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Chronic Ethanol Ingestion (chronic + ethanol_ingestion)
Selected AbstractsImpaired Terminal Differentiation of Pulmonary Macrophages in a Guinea Pig Model of Chronic Ethanol IngestionALCOHOLISM, Issue 10 2009Sheena D. Brown Background:, Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function. Methods:, Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation. Results: Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by ,60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus aureus. Alveolar macrophages from ethanol-fed animals had ,80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor , (GM-CSFR-,), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S -adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-,. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation. Conclusion:, This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion. [source] N -Acetylcysteine Improves Group B Streptococcus Clearance in a Rat Model of Chronic Ethanol IngestionALCOHOLISM, Issue 7 2009Sonja M. Tang Background:, Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40,60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N -acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. Methods:, After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. Results:, Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. Conclusions:, These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection. [source] Effect of Chronic Ethanol Ingestion and Gender on Heart Left Ventricular p53 Gene ExpressionALCOHOLISM, Issue 8 2005Heidi Jänkälä Background: Although the beneficial effects of mild to moderate ethanol consumption have been implied with respect to heart, alcohol abuse has proven to be a major cause of nonischemic cardiomyopathy in Western society. However, the biochemical and molecular mechanisms, which mediate the pathologic cardiac effects of ethanol, remain largely unknown. The aim of the present study was to explore the effects of chronic ethanol exposure on cardiac apoptosis and expression of some of the genes associated with cardiac remodeling in vivo. Methods: Alcohol-avoiding Alko Non Alcohol rats of both sexes were used. The ethanol-exposed rats (females, n= 6; males, n= 8) were given 12% (v/v) ethanol as the only available fluid from age of three to 24 months of age. The control rats (females, n= 7; males, n= 5) had only water available. At the end of the experiment, free walls of left ventricles of hearts were immediately frozen. Cytosolic DNA fragmentation, reflecting apoptosis, was measured using a commercial quantitative sandwich enzyme-linked immunosorbent assay kit, and mRNA levels were analyzed using a quantitative reverse transcriptase,polymerase chain reaction method. Results: Ethanol treatment for two years increased cardiac left ventricular p53 mRNA levels significantly (p= 0.014) compared with control rats. The gene expression was also dependent on the gender (p= 0.001), so that male rats had higher left ventricular p53 mRNA levels than female rats. However, no significant differences in levels of DNA fragmentation were detected. Conclusions: Chronic ethanol exposure in vivo induces rat cardiac left ventricular p53 gene expression. Expression of p53 is also gender-dependent, males having higher p53 mRNA levels than females. This preliminary finding suggests a role for the p53 gene in ethanol-induced cardiac remodeling. The results might also have some relevance for the known gender-dependent differences in propensity to cardiovascular disease. [source] Cardiac Overexpression of Alcohol Dehydrogenase Exacerbates Cardiac Contractile Dysfunction, Lipid Peroxidation, and Protein Damage After Chronic Ethanol IngestionALCOHOLISM, Issue 7 2003Kadon K. Hintz Background: Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac-specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake. Methods: ADH transgenic and wild-type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined. Results: FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non-ethanol-consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol-fed mice than FVB ethanol-fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re-sequestration at low pace frequency. Myocytes from ethanol-fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol-induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene. Conclusion: These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake. [source] Effect of Chronic Ethanol Ingestion on Alveolar Type II Cell: Glutathione and Inflammatory Mediator-Induced ApoptosisALCOHOLISM, Issue 7 2001Lou Ann S. Brown Background : In septic patients, chronic alcohol abuse increases the incidence of the acute respiratory distress syndrome, a syndrome that requires alveolar type II cell proliferation and differentiation for repair of the damaged alveolar epithelium. We previously showed in a rat model that chronic ethanol ingestion decreased the antioxidant glutathione (GSH) in type II cells and exacerbated endotoxin-mediated acute lung injury. We hypothesized that this GSH depletion by ethanol, particularly mitochondrial GSH, predisposed type II cells to inflammatory mediator-induced apoptosis. Methods: Adult male rats were fed the Lieber-DeCarli diet for 2, 6, or 16 weeks. Alveolar type II cells were then isolated and treated with hydrogen peroxide or TNF-,. The effect on glutathione (cytosolic and mitochondrial), apoptotic events, and necrosis were determined. In other studies, rats were fed ethanol for 6 weeks and were treated with endotoxin and apoptosis of type II cells determined by the TUNEL method. Results: Chronic ethanol ingestion alone resulted in a progressive decrease in mitochondrial GSH and a progressive increase in the basal apoptosis and necrosis rate (p, 0.05). Furthermore, there was a progressive increase in the sensitivity of the cells to H2O2 or TNF-, induced cytochrome c release, caspase 3 activation, apoptosis, and