of its expression in the brain. We examined the expression of E-selectin on cultured human brain microvascular endothelial cells (HBMEC). There was no basal expression of E-selectin on HBMEC but with I1-1b, tumor necrosis factor (TNF), or lipopolysaccharide (LPS) stimulation there was surface expression at 4 h. The expression was quantitatively less than on cultured human umbilical vein endothelial cells (HUVEC). The cytokine-induced upregulation was partially inhibited with the glutathione donor, N-acetylcysteine (NAC), the free radical scavenger, dimethylthiourea (DMTU; 15 mM) and dexamethasone (1 microM). Allopurinol (100 microM) had no effect. TNF activated nuclear factor kappa B (NF kappa B) in HBMEC. This activation could be attenuated by prior treatment with NAC and dexamethasone. Thiol donors and corticosteroids could play a role in inhibiting potentially deleterious neutrophil-endothelial interactions in inflammatory conditions involving the brain.
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PMID:E-selectin expression on human brain microvascular endothelial cells. 884 7

Generation of reactive oxygen species (ROS) is a common event in the pathogenesis of acute lung injury. Endothelial cells may be both a target and a source of the ROS. Exposure of bovine pulmonary endothelial cells (BPAEC) to lipopolysaccharide (LPS) has been shown to result in intracellular generation of both ROS and the antioxidant enzyme, mangano superoxide dismutase (MnSOD). The present study investigates whether alterations in intracellular oxidant state affect LPS-stimulated cytotoxicity and induction of MnSOD mRNA. BPAEC were pretreated with either the free radical scavenger, dimethylsulfoxide (DMSO), the xanthine oxidase inhibitor, allopurinol, or N-acetylcysteine (a cysteine derivate capable of increasing glutathione stores) prior to exposure to LPS (0.1 microgram/ml) for either 4, 8 or 18 hours. We found that pretreatment of BPAEC with DMSO blocked both LPS-induced cytotoxicity and induction of the MnSOD gene. Nuclear run-off experiments demonstrated that LPS-stimulated induction of the MnSOD mRNA occurred at the transcriptional level and that DMSO blocked this event. Pretreatment with allopurinol also prevented the cytotoxicity associated with LPS but, in contrast to DMSO, did not alter induction of MnSOD mRNA. N-acetylcysteine did not affect the LPS-stimulated cytotoxicity but resulted in an early and transient reduction in induction of the MnSOD gene. We conclude that LPS stimulates generation of intracellular ROS that regulate induction of the MnSOD gene at the transcriptional level further, we conclude that LPS-stimulated cytotoxicity involves both the xanthine oxidase pathway and perhaps intracellular generation of hydroxyl radicals. The difference in the protective effect between DMSO, NAC and allopurinol suggest that upregulation of the MnSOD gene does not contribute to LPS-induced cytotoxicity.
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PMID:Effect of antioxidants on lipopolysaccharide-stimulated induction of mangano superoxide dismutase mRNA in bovine pulmonary artery endothelial cells. 890

1. The aim of this study was to assess whether or not vasoactive nitric oxide (NO) stores exist within vascular tissue after lipopolysaccharide (LPS)-treatment. 2. Rat thoracic aortic rings (for contraction experiments) or whole thoracic aortae (for electron paramagnetic resonance (e.p.r.) spectroscopy) were incubated for 18 h at 37 degrees C in the absence (control) or in the presence of LPS (10 micrograms ml-1), with or without L-arginine (L-Arg, 1 mM), the substrate of NO synthase (NOS) or N omega-nitro-L-arginine methyl ester (L-NAME, 1 mM), an inhibitor of NOS. 3. Incubation of rat aortic rings with LPS and L-Arg resulted in a significant decrease of the maximum contractile response to noradrenaline (NA, 3 microM). Addition of L-NAME (3 mM) enhanced contraction towards control values. After precontraction with NA and L-NAME, addition of N-acetyl-L-cysteine (NAC, 0.1 to 10 mM) evoked a concentration-dependent relaxation in rings incubated with LPS and L-Arg, but not in control rings, rings incubated with LPS in the absence of L-Arg or rings incubated with LPS in the presence of L-Arg and L-NAME. Removal of the endothelium did not significantly modify the relaxation induced by NAC. Methylene blue (3 microM), an inhibitor of the activation of guanylyl cyclase by NO, completely abolished the relaxing effect of NAC. 4. The presence of protein-bound dinitrosyl non-haem iron complexes (DNIC) was detected by e.p.r. spectroscopy in aortae incubated with LPS and L-Arg, but not in control aortae. Furthermore in LPS-treated aortae, addition of NAC (20 mM) gave rise to the appearance of an e.p.r. signal characteristic of low molecular weight DNIC. 5. These results provide evidence that, within vascular tissue, NO generated from L-Arg by LPS-induced NOS activity can be stored as protein-bound DNIC in non-endothelial cells. Upon addition of NAC, low molecular weight DNIC are released from these storage sites and induce vascular relaxation probably through guanylyl cyclase activation.
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PMID:Evidence for N-acetylcysteine-sensitive nitric oxide storage as dinitrosyl-iron complexes in lipopolysaccharide-treated rat aorta. 893 35

