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Potentiation of Liver Function Recovery and Its Regeneration by the Modulation of Extracellular Matrix During the Early Phase after Liver Transplantation

肝移植术后早期细胞外基质调节促进肝功能恢复及其再生

基本信息

批准号：
10670523
负责人：
YAMADA Shinwa
金额：
$ 2.18万
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：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670523/
关键词：
Transplantation Fatty Liver Ischemia-Reperfusion Neutrophil NF-κB Chemokine Apoptosis Gender-Difference

项目摘要

1) Long-term ethanol consumption enhances an ability to produce cytokine-induced neutrophil chemoattractant (CINC) in the rat liver : Rats were pair-fed a liquid diet containing ethanol or dextrose for 6-8 wk. They were given lipopolysaccharide (LPS) and chemokine mRNA expression in the liver was evaluated. CINC mRNA expressions in the liver after 2 and 6 hr were significantly higher in the ethanol-fed group than the control. Female alcoholic rats showed higher level of CINC mRNA in the liver than the male rats 2 hr after LPS injection. It was shown that gonadectomy totally abolished the gender difference in CINC mRNA of the liver. We conclude that CINC induction may be responsible for alcoholic hepatitis, and that the difference in ability to produce CINC is a factor contributory to the gender-difference of alcoholic liver disease.2) Alcoholic fatty liver differentially induces CINC and hepatic necrosis after ischemia-reperfusion (I/R) : Next, we investigated a cascade of events from transcription factor activation to necrosis through cytokine-induction and apoptosis in fatty liver after I/R. Rats with alcoholic or non-alcoholic fatty liver were subjected to warm I/R and compared with control rats. Rats with alcoholic fatty liver developed severe hepatic necrosis after I/R, compared to rats with non-alcoholic fatty liver or control. Hepatic apoptosis increased in the 2 fatty liver models compared with the control. Alcoholic fatty liver showed a rapid increase in NF-κB binding activity at 1 hr after I/R, which preceded an increased expression of TNF-α and CINC. In contrast, non-alcoholic fatty liver showed neither NF-κB activation nor cytokine induction after I/R. Our results indicate that alcoholic fatty liver may differentially induce CINC production and hepatic necrosis after I/R. Furthermore, the present study suggests that apoptosis be responsible for the progression to hepatic necrosis when neutrophils are activated and recruited to the liver.

1)长期摄入乙醇可提高大鼠肝脏产生细胞因子诱导的中性粒细胞化学引诱剂（CINC）的能力：大鼠分别饲喂含有乙醇或葡萄糖的液体饲料6-8周。给予脂多糖（LPS），观察肝脏趋化因子mRNA的表达。2、6 h后，乙醇喂养组肝脏cnc mRNA表达量显著高于对照组。注射LPS后2小时，雌性酒精大鼠肝脏cnc mRNA水平高于雄性大鼠。结果表明，性腺切除术完全消除了肝脏cnc mRNA的性别差异。我们得出结论，CINC诱导可能是酒精性肝炎的原因，而产生CINC能力的差异是导致酒精性肝病性别差异的一个因素。2)酒精性脂肪肝在缺血再灌注（I/R）后诱导CINC和肝坏死的差异：接下来，我们研究了I/R后脂肪肝从转录因子激活到细胞因子诱导和凋亡的级联事件。对酒精性和非酒精性脂肪肝大鼠进行热I/R，并与对照大鼠进行比较。与非酒精性脂肪肝或对照组大鼠相比，酒精性脂肪肝大鼠在I/R后出现严重的肝坏死。与对照组相比，2种脂肪肝模型的肝细胞凋亡增加。酒精性脂肪肝在I/R后1小时NF-κB结合活性迅速升高，随后TNF-α和CINC表达升高。相比之下，非酒精性脂肪肝在I/R后既没有NF-κB活化，也没有细胞因子诱导。我们的研究结果表明，酒精性脂肪肝可能在I/R后不同程度地诱导CINC的产生和肝坏死。此外，本研究表明，当中性粒细胞被激活并被募集到肝脏时，细胞凋亡负责肝坏死的进展。