necrosis (p, 0.05). Finally, there was a 2-fold increase in apoptotic type II cells in vivo when chronic ethanol ingestion was superimposed on endotoxemia. Conclusions: These results suggested that chronic ethanol ingestion resulted in a progressive depletion of mitochondrial GSH and sensitization of type II cells to inflammatory mediator-induced apoptosis and necrosis. These effects may be particularly relevant during acute stress when proliferation and differentiation of these cells are critical to repair of the damaged alveolar epithelium and may have important ramifications for the treatment of acute respiratory distress syndrome in patients with a history of alcohol abuse. [source] Impaired Terminal Differentiation of Pulmonary Macrophages in a Guinea Pig Model of Chronic Ethanol IngestionALCOHOLISM, Issue 10 2009Sheena D. Brown Background:, Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function. Methods:, Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation. Results: Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by ,60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus aureus. Alveolar macrophages from ethanol-fed animals had ,80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor , (GM-CSFR-,), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S -adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-,. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation. Conclusion:, This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion. [source] Inhibition of bacterial translocation by chronic ethanol consumption in the rat,APMIS, Issue 12 2001VALERIA BENDER BRAULIO Chronic ethanol ingestion has been associated with small intestine morphological changes, disrupted host mucosal defenses and bacterial overgrowth. Since bacterial translocation (BT) may result from such alterations, we have investigated the potential effect of chronic ethanol consumption on BT. For this purpose, male Wistar rats were fed a liquid diet containing 5% v/v ethanol for 4 weeks (EG, n=16), and a pair-fed group received equal daily amounts of calories in a similar diet without ethanol (PFG, n=16). On experimental day 29, distal ileum ligature and small intestine inoculation of a tetracycline-resistant E. coli strain (Tc®E. coli R6) followed by duodenal ligature was performed. After 1 or 5 h post inoculation, mesenteric lymph nodes, liver, spleen and kidney were excised. Unexpectedly, rats of the EG presented markedly less BT to the mesenteric lymph nodes (p<0.001) and to the other organs examined compared to rats of the PFG. This BT inhibition was observed at 1 and 5 h after bacterial inoculation, and may be attributed exclusively to chronic ethanol ingestion. Since alcoholism is well known to decrease host immunity, these results suggest that other factors, independent of the immune function, may be involved in the BT inhibition observed in this study. [source] Impaired Terminal Differentiation of Pulmonary Macrophages in a Guinea Pig Model of Chronic Ethanol IngestionALCOHOLISM, Issue 10 2009Sheena D. Brown Background:, Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function. Methods:, Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation. Results: Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by ,60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus aureus. Alveolar macrophages from ethanol-fed animals had ,80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor , (GM-CSFR-,), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S -adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-,. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation. Conclusion:, This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion. [source] N -Acetylcysteine Improves Group B Streptococcus Clearance in a Rat Model of Chronic Ethanol IngestionALCOHOLISM, Issue 7 2009Sonja M. Tang Background:, Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40,60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N -acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. Methods:, After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. Results:, Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. Conclusions:, These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection. [source] Chronic Ethanol Feeding Alters Hepatocyte Memory Which is not Altered by Acute FeedingALCOHOLISM, Issue 4 2009F. Bardag-Gorce Background:, Gene expression changes in the liver after acute binge drinking may differ from the changes seen in chronic ethanol feeding in the rat. The changes in gene expression after chronic ethanol feeding may sensitize the liver to alcohol-induced liver damage, which is not seen after acute binge drinking. Methods:, To test this hypothesis, gene microarray analysis was performed on the livers of rats (n = 3) fed an acute binge dose of ethanol (6 g/kg body wt) and killed at 3 and 12 hours after ethanol by gavage. The gene microarrays were compared with those made on the liver of rats from a previous study, in which the rats were fed ethanol by intragastric tube for 1 month (36% of calories derived from ethanol). Results:, Microarray analysis data varied between the acute and chronic models in several important respects. Growth factors increased mainly in the chronic alcohol fed rat. Changes in enzymes involved in oxidative stress were noted only with chronic ethanol feeding. Gene expression of fat metabolism was increased only with chronic ethanol feeding. Most importantly, epigenetic related enzymes and acetylation and methylation of histones changed only after chronic ethanol feeding. Conclusions:, The results support the concept that chronic ethanol ingestion induces altered gene expression as a result of changes in epigenetic mechanisms, where acetylation and methylation of histones were altered. [source] Inhibition of the Activity of Excitatory Amino Acid Transporter 4 Expressed in Xenopus Oocytes After Chronic Exposure to EthanolALCOHOLISM, Issue 