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)

Chronic alcohol consumption has been associated with increased migration of neutrophils into liver that could contribute to the development of alcoholic liver disease. Mild endotoxemia may be at least partially responsible for this condition since endotoxemia was shown to be present in virtually all chronic alcoholics. This study examines the release of superoxide anion and chemotactic activity by Kupffer cells and sequestered hepatic as well as blood neutrophils during chronic alcohol intoxication (16 weeks) alone, and following an intravenous injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) 3 hr before cell isolation. Chronic ethanol consumption increased the total neutrophil yield per liver, but did not change the f-met-leu-phe induced chemotactic activity by both hepatic and blood neutrophils. However, the combined insults of ethanol and LPS increased the chemotactic activity and superoxide anion generation by these cells. Plasma from ethanol-fed rats was highly chemotactic to syngeneic normal rat neutrophils. This activity was increased 1.75-fold in the plasma obtained from chronic ethanol plus endotoxin-injected rats. The chemotactic activity of Kupffer cells was not significantly modulated during ethanol intoxication plus endotoxin treatment. The f-met-leu-phe-induced superoxide anion release by Kupffer cells was enhanced after LPS treatment. Chronic ethanol consumption did not induce any effect on this parameter. These observations suggest that functional alterations in neutrophils during chronic ethanol intoxication may contribute to hepatic injury.
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PMID:Modulation of f-met-leu-phe induced chemotactic activity and superoxide production by neutrophils during chronic ethanol intoxication. 132 6

Ethanol intoxication has been shown to suppress selected functions of the immune system, thereby compromising host defenses against bacterial infections. Because the macrophage secretory protein, tumor necrosis factor (TNF), plays a central role in the inflammatory cascade, the effect of acute and chronic alcoholism on lipopolysaccharide (LPS)-induced TNF activity was studied. Saline or ethanol was given intraperitoneally to normal or chronic alcoholic rats followed 30 min later by either intravenous or intratracheal LPS. Intravenous LPS caused a substantial increase in serum TNF at 90 min in both normal and chronic alcoholic rats. In marked contrast, peak serum TNF levels were significantly suppressed in normal and chronic alcoholic rats given an acute injection of ethanol. When LPS was instilled intratracheally into normal rats, high levels of TNF appeared in the bronchoalveolar lavage fluid. Similar levels of TNF were found in chronic alcoholic rats after intratracheal LPS. However, acute ethanol intoxication significantly inhibited LPS-induced TNF in bronchoalveolar lavage fluid. In a similar manner, acute ethanol intoxication, but not chronic alcohol consumption, markedly inhibited both systemic and intrapulmonary polymorphonuclear leukocyte aggregation in response to either intravenous or intratracheal LPS. Alcohol-induced inhibition of TNF is a potential mechanism of the antiinflammatory effects of ethanol.
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PMID:The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response. 266 25

We performed a liver biopsy and measured plasma concentrations of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), and spontaneous and lipopolysaccharide-stimulated in vitro monocyte production of IL-1 beta and TNF-alpha in 19 obese and 17 age-matched, normal-weight alcoholics admitted for treatment of their alcoholism. Nine healthy normal-weight alcoholics had cirrhosis in their liver biopsy (Fisher's exact test: P=0.031). A histologic score (derived from the sum of fat, necrosis, fibrosis, and inflammation in the biopsy) correlated with body mass index and the percentage body fat, calculated by using the sum of four skinfold-thickness measures. Plasma concentrations and spontaneous in vitro monocyte production of IL-1 beta and TNF-alpha were below detection limits. No significant differences were observed between normal-weight and obese alcoholics with or without cirrhosis and normal control subjects in lipopolysaccharide-stimulated monocyte production of IL-1 beta (6.5 +/- 0.8, 10.1 +/- 2.7, 7.9 +/- 1.6, and 5.28 +/- 4.24 micrograms/L, respectively) or TNF-alpha (2.8 +/- 0.4, 3.7 +/- 1.0, 3.0 +/- 0.44, and 1.97 +/- 1.01 micrograms/L, respectively). However, a positive correlation was found between IL-1 beta production and body mass index (r=0.333, P=0.047), percentage body fat (r=0.412, p=0.013), abdominal circumference (r=0.416, P=0.012), and total histologic score (r=0.331, P=0.049). A multiple-regression model accepted abdominal circumference as the only independent predictor of IL-1 beta production. TNF-alpha did not correlate with any of the above-mentioned indexes. We conclude that obese alcoholics have a higher frequency of histologic liver damage and that IL- 1 beta production by stimulated monocytes is related to abdominal fat accumulation.
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PMID:Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. 860 95

