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)

The continuous intragastric in vivo enteral feeding model in the rat developed by Tsukamoto and French has been very useful; however, it requires surgical expertise. Recently, we found that Kupffer cells isolated from rats treated only once with ethanol were sensitized to endotoxin 24 hours later. Accordingly, these experiments were designed to determine if a new, simple animal model of ethanol hepatotoxicity could be developed based on Kupffer cell sensitization. Female Wistar rats were given ethanol (5 g/kg body weight) once every 24 hours intragastrically. Livers were stained with hematoxylin-eosin to assess steatosis, inflammation, and necrosis, and tissue triglycerides, serum transaminases, and plasma endotoxin were measured. Kupffer cells were isolated 0 to 24 hours after one intragastric dose of ethanol daily, and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, while tumor necrosis factor alpha (TNF-alpha) was measured by enzyme-linked immunosorbent assay. CD14 was evaluated by Western and Northern analysis. Ethanol caused steatosis, necrosis, and inflammation in only a few weeks, and after 8 weeks, serum aspartate transaminase (AST) levels were doubled. Values were similar to levels achieved in the enteral feeding model. Triglycerides were also increased significantly by ethanol as expected, and endotoxin levels were increased to 70 to 80 pg/mL. This latter increase was prevented (<20 pg/mL) by antibiotics implicating endotoxin. In isolated Kupffer cells from untreated control rats, [Ca2+]i increased to 82 +/- 7 nmol/L after addition of lipopolysaccharide (LPS) (100 ng/mL), and levels were elevated about twofold by ethanol given 24 hours earlier (174 +/- 15 nmol/L). In addition, TNF-alpha production by Kupffer cells was increased fourfold in cells isolated from rats treated with ethanol 24 hours earlier. Sterilization of the gut with antibiotics blocked all effects of ethanol on [Ca2+]i and TNF-alpha release completely. Moreover, 4 weeks after ethanol, CD14 in Kupffer cells was elevated about twofold. A new, simple chronic model of ethanol hepatotoxicity has been developed here based on sensitization of Kupffer cells to endotoxin.
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PMID:Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells. 1034 8

Hepatic macrophages are sensitized to alcohol in 24 h due to increases in the endotoxin receptor, CD14; however, desensitization to lipopolysaccharide (LPS), which occurred earlier, could not be explained by changes in CD14. Therefore, the purpose of this work was to attempt to understand factors responsible for ethanol-induced desensitization to LPS in hepatic macrophages. Rats were given ethanol (5 g/kg body wt) intragastrically, and hepatic macrophages were isolated 2 h later. After addition of endotoxin, intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured using fura 2 and tumor necrosis factor (TNF)-alpha was measured by ELISA. Ethanol given 2 h before injection of LPS totally prevented liver injury and blunted LPS-induced increases in [Ca(2+)](i) and TNF-alpha in hepatic macrophages. Furthermore, the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate and acute ethanol treatment both activated PKC and largely prevented the influx of [Ca(2+)](i) caused by LPS. Sterilization of the gut with antibiotics completely blocked all effects of ethanol on [Ca(2+)](i) and TNF-alpha release. Thus ethanol-induced desensitization of hepatic macrophages correlates with gut-derived endotoxin after ethanol and involves the effect of PKC on voltage-dependent Ca(2+) channels.
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PMID:Desensitization to LPS after ethanol involves the effect of endotoxin on voltage-dependent calcium channels. 1060 Aug 23

