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Relationship between sudden death syndrome of alcohol drinker and the role of bone marrow-derived stellate cells in alcohol-induced fatty liver

饮酒者猝死综合征与骨髓源性星状细胞在酒精性脂肪肝中作用的关系

基本信息

批准号：
20590680
负责人：
FUJIMIYA Tatsuya
金额：
$ 3.08万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Chronic alcohol consumption activates hepatic stellate cells (HSCs) and cause fatty degeneration in the liver. However, the origin of HSCs and the mechanism of fatty changes of the liver have not been fully elucidated. Here, we examined the roles of bone marrow-derived cells (BMDCs) in a mouse model with chronic alcohol consumption. We performed bone marrow transplantation from transgenic mice expressing green fluorescence protein (GFP) to female wild-type and ROSA mice and treated them with ethanol (EtOH) for 8 or 16 wk. GFP-expressing BMDCs increased in the liver with EtOH treatment in a time-dependent manner. In response to excess alcohol consumption, ~68% of the BMDCs became activated HSCs in that they expressed α-smooth muscle actin. Meanwhile, ~67% and ~66% of these BMDCs expressed Tnf-α and transforming growth factor (Tgf)-β1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-α and Tgf-β1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of β-gal/GFP and further supported by the Y-chromosome staining. The EtOH withdrawal normalized most of the abnormalities produced by chronic alcohol consumption. These results indicate that excess alcohol consumption stimulates both the homing of HSCs from the bone marrow and their profibrogenic cytokine production in a mouse model of alcohol-induced fatty liver disease.

长期饮酒会激活肝星状细胞（HSC）并导致肝脏脂肪变性。然而，肝星状细胞的起源和肝脏脂肪化的机制尚未完全阐明。在这里，我们研究了骨髓源性细胞（BMDCs）在慢性饮酒小鼠模型中的作用。我们从表达绿色荧光蛋白（GFP）的转基因小鼠向雌性野生型和ROSA小鼠进行骨髓移植，并用乙醇（EtOH）处理8或16周。表达GFP的BMDCs在肝脏中以时间依赖性的方式随着EtOH处理而增加。作为对过量饮酒的反应，约68%的BMDC成为活化的HSC，因为它们表达α-平滑肌肌动蛋白。RT-PCR结果显示，TNF-α和TGF-β 1在BMDCs中的表达率分别为67%和66%。β-gal/GFP双染证实BMDC与非实质细胞之间发生细胞融合，但BMDC与肝细胞之间几乎不发生细胞融合，Y染色体染色进一步证实了这一点。乙醇戒断使慢性饮酒产生的大部分异常正常化。这些结果表明，在酒精诱导的脂肪肝小鼠模型中，过量饮酒刺激骨髓HSC的归巢及其促纤维化细胞因子的产生。