Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice
Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice
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DOI：
10.1016/j.taap.2007.08.020
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发表时间：
2008-01-15
影响因子：
3.8
通讯作者：
States, J. Christopher
中科院分区：
文献类型：
--
作者：
Arteel, Gavin E.;Guo, Luping;States, J. Christopher
在美国，通过饮用水接触砷是一个严重的健康问题。虽然研究已经确定砷单独作为肝脏疾病的独立风险因素，但损害该器官所需的砷浓度通常高于美国供水中的砷浓度。本研究的目的是检验砷（亚肝毒性剂量）也可能使肝脏对第二种肝毒素敏感的假设。为了验证这一假设，在小鼠中测定了慢性砷暴露对急性脂多糖（LPS）引起的肝损伤的影响。雄性C57 B1/6 J小鼠（4-6周）暴露于砷（49 ppm，以饮用水中的亚砷酸钠计）。暴露7个月后，将动物用LPS（10 mg/kg i. p.）24 h后处死。砷单独引起没有明显的肝毒性，血浆酶和组织学测定。相反，砷暴露显着增强LPS引起的肝损伤，增加坏死性炎症灶的数量和大小。砷的这种作用与氧化应激指数的增加（4-HNE加合物，GSH和蛋氨酸池的消耗）相结合。凋亡（TUNEL）肝细胞的数量在LPS和砷/LPS组中相似。与此相反，砷预暴露钝化的增加增殖（PCNA）的肝细胞引起的LPS，这种变化之间的平衡细胞死亡和增殖加上一个强大的损失，在砷/LPS相比，单独的LPS组的肝脏重量。砷引起的LPS后的增殖损伤也与细胞周期进展的关键介质（p27，p21，CDK 6和Cyclin D1）表达的改变相关联。总之，这些结果表明，砷，在剂量本身并不明显肝毒性，显着增强LPS诱导的肝损伤。这些结果进一步表明，饮用水中的砷水平可能是慢性肝病发展的风险因素。(c)2007爱思唯尔公司All rights reserved.
Exposure to arsenic via drinking water is a serious health concern in the US. Whereas studies have identified arsenic alone as an independent risk factor for liver disease, concentrations of arsenic required to damage this organ are generally higher than found in the US water supply. The purpose of the current study was to test the hypothesis that arsenic (at subhepatotoxic doses) may also sensitize the liver to a second hepatotoxin. To test this hypothesis, the effect of chronic exposure to arsenic on liver damage caused by acute lipopolysaccharide (LPS) was determined in mice. Male C57B1/6J mice (4-6 weeks) were exposed to arsenic (49 ppm as sodium arsenite in drinking water). After 7 months of exposure, animals were injected with LPS (10 mg/kg i.p.) and sacrificed 24 h later. Arsenic alone caused no overt hepatotoxicity, as determined by plasma enzymes and histology. In contrast, arsenic exposure dramatically enhanced liver damage caused by LPS, increasing the number and size of necroinflammatory foci. This effect of arsenic was coupled with increases in indices of oxidative stress (4-HNE adducts, depletion of GSH and methionine pools). The number of apoptotic (TUNEL) hepatocytes was similar in the LPS and arsenic/LPS groups. In contrast, arsenic pre-exposure blunted the increase in proliferating (PCNA) hepatocytes caused by LPS; this change in the balance between cell death and proliferation was coupled with a robust loss of liver weight in the arsenic/LPS compared to the LPS alone group. The impairment of proliferation after LPS caused by arsenic was also coupled with alterations in the expression of key mediators of cell cycle progression (p27, p21, CDK6 and Cyclin D1). Taken together, these results suggest that arsenic, at doses that are not overtly hepatotoxic per se, significantly enhances LPS-induced liver injury. These results further suggest that arsenic levels in the drinking water may be a risk modifier for the development of chronic liver diseases. (c) 2007 Elsevier Inc. All rights reserved.