Pulmonary infections are a significant cause of morbidity and mortality in patients with alcohol abuse and human immunodeficiency virus (HIV) infection, two immunocompromising conditions that frequently coexist. This study examined the separate and combined effects of in vivo lentiviral infection and in vitro alcohol exposure on alveolar macrophage (AM) production of tumor necrosis factor- alpha (TNF-alpha), a proinflammatory cytokine that is critical to normal pulmonary host defense. AMs, recovered by bronchoalveolar lavage (BAL) from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques, at the asymptomatic and terminal stages of infection, were cultured in ethanol 2 h prior to stimulation with lipopolysaccharide (LPS). Median TNF-alpha concentrations were measured 15 h later. Spontaneous TNF-alpha production was similar in all groups examined. LPS increased TNF-alpha protein production similarly in SIV(-) (2, 381 +/- 359 pg/ml) and SIV(+) animals at the terminal stage of infection (2,019 +/- 507 pg/ml). In contrast, cells from SIV(+) asymptomatic animals had a depressed response (763 +/- 304 pg/ml). Ethanol (100 mM) suppressed the LPS-induced AM TNF-alpha response by approximately 50% in both SIV(-) and (+) animals. Ethanol-induced suppression of the TNF-alpha response occurred at a post-transcriptional level. These data suggest that ethanol-induced suppression of the pulmonary TNF-alpha response may further increase the susceptibility to and severity of secondary infectious complications in HIV-infected hosts.
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PMID:In vitro ethanol suppresses alveolar macrophage TNF-alpha during simian immunodeficiency virus infection. 1061 10

Both chronic and acute ethanol exposure have been shown to be cytotoxic and also to disrupt normal cell function or responses in a variety of cell types. Macrophage function has specifically been shown to be disrupted by chronic ethanol exposure by mechanisms that have not been elucidated. It is known that exposure of macrophages to lipopolysaccharide (LPS) from gram-negative bacteria will decrease the number of cells. Since increased exposure to endotoxin is often associated with chronic alcoholism, this may be one mechanism to account for loss of macrophages in alcoholic patients. The loss of macrophages, as a consequence of endotoxin treatment, appears to be linked to cell activation and, in particular, LPS-stimulated synthesis of nitric oxide which has been suggested to cause an increase in apoptosis. Ethanol also increases apoptosis in some cell types but, in general, ethanol inhibits activation of macrophages. Thus, the overall effect on cell numbers and cell proliferation elicited by treating macrophages concomitantly with ethanol and LPS depends on the balance between inhibiting LPS-mediated activation and the actions of ethanol. The interaction between ethanol and LPS was investigated in a macrophage cell line (RAW 264.7 cells) by measuring nitric oxide production and cell proliferation. A 24-h exposure to ethanol (100 mM) decreased [3H]-thymidine incorporation significantly. LPS treatment elicited a concentration-dependent decrease in [3H]-thymidine incorporation at LPS concentrations of 0.1 ng/ml to 1000 ng/ml and stimulated nitric oxide production at concentrations above 1 ng/ml. LPS-stimulated nitric oxide production was inhibited by ethanol (20 to 100 mM) and the nitric oxide synthesis inhibitor, N(G)Nitro-L-arginine methyl L-NAME) ester (100 and 500 microM). However, LPS-inhibited [3H]-thymidine incorporation was not be totally reversed by ethanol- or L-NAME-treatment. A direct correlation between nitric oxide production and inhibition of cell proliferation could not be demonstrated. However, it appears that ethanol and LPS do affect some common mechanism(s) in this cell line.
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PMID:Lipopolysaccharide-stimulated nitric oxide production and inhibition of cell proliferation is antagonized by ethanol in a clonal macrophage cell line. 1068 Jul 15

