A long graft survival of the steatotic liver after the inhibition of chemokine production and the remodeling of the altered extracellular matrix

抑制趋化因子产生和改变的细胞外基质重塑后脂肪变性肝脏的长期移植存活

• 批准号: 13670577
• 负责人: YAMADA Shinwa
• 金额: $ 2.24万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670577/
• 关键词: liver transplantation; fatty liver; ischemia-reperfusion; neutrophil chemokine; extracellular matrix; mitochondrial function; hepatic macrophage

The aim of this research project is to approach an effective strategy against the hepatic ischemia-reperfusion (IR) injury. The IR injury plays a crucial role in the primary non-function after hepatic transplantation using a steatotic graft.Our group has previously found that in the alcoholic fatty liver a neutrophil-chemokine contributes to hepatocyte necrosis which is associated with apoptosis after IR (Hepatology 32:278, 2000). Additionally, in this model in vivo, the suppression of hepatic macrophage activity completely inhibits the production of the chemokine and protects the liver from the extensive necrosis after IR.When we evaluated the above results, we fortunately found that a firm attachment of the chemokine with extracellular matrices was prerequisite for the neutrophil infiltration and inflammatory necrosis in the liver. In an in vivo study using primary hepatocytes, we had an evidence for a contribution of the altered mitochondrial function to hepatic apoptosis in fatty liver.Thus, we raise three possible strategies for graft survival of the fatty livers as follows; 1. An inhibition of the chemokine production; 2. A remodeling of the extracellular matrix in the damaged liver; 3. An improvement of the mitochondrial function of the liver cells.

本研究旨在探讨肝缺血再灌注损伤的有效防治策略。IR损伤在使用脂肪变性移植物的肝移植后的原发性无功能中起关键作用。我们的小组先前发现，在酒精性脂肪肝中，嗜中性粒细胞趋化因子导致肝细胞坏死，这与IR后的细胞凋亡有关（Hepatology 32：278，2000）。此外，在该模型中，在体内，抑制肝巨噬细胞活性完全抑制了生产的趋化因子，并保护肝脏广泛坏死后IR。当我们评估上述结果，我们幸运地发现，一个坚定的附着的趋化因子与细胞外基质是必要的中性粒细胞浸润和炎性坏死的肝脏。在原代肝细胞的体内研究中，我们发现脂肪肝中线粒体功能的改变对肝细胞凋亡有贡献，因此我们提出了三种可能的脂肪肝移植存活策略：1.抑制趋化因子的产生; 2.受损肝脏中细胞外基质的重塑; 3.改善肝细胞的线粒体功能。

项目成果

Yamada S.: "Alcoholic fatty liver differentially induces a neutrophil-chemokine and hepatic necrosis after ischemia-reperfusion in rat."Hepatology. 32. 278-288 (2000)

Yamada S.：“酒精性脂肪肝在大鼠缺血再灌注后差异性地诱导中性粒细胞趋化因子和肝坏死。”肝病学。

Okabe K.: "CD45RC^-γσ^+ T-cell infiltration is associated with immunologic unresponsiveness induced by prior donor-specific blood transfusion in rat hepatic allografts"Hepatology. 33. 877-886 (2001)

Okabe K.：“CD45RC^-γσ^+ T 细胞浸润与大鼠同种异体肝移植物中先前供体特异性输血引起的免疫无反应有关”Hepatology 33. 877-886 (2001)。

Zhang.JL: "A serine protease inhibitor, N-d-tosyl-L-lysine chloromethyl ketone. prolongs rat hepatic allograft survival"J Surg Res. 96. 296-303 (2001)

张建良：“一种丝氨酸蛋白酶抑制剂，N-d-甲苯磺酰基-L-赖氨酸氯甲基酮。可延长大鼠同种异体肝移植物的存活”J Surg Res。

Okabe K: "CD45RC-γδ + T-cell infiltration is associated with immunologic unresponsiveness induced by prior donor-specific blood transfusion in rat hepatic allografts"Hepatology. 33(4). 877-886 (2001)

Okabe K：“CD45RC-γδ + T 细胞浸润与大鼠同种异体肝移植物中先前供者特异性输血引起的免疫无反应有关”Hepatology 33(4) (2001)。

Yamada S: "Alcoholic fatty liver differentially induces a neutrophil-chemokine and hepatic necrosis after ischemia-reperfusion in rat"Hepatology. 32. 278-288 (2000)

Yamada S：“酒精性脂肪肝在大鼠缺血再灌注后差异性地诱导中性粒细胞趋化因子和肝坏死”肝病学。