Lipopolysaccharide induced apoptosis and necrosis of human umbilical venous endothelial cells in a time-dependent manner. Lipopolysaccharide (1 microgram/ml)-induced apoptosis was maximal after 18 h, whereas necrosis occurred after prolonged incubation for more than 24 h. The increase in apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor. Furthermore, lipopolysaccharide treatment upregulated Bax, which heterodimerizes with and thereby inhibits Bcl-2. Both the antioxidant N-acetylcysteine and the combination of vitamin C and E (10 microM) completely inhibited lipopolysaccharide-induced apoptosis, whereas vitamin C or E alone was less effective. The reduction of lipopolysaccharide-induced apoptosis by vitamin C and E was paralleled by an increase in Bcl-2 and a decrease in Bax protein levels. Thus, vitamin C and E seem to interfere with the Bcl-2 family of apoptosis regulators in human umbilical venous endothelial cells.
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PMID:Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax. 899 28

Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.
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PMID:Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells. 900 92

N-Acetylcysteine (NAC) is a pro-glutathione drug used to treat chronic lung disorders and because of its anti-AIDS virus activity in vitro, has been proposed for AIDS therapy. The effect of NAC on mitogen-activated-lymphocyte blastogenesis in C57B1/6 mouse splenocytes and ability of NAC to protect lymphocytes against mitogen-induced cytotoxicity was examined in vitro. NAC increased splenocyte proliferation in the presence of optimal and suboptimal concentrations of concanavalin A (Con A) and lipopolysaccharide (LPS). Stimulatory and costimulatory effects of NAC on mitogen-induced responses were also evident. The dose-response relationship describing the effects of NAC on lymphocyte proliferation with Con A-induced responses were enhanced in a dose-dependent manner, whereas the corresponding LPS-induced responses increased to a maximum level followed by decline in responses at higher concentrations of NAC. When splenocytes were incubated with inhibitory supraoptimal concentrations of Con A (10 microg/ml) or LPS (150 microg/ml), NAC partially enhanced the Con A-induced response but completely prevented the inhibitory effect of supraoptimal concentrations of LPS on splenocyte blastogenesis. Optimal and supraoptimal concentrations of Con A caused activation-induced cell death in the splenocytes whereas comparable concentrations of LPS did not produce a similar effect. Splenocyte cell death produced by the optimal mitogenic concentrations of Con A was completely blocked by the addition of NAC to cultures. Immunomodulation and protective effects of NAC were observed in mitogen-activated lymphocytes in vitro.
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PMID:Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro. 902 May 24

Nitric oxide (NO) plays an important role in the cytotoxic activity of macrophages towards tumour cells and microbial pathogens. We investigated whether alteration of intracellular thiol levels modulates the cytotoxic effects of different NO donors and lipopolysaccharide-induced NO in the murine macrophage cell lin J774A.1. The NO-releasing compound S-nitroso-N-acetylpenicillamine caused a significant concentration-dependent loss of viability of the macrophages only under glucose-limiting conditions. The cytotoxic effect of S-nitroso-N-acetylpenicillamine was prevented by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO). Depletion of total glutathione before exposure to S-nitroso-N-acetylpenicillamine further decrease cell viability while pretreatment with N-acetylcysteine was protective. Comparing equimolar concentrations of various NO donors including S-nitrosoglutathione, S-nitrosocysteine and 3-morpholino-sydnonimine hydrochloride, cytotoxicity appeared to be related to the relative stability of the test compound. Both the order of stability and the order of potency for cell killing was S-nitrosoglutathione > S-nitroso-N-acetylpenicillamine > S-nitrosocysteine = 3-morpholino-sydnonimine hydrochloride. Stimulation of the macrophages with lipopolysaccharide and interferon-gamma resulted in dose-dependent cell injury and NO production. Glutathione depletion prior to stimulation considerably decreased macrophage viability as well as the NO production. In contrast to the protective effect on S-nitroso-N-acetylpenicillamine-mediated injury, pretreatment with N-acetylcysteine did not influence the lipopolysaccharide-mediated cytotoxicity. These results demonstrate that (a) reduction in the availability of glucose and intracellular glutathione renders the cells more vulnerable to the cytotoxic effects of NO donors, (b) in this model of cytotoxicity, long-lived NO donors were more cytotoxic than short-lived NO donors, (c) the differential effects of N-acetylcysteine on S-nitroso-N-acetylpenicillamine-induced and bacterial lipopolysaccharide-mediated cytotoxicity support the existence of other toxic species different from NO or NO-related compounds with a potent cytotoxic activity in immunostimulated macrophages, and (d) other non-protein thiols like N-acetylcysteine may substitute for glutathione as a major component of the cellular antioxidant defense system.
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PMID:The protective role of thiols against nitric oxide-mediated cytotoxicity in murine macrophage J774 cells. 908 90