This study examines the effects of chronic alcohol consumption on thymic apoptosis with or without pretreatment with E. coli lipopolysaccharide (LPS). Apoptotic cell death of thymocytes was monitored by DNA fragments in gel electrophoresis and the appearance of apoptotic cells by flow cytometry. Changes in mitochondrial membrane potential (MMP), as indicated by 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] uptake, and hydrogen peroxide (H2O2) production as indicated by oxidation of 2',7'-dichlorofluresin diacetate (DCFH-DA), were used to assess altered mitochondrial function. Glutathione levels were also determined to obtain information concerning alterations in the antioxidant potential in the cells. Male Sprague-Dawley rats, fed a nutritionally adequate liquid diet for 8-9 weeks, were divided in four groups: 1) saline-injected, diet controls; 2) LPS-injected, diet controls; 3) saline-injected, alcohol-consuming; and 4) LPS-injected, alcohol-consuming animals. LPS (0.5 mg/kg in 4 ml saline) or saline (4 ml) was continuously infused i.v. for 12 h before the experiments. The results showed that the weight and cell numbers of thymus from the chronic alcoholic rats were significantly less than values found in diet controls. Administration of LPS aggravated thymic apoptosis, as indicated by the presence of significant DNA fragments in gel electrophoresis and increased rate of apoptotic cells in flow cytometry. The alcohol-induced apoptotic changes were also accompanied by decreased MMP, indicating impaired mitochondrial function. Although H2O2 production by the total thymocyte population did not show marked changes among the experimental groups, the subpopulation of thymocytes exhibiting low H2O2 production was increased markedly in the LPS-treated groups. Ethanol consumption or LPS treatment decreased total glutathione concentration in the thymocytes. In summary, 1) chronic administration of alcohol induces atrophy of the thymus gland; 2) apoptosis is a major factor in thymic atrophy under these conditions; 3) chronic alcohol consumption is accompanied by alterations in mitochondrial function of the thymocytes, as indicated by decreased MMP and an increase in the low H2O2-producing cell subpopulation; 4) chronic alcohol abuse may impair intracellular defense mechanisms as reflected by the depletion of the intracellular antioxidant, glutathione; and 5) administration of LPS further enhances thymic apoptosis in chronic alcohol-consuming rats, suggesting that the dual insults of infection and chronic alcoholism exaggerate in vivo immunosuppression.
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PMID:Alcohol-induced thymocyte apoptosis is accompanied by impaired mitochondrial function. 901 30

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

It is well recognized that alcohol passes through the placenta and affects the fetal immune system. The underlying mechanism accounting for immune suppression is not clear. Cytokines are recognized as the principal mediators of a variety of immunologic and pathophysiologic events. The study was designed to examine whether alcohol use during pregnancy affects cytokine synthesis and secretion in the human fetus. Fetal (cord blood) and mother's blood were used for the study. Studies were conducted in vivo and in vitro. For the in vivo study, cytokine levels were measured in cord blood in mothers who drank moderate to heavy (chronic) amounts of alcohol during pregnancy. For the in vitro study, cord blood was obtained from mothers who were drug-free throughout pregnancy. Lymphocytes were isolated and stimulated with lipopolysaccharide (LPS; Escherichia coli, 26:B6). The capacity of lymphocytes to synthesize cytokines was examined in the presence of 20, 50, and 100 mM alcohol. Among the cytokines examined were the tumor necrosis factor (TNF alpha) and interleukins (IL-1 alpha and beta and IL-6). The selection of cytokines was based on their presumptive role in the pathophysiology of alcoholism. Cytokines were measured by using a specific immunoassay. When data obtained from moderate alcohol users were compared with those obtained from nonusers, no significant differences were observed in any of the cytokines examined (p>0.05). In chronic alcohol users, levels for all cytokines increased significantly (p<0.001) in both the fetus and the mother. Among the cytokines, IL-1beta, IL-6, and TNFalpha were the predominant cytokines affected by chronic use of alcohol during pregnancy. The order of stimulation was IL-6, IL-1 beta, TNFalpha, and IL-1 alpha in descending order. In the in vitro study, alcohol blunted LPS stimulation of cytokines, and the alcohol-induced decrease in cytokine synthesis was proportional to the level of alcohol in the media, suggesting a direct effect of alcohol on cytokine synthesis. In general, the blunting effect of alcohol on LPS stimulation was more prominent in the fetus compared with that in mother. We conclude that chronic alcohol use during pregnancy stimulated the fetal cytokine synthesis and secretion, and IL-1beta, IL-6, and TNF alpha were the predominant cytokines affected by alcohol. The in vitro data suggest a direct effect of alcohol on cytokine synthesis.
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PMID:Alcohol modulates cytokine secretion and synthesis in human fetus: an in vivo and in vitro study. 1109 Oct 23

