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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590680/
• 关键词: アルコール; 大酒家; 突然死; 脂肪肝; アルコール性臓器障害; 骨髄幹細胞; 法医学; 伊東細胞; 細胞融合; アルコール; 大酒家; 突然死; 脂肪肝; アルコール性臓器障害; 骨髄幹細胞; 法医学; 伊東細胞; 細胞融合

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.

慢性酒精消耗会激活肝脏星状细胞（HSC），并在肝脏中引起脂肪变性。但是，HSC的起源和肝脏的脂肪变化机理尚未完全阐明。在这里，我们检查了骨髓衍生细胞（BMDC）在长期饮酒的小鼠模型中的作用。我们从表达绿色荧光蛋白（GFP）的转基因小鼠到雌性野生型和Rosa小鼠进行了骨髓移植，并用乙醇（ETOH）处理了8或16周。通过时间依赖性的方式，通过ETOH处理在肝脏中表达GFP的BMDC在肝脏中增加。为了响应过量的酒精消耗，约有68％的BMDC被激活的HSC，因为它们表达了α-平滑肌肌动蛋白。同时，这些BMDC中的约67％和〜66％分别表达了TNF-α和转化生长因子（TGF）-β1，分别通过RT-PCR中TNF-α和TGF-β1的过量mRNA表达进一步支持了活性。细胞融合发生在BMDC和非肾小管细胞之间，但几乎不发生BMDC和肝细胞之间，这是通过β-GAL/GFP的双重染色所证明的，并由Y染色体体染色进一步支持。 ETOH戒断使长期饮酒产生的大多数异常标准化。这些结果表明，超过酒精消耗会刺激骨髓中HSC的归巢及其在酒精诱导的脂肪肝病的小鼠模型中的纤维化细胞因子产生。