This work tests the hypotheses that Kupffer cells are a major source of CC-chemokines (MIP-1alpha, MCP-1, RANTES) during acute endotoxemia and that acute ethanol intoxication modulates Escherichia coli lipopolysaccharide (LPS, 1 mg/Kg, i.v.)-induced chemokine release in the rat. LPS stimulated the release of CC-chemokines into the circulation, hepatic sequestration of leukocytes and liver injury. LPS-induced serum chemokines peaked at 1-3 h and could not be detected at 24-h posttreatment. Splenectomy significantly suppressed LPS-induced RANTES release, but not MIP-1alpha and MCP-1. Kupffer cell depletion by gadolinium chloride or acute ethanol intoxication significantly attenuated LPS-induced CC-chemokine release and hepatic injury. Hepatic sequestration of leukocytes during endotoxemia was also suppressed by acute ethanol. LPS downregulated the expression of MIP-1alpha and MCP-1 mRNAs and upregulated RANTES mRNA in Kupffer cells at 3-h post endotoxin. The expression of mRNAs was further suppressed in ethanol plus the LPS-treated group. Ethanol also suppressed the LPS-mediated priming of Kupffer cells for enhanced CC-chemokine release in vitro. Ethanol alone significantly upregulated the expression of CC-chemokine mRNA, and primed the Kupffer cells for enhanced RANTES release. CC-chemokine release and mRNA expression in hepatic sinusoidal endothelial cells were not significantly altered by ethanol, except for MCP-1 release. These data show that acute ethanol may be beneficial in tissue injury during acute endotoxemia.
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PMID:Acute alcohol intoxication and gadolinium chloride attenuate endotoxin-induced release of CC chemokines in the rat. 1071 99

Ethanol may be detrimental to immune cells due to the generation of free radicals during detoxification. If this is true, then alcoholic beverages that contain antioxidants, like red wine, should be protective against immune cell damage. We investigated this by giving mice either a red muscadine wine (Vitis rotundifolia), a cabernet sauvignon (Vitis vinifera), ethanol (all at 6% alcohol) or water in the water bottles as the sole fluid for 8 wk. Plasma antioxidant capacity was measured with alphaalpha-diphenyl-beta-picrylhydrazyl and was more than doubled in the mice that consumed wine compared to control mice that consumed water or ethanol. Cytochrome P450-2E1 levels and glutathione-S-transferase activity were modified in such a way as to be interpreted as protective. An immune response was elicited by an intraperitoneal injection of lipopolysaccharide. Later (24 h), natural killer cells and T-lymphocytes derived from the circulation were quantitated in the leukocyte fraction by flow cytometry. Ethanol consumption, as ethanol, significantly suppressed baseline cell numbers relative to the other groups. However, the mice that consumed the same amount of alcohol as wine had baseline cell numbers not different from the water-consuming controls. The lymphocyte response to lipopolysaccharide challenge was inhibited in the mice that consumed ethanol, but was normal in those that consumed the same amount of alcohol in the form of wine. We conclude that there are phytochemicals acting as antioxidants and impacting on the detoxification pathway in the wine that offset the detrimental effects of ethanol on immunity.
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PMID:Wine modifies the effects of alcohol on immune cells of mice. 1080 3

In atherosclerosis and tumor initiation, inducible nitric oxide synthase (iNOS) has been implicated in the damage of vascular walls and DNA, respectively. Moderate consumption of red wine has been ascribed as a preventive for coronary heart disease; however, there has been much debate over whether the beneficial effect is from grape polyphenolic components or ethanol. We studied the interaction of grape compounds on nitric oxide (NO) production by macrophages, mediators of blood vessel damage in atherosclerosis. For the murine macrophage cell line RAW 264.7, stimulation with lipopolysaccharide and interferon-gamma led to expression of the iNOS gene and production of NO. The polyphenols quercetin and resveratrol at a micromolar range suppressed iNOS gene expression and NO production, as determined by reverse transcription-polymerase chain reaction and nitrite assay. The polyphenols were also found to be scavengers of NO in an acellular system using sodium nitroprusside under physiological conditions. Ethanol, at a moderate level, did not produce any appreciable level of reduction of iNOS or NO activity. However, its presence at 0.1 to 0.75% enhanced the effect of grape polyphenols concentration-dependently. Thus, the interaction between these components plays a significant role in the health effects of red wine, especially with respect to their effect on the NO pathway.
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PMID:Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. 1102 Apr 57

