von Montfort Claudia, Beier Juliane I, Guo Luping, Kaiser J Phillip, Arteel Gavin E
Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1227-34. doi: 10.1152/ajpgi.00050.2008. Epub 2008 Mar 6.
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.
众所周知，乙醇预先暴露会使肝脏对脂多糖（LPS）的肝毒性敏感。乙醇增强LPS诱导的肝损伤的机制尚未完全阐明，但已知涉及炎症反应增强。乙醇暴露还会增加肝脏的代谢率，乙醇对肝脏的这种作用至少部分是由交感激素肾上腺素介导的。然而，交感神经系统是否也参与乙醇预先暴露对LPS诱导的肝损伤的致敏作用尚未确定。因此，本研究的目的是检验以下假设：1）肾上腺素预先暴露会增强LPS诱导的肝损伤（与乙醇预先暴露的情况相当），以及2）交感神经系统参与乙醇的致敏作用。相应地，通过渗透泵给雄性C57BL/6J小鼠连续5天注射肾上腺素（每天2 mg/kg），或通过灌胃给小鼠连续3天注射大剂量乙醇（每天6 g/kg）。24小时后，给小鼠腹腔注射LPS（10 mg/kg）。肾上腺素和乙醇预先暴露均加剧了LPS诱导的肝损伤和炎症。普萘洛尔与乙醇同时给药可显著减弱乙醇对LPS诱导的肝损伤的致敏作用。这些数据支持了交感神经系统至少部分参与乙醇致敏作用机制的假设。这些结果还表明，交感神经张力可能参与酒精性肝病的发生和发展。
