title: Contribution of the sympathetic hormone epinephrine to the sensitizing effect of ethanol on LPS-induced liver damage in mice.
abstract: It is well known that ethanol preexposure sensitizes the liver to LPS hepatotoxicity. The mechanisms by which ethanol enhances LPS-induced liver injury are not completely elucidated but are known to involve an enhanced inflammatory response. Ethanol exposure also increases the metabolic rate of the liver, and this effect of ethanol on liver is mediated, at least in part, by the sympathetic hormone, epinephrine. However, whether or not the sympathetic nervous system also contributes to the sensitizing effect of ethanol preexposure on LPS-induced liver damage has not been determined. The purpose of this study was therefore to test the hypotheses that 1) epinephrine preexposure enhances LPS-induced liver damage (comparable to that of ethanol preexposure) and that 2) the sympathetic nervous system contributes to the sensitizing effect of ethanol. Accordingly, male C57BL/6J mice were administered epinephrine for 5 days (2 mg/kg per day) via osmotic pumps or bolus ethanol for 3 days (6 g/kg per day) by gavage. Twenty-four hours later, mice were injected with LPS (10 mg/kg ip). Both epinephrine and ethanol preexposure exacerbated LPS-induced liver damage and inflammation. Concomitant administration of propranolol with ethanol significantly attenuated the sensitizing effect of ethanol on LPS-induced liver damage. These data support the hypothesis that the sympathetic nervous system contributes, at least in part, to the mechanism of the sensitizing effect of ethanol. These results also suggest that sympathetic tone may contribute to the initiation and progression of alcoholic liver disease.
authors.affiliation: Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: von Montfort
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
authors.forename: Luping
authors.initials: L
authors.lastname: Guo
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kaiser
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000431:Ethanol; D011433:Propranolol; D009195:Peroxidase; D000637:Transaminases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D002265:Carboxylic Ester Hydrolases; C019873:chloroacetate esterase; D004837:Epinephrine