7 2008Seung-Yeon Yoo Background:, The extracellular glutamate concentration is tightly controlled by excitatory amino acid transporters (EAATs). EAAT4 is the predominant EAAT in the cerebellar Purkinje cells. Purkinje cells play a critical role in motor coordination and may be an important target for ethanol to cause motor impairments. We designed this study to determine the effects of chronic ethanol exposure on the activity of EAAT4 and evaluate the involvement of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) in these effects. Methods:, EAAT4 was expressed in Xenopus oocytes following injection of EAAT4 mRNA. Oocytes were incubated with ethanol-containing solution for 24 to 96 hours. Membrane currents induced by l -aspartate were recorded using 2-electrode voltage clamps. Responses were quantified by integration of the current trace and reported in microCoulombs (,C). Results:, Ethanol dose- and time-dependently reduced EAAT4 activity. EAAT4 activity after a 96-hour exposure was significantly decreased compared to the control values at all concentrations tested (10 to 100 mM). Ethanol (50 mM) significantly decreased the Vmax (2.2 ± 0.2 ,C for control vs. 1.6 ± 0.2 ,C for ethanol, n = 18, p < 0.05) of EAAT4 for l -aspartate. Preincubation of ethanol-treated (50 mM for 96 hours) oocytes with phorbol-12-myrisate-13-acetate (100 nM for 10 minutes) abolished the ethanol-induced decrease in EAAT4 activity. While staurosporine (2 ,M for 1 hour) or chelerythrine (100 ,M for 1 hour) significantly decreased EAAT4 activity, no difference was observed in EAAT4 activity among the staurosporine, ethanol, or ethanol plus staurosporine groups. Similarly, EAAT4 activity did not differ among the chelerythrine, ethanol, or ethanol plus chelerythrine groups. Pretreatment of the oocytes with wortmannin (1 ,M for 1 hour) also significantly decreased EAAT4 activity. However, no difference was observed in the wortmannin, ethanol, or ethanol plus wortmannin groups. Conclusions:, The results of this study suggest that chronic ethanol exposure decreases EAAT4 activity and that PKC and PI3K may be involved in these effects. These effects of ethanol on EAAT4 may cause an increase in peri-Purkinje cellular glutamate concentration, and may be involved in cerebellar dysfunction and motor impairment after chronic ethanol ingestion. [source] Effect of Chronic Ethanol Ingestion on Alveolar Type II Cell: Glutathione and Inflammatory Mediator-Induced ApoptosisALCOHOLISM, Issue 7 2001Lou Ann S. Brown Background : In septic patients, chronic alcohol abuse increases the incidence of the acute respiratory distress syndrome, a syndrome that requires alveolar type II cell proliferation and differentiation for repair of the damaged alveolar epithelium. We previously showed in a rat model that chronic ethanol ingestion decreased the antioxidant glutathione (GSH) in type II cells and exacerbated endotoxin-mediated acute lung injury. We hypothesized that this GSH depletion by ethanol, particularly mitochondrial GSH, predisposed type II cells to inflammatory mediator-induced apoptosis. Methods: Adult male rats were fed the Lieber-DeCarli diet for 2, 6, or 16 weeks. Alveolar type II cells were then isolated and treated with hydrogen peroxide or TNF-,. The effect on glutathione (cytosolic and mitochondrial), apoptotic events, and necrosis were determined. In other studies, rats were fed ethanol for 6 weeks and were treated with endotoxin and apoptosis of type II cells determined by the TUNEL method. Results: Chronic ethanol ingestion alone resulted in a progressive decrease in mitochondrial GSH and a progressive increase in the basal apoptosis and necrosis rate (p, 0.05). Furthermore, there was a progressive increase in the sensitivity of the cells to H2O2 or TNF-, induced cytochrome c release, caspase 3 activation, apoptosis, and necrosis (p, 0.05). Finally, there was a 2-fold increase in apoptotic type II cells in vivo when chronic ethanol ingestion was superimposed on endotoxemia. Conclusions: These results suggested that chronic ethanol ingestion resulted in a progressive depletion of mitochondrial GSH and sensitization of type II cells to inflammatory mediator-induced apoptosis and necrosis. These effects may be particularly relevant during acute stress when proliferation and differentiation of these cells are critical to repair of the damaged alveolar epithelium and may have important ramifications for the treatment of acute respiratory distress syndrome in patients with a history of alcohol abuse. [source] Inhibition of bacterial translocation by chronic ethanol consumption in the rat,APMIS, Issue 12 2001VALERIA BENDER BRAULIO Chronic ethanol ingestion has been associated with small intestine morphological changes, disrupted host mucosal defenses and bacterial overgrowth. Since bacterial translocation (BT) may result from such alterations, we have investigated the potential effect of chronic ethanol consumption on BT. For this purpose, male Wistar rats were fed a liquid diet containing 5% v/v ethanol for 4 weeks (EG, n=16), and a pair-fed group received equal daily amounts of calories in a similar diet without ethanol (PFG, n=16). On experimental day 29, distal ileum ligature and small intestine inoculation of a tetracycline-resistant E. coli strain (Tc®E. coli R6) followed by duodenal ligature was performed. After 1 or 5 h post inoculation, mesenteric lymph nodes, liver, spleen and kidney were excised. Unexpectedly, rats of the EG presented markedly less BT to the mesenteric lymph nodes (p<0.001) and to the other organs examined compared to rats of the PFG. This BT inhibition was observed at 1 and 5 h after bacterial inoculation, and may be attributed exclusively to chronic ethanol ingestion. Since alcoholism is well known to decrease host immunity, these results suggest that other factors, independent of the immune function, may be involved in the BT inhibition observed in this study. [source] | ||||||||||