The central nervous system is particularly susceptible to alcohol effects and toxicity. Glial cells constitute the most common cell type in the brain and play critical roles in normal brain function and during infection and injury. Astrocytes in particular seem to be important targets for alcohol neurotoxicity during both development and in adulthood. To gain more insight into alcohol-mediated effects on astrocytes at the molecular level, gene expression in rat C6 glial cells was studied in the presence or absence of ethanol. The differential display of mRNA technique was used to screen the expressed genes in ethanol-treated rat C6 cells before and after treatment with lipopolysaccharide (LPS) combined with phorbol-12-myristate-13-acetate (PMA), conditions that mimic an infectious inflammatory state and cause immunologic activation. The present data show that fibronectin appeared as a major gene whose expression is increased in C6 cells by LPS plus PMA stimulation and decreased by chronic ethanol exposure, both in mRNA and protein levels. Fibronectin is a dimeric glycoprotein found in the extracellular matrix of most tissues, in the blood, and on cell surfaces and is involved in many cellular processes. These results show that chronic exposure to ethanol is associated with changes in astrocyte properties during immunologic activation that reduce fibronectin expression. The discovery of astrocyte fibronectin expression as a potential regulated target for chronic alcohol abuse may be useful in understanding, preventing, and treating some brain disorders associated with alcohol abuse and alcoholism.
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PMID:Differential fibronectin expression in activated C6 glial cells treated with ethanol. 1109 67

Proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada; organized and co-chaired by Patricia E. Molina and Manuela Neuman. The presentations were (1) Mechanisms of alcohol-induced cell injury by Craig McClain; (2) Cytokines in alcoholic steatohepatitis and non-alcoholic steatohepatitis by Manuela Neuman; (3) Combination of alcohol and hepatitis C virus and liver injury by Dominique Valla; (4) Chronic ethanol exposure potentiates lipopolysaccharide liver injury, despite inhibiting Jun N-Terminal kinase and caspase 3 activation by Anna Mae Diehl; (5) Glutathione homeostasis in alcoholism: Role in alveolar epithelial barrier and lung injury by David M. Guidot; (6) Metabolic and inflammatory contribution of alcohol to trauma-induced tissue injury by Patricia E. Molina; (7) Growth factor and protein synthesis dysregulation: Role in alcoholic myopathy by Charles H. Lang.
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PMID:Molecular pathology and clinical aspects of alcohol-induced tissue injury. 1182 62

Chronic alcohol abuse increases the risk of developing acute lung injury approximately threefold in septic patients, and ethanol ingestion for 6 wk in rats impairs alveolar epithelial barrier function both in vitro and in vivo. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a trophic factor for the alveolar epithelium, and a recent phase II clinical study suggests that GM-CSF therapy decreases sepsis-mediated lung injury. Therefore, we hypothesized that GM-CSF treatment could improve ethanol-mediated defects in the alveolar epithelium during acute stresses such as endotoxemia. In this study, we determined that recombinant rat GM-CSF improved lung liquid clearance (as reflected by lung tissue wet:dry ratios) in ethanol-fed rats anesthetized and then challenged with 2 ml of saline via a tracheostomy tube. Furthermore, GM-CSF treatment improved lung liquid clearance and decreased epithelial protein leak in both control-fed and ethanol-fed rats after 6 h of endotoxemia induced by Salmonella typhimurium lipopolysaccharide given intraperitoneally, but with the greater net effect seen in the ethanol-fed rats. Our previous studies indicate that chronic ethanol ingestion decreases lung liquid clearance by increasing intercellular permeability. Consistent with this, GM-CSF treatment in vitro decreased permeability of alveolar epithelial monolayers derived from both control-fed and ethanol-fed rats. As in the endotoxemia model in vivo, the effect of GM-CSF was most dramatic in the ethanol group. Together, these results indicate that GM-CSF treatment has previously unrecognized effects in promoting alveolar epithelial barrier integrity and that these salutary effects may be particularly relevant in the setting of chronic alcohol abuse.
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PMID:Granulocyte/macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung. 1450 66

Endotoxin (lipopolysaccharide, LPS)-induced tumor necrosis factor-alpha (TNF-alpha) release from Kupffer cells is critically involved in the pathogenesis of alcohol-induced liver injury. We recently reported that inhibition of alcohol-induced plasma endotoxin elevation contributes to the protective action of zinc against alcoholic hepatotoxicity. The present study was undertaken to determine whether zinc interferes with the endotoxin-TNF-alpha signaling pathway, and possible mechanism(s) by which zinc modulates the endotoxin-TNF-alpha signaling. Administration of LPS to metallothionein (MT)-knockout (MT-KO) mice and 129/Sv wild-type (WT) controls at 4 mg/kg induced hepatic TNF-alpha elevation at 1.5 hours, followed by liver injury at 3 hours. Zinc pretreatment (two doses at 5 mg/kg) attenuated TNF-alpha production and liver injury in both MT-KO and WT mice, indicating a MT-independent action of zinc. Immunohistochemical detection of the phosphorylation of I-kappaB and nuclear factor (NF)-kappaB in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-kappaB activation in the Kupffer cells. Fluorescent microscopy of superoxide by dihydroethidine and of zinc ions by Zinquin in the liver of MT-KO mice showed that zinc pretreatment increased the intracellular labile zinc ions and inhibited LPS-induced superoxide generation. These results demonstrate that zinc inhibits LPS-induced hepatic TNF-alpha production through abrogation of oxidative stress-sensitive NF-kappaB pathway, and the action of zinc is independent of MT. Thus, zinc may be beneficial in the treatment of LPS-induced liver injuries, such as sepsis and alcoholism.
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PMID:Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. 1511 1


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