Agonist signals delivered through cell surface Fas induce apoptosis. However, the apoptotic program can be modulated by signals from the environment, and in particular, by signals delivered through adhesion molecules. Because neutrophil functional activity in inflammation is contingent on cell survival, and because circulating neutrophils normally die rapidly through a constitutively expressed apoptotic program, we evaluated Fas-mediated apoptosis in resting and inflammatory human neutrophils. We show that normal neutrophils respond to Fas engagement with accelerated rates of apoptosis, but cross-linking of beta2 integrins or priming with bacterial lipopolysaccharide (LPS) prevents this increase. Adhesion molecule cross-linking results in increased intracellular glutathione (GSH). Augmentation of intracellular GSH with exogenous GSH or N-acetylcysteine is sufficient to reduce the Fas-triggered increase in apoptotic rates. Prevention of the activation induced GSH increase by buthionine sulfoximine, a cell permeable inhibitor of GSH biosynthesis, restored Fas responsiveness in activated neutrophils, an effect that could be blocked with exogenous GSH. Taken together, these data show that Fas-induced signaling for neutrophil apoptosis is blocked in a redox sensitive manner by costimulatory signals delivered through beta2 integrins or activation by LPS, and provide a biologic explanation for sustained neutrophil survival in the inflammatory environment.
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PMID:Augmented intracellular glutathione inhibits Fas-triggered apoptosis of activated human neutrophils. 916 61

Reactive oxygen intermediates such as hydrogen peroxide play an important role in the pathophysiology of acute lung injury, not only as terminal effectors, but also as second messengers in signal transduction; we studied their role in adhesion molecule expression and cytokine production. N-acetylcysteine, an antioxidant, decreased the TNF alpha-induced expression of intercellular adhesion molecule-1 on cultured epithelial cells from human bronchi (BEAS-2A), and inhibited IL-8 production by those cells. In vivo, N-acetylcysteine attenuated the sequestration of polymorphonuclear neutrophils in rat lungs caused by intratracheal lipopolysaccharide. These findings suggest that adhesion molecule expression and cytokine production in the lung are mediated by the production of reactive oxygen intermediates. Because adhesion molecules and cytokines play a crucial role in the pathophysiology of neutrophil-mediated acute lung injury, the inhibition of adhesion molecule expression and cytokine production with anti-oxidants such as N-acetylcysteine may be a useful therapeutic strategy.
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PMID:[Role of oxidants in adhesion molecule expression and cytokine production]. 921 1

This study demonstrates that exposure of primary rat hepatocytes or mouse BNL Cl.2 liver cell line to ethanol causes potentiation of tumor necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-stimulated nitrite accumulation. The potentiating effect of ethanol (0.02-2 mM) appears to be time and concentration dependent. Consistent with nitrite production, the amount of inducible nitric oxide synthase (iNOS) mRNA and protein is initially detected at 4 hr after treatment with TNF-alpha/LPS/ethanol. Furthermore, the capability of these agents to induce iNOS expression is primarily determined by the age of the animals. Interestingly, antioxidants such as N-acetylcysteine (NAC), ascorbic acid, or alpha-tocopherol fail to inhibit TNF-alpha/LPS/ethanol-induced increase in iNOS protein. In addition, several kinase inhibitors, including staurosporine, genistein, curcumin, and herbimycin A, were used to examine their effects on this induction. Among them, only herbimycin A potently inhibits the accumulation of nitrite and iNOS expression. In vitro kinase assay verifies that Src tyrosine kinase is rapidly activated with a peak at 1 hr after treatment with TNF-alpha/LPS/ethanol but is not activated by these agents singly or doubly. As expected, herbimycin A can block Src kinase activity under circumstances in which iNOS expression is also inhibited. However, our results do not indicate that the mitogen-activated protein kinase is activated after treatment with these agents. The study results suggest that Src tyrosine kinase plays a prominent role in transducing the signal to induce iNOS expression in hepatocytes treated with TNF-alpha/LPS/ethanol.
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PMID:The role of Src kinase in the potentiation by ethanol of cytokine- and endotoxin-mediated nitric oxide synthase expression in rat hepatocytes. 928 16


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