The effect of cytokines, lipopolysaccharide, and ethanol on inducible nitric-oxide synthase (iNOS) expression was studied in C6 glial cells. Maximal induced activity, measured by the accumulation of nitrite in culture medium, occurred following treatment with lipopolysaccharide and interferon-gamma. Each cytokine alone was ineffective, whereas an optimal combination of interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma was near maximal, indicating synergistic interactions. Other combinations caused submaximal activity. Ethanol is known to suppress iNOS expression in C6 cells induced by a phorbol ester plus lipopolysaccharide. The current work shows ethanol also suppresses cytokine-induced iNOS expression and reduces interleukin-1beta and tumor necrosis factor-alpha potency without affecting interferon-gamma potency. Ethanol-mediated reductions in cytokine-induced iNOS mRNA and immunoreactive protein levels suggested an effect on gene transcription. Therefore, C6 cells stably expressing 1846 and 526 base fragments of the rat iNOS gene promoter fused to a luciferase reporter gene were prepared and characterized and used to study the effect of ethanol on iNOS promoter activity. Promoter activity in stable transfected C6 cells was inhibited by ethanol exposure with a similar concentration dependence as observed for inhibition of nitrite production, indicating that iNOS inhibition by ethanol is transcriptional. Furthermore, ethanol inhibition of the 526 base fragment activity, which lacks interferon-gamma enhancement of lipopolysaccharide-induced luciferase activity, confirmed that interferon-gamma-responsive elements do not participate in acute ethanol-induced inhibition of rat iNOS gene transcription.
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PMID:Cytokine-induced iNOS expression in C6 glial cells: transcriptional inhibition by ethanol. 1145 39

Because neutropenia may aggravate infections in alcoholics, effects of ethanol on the generation of myeloid growth factors by human umbilical vein endothelial cells (HUVECs) and on interactions with neutrophils were examined in vitro. Exposure of HUVECs to ethanol (0.01%-1%) dose-dependently inhibited (by 12%-27%) the release of stem cell factor, granulocyte-macrophage and granulocyte colony-stimulating factors (CSFs), or interleukin (IL)-8, but not of macrophage CSF triggered by lipopolysaccharide (LPS) or IL-1. Ethanol also inhibited the LPS-induced increase in HUVECs to bind neutrophils by 28% (without affecting the expression of intracellular adhesion molecule-1 and E-selectin) and inhibited the translocation of the p65 subunit of NF-kappaB from the cytoplasm to the nucleus by 46%. Thus, exposure of HUVECs to ethanol inhibited the generation of cytokines important for myeloid cell development and reduced the adhesiveness of HUVECs for neutrophils: effects that are possibly linked to the reduced activation of NF-kappaB.
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PMID:Effects of ethanol on NF-kappaB activation, production of myeloid growth factors, and adhesive events in human endothelial cells. 1151 38

The effects of ethanol on inducible prostaglandin production in RAW macrophages were investigated. Indomethacin (1 microM) or cycloheximide (1 microM) abolished prostaglandin E2 (PGE2) production induced by lipopolysaccharide (LPS, 1 microg/ml). Ethanol at concentrations from 100 mM to 600 mM concentration-dependently inhibited inducible PGE2 production, while ethanol only at higher concentrations (400 mM or more) showed cytotoxity to the cells. Cyclooxygenase-2 (COX-2) activity, estimated by transformation of exogenous arachidonic acid into PGE2, was not affected by ethanol (100-400 mM). LPS-induced expression of COX-2 mRNA was inhibited by ethanol (50-400 mM). On the other hand, protein expression of COX-2 by LPS was significantly increased by ethanol (100-400 mM). Ethanol alone at concentrations up to 600 mM did not induce expression of COX-2 protein. In a medium containing arachidonic acid (1 microM), ethanol at a low concentration (100 mM) did not significantly affect LPS-induced PGE2 production. These results suggest that ethanol shows diverse effects on the pathway of inducible PGE2 production in macrophages. Finally, ethanol may suppress utilization of arachidonic acid, resulting in reduction of inducible PGE2 production. Further study is needed to elucidate the mechanism of dissociation of ethanol effects on protein and mRNA expression.
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PMID:Diverse effects of ethanol on the pathway of inducible prostaglandin E2 production in macrophages. 1178 98


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