Molecular biology of rejection after liver transplantation

肝移植后排斥反应的分子生物学

基本信息

批准号：
14370350
负责人：
HASHIKURA Yasuhiko
金额：
$ 8.83万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

1.Hepatic warm ischemia-reperfusion injury (IRI) during hepatectomy and liver transplantation is a major cause of liver dysfunction in which the pathologic role of free radicals is a major concern. To assess the effect of MCI-186 (edaravone) on hepatic IRI, male Wistar rats were subjected to partial hepatic ischemia for 60 min after pretreatment with vehicle (group C) or MCI-186 (group M). Group M showed significantly lower levels of serum alanine aminotransferase and hepatic lipid peroxidation than group C, and also significantly lower expression levels of mRNA for cytokines, chemokines and intercellular adhesion molecule-1. There were fewer tissue monocytes and neutrophils in group M than in group C. Our findings suggest that treatment with MCI-186 attenuates hepatic IRI in this rat in vivo model.2.The mechanisms of Fas-Fas ligand (Fas-FasL)-mediated apoptosis in the pathogenesis of fulminant hepatic failure (FHF) have not been well defined. This clinical study was carried out to ass … More ess which cells expressed Fas-FasL and to determine their involvement. As the results, the numbers of TUNEL-, FasL-, and CD68-positive cells in the livers of patients with FHF were significantly larger than in those with CH or with normal livers. Double immunofluorescence staining showed that FasL was expressed predominantly on liver macrophages and rarely on CD8-positive lymphocytes. Macrophages and their expression of FasL may play roles in the pathogenesis of FHF.3.We selected sublines with a high capability for differentiation to contracting cardiomyocytes and also produced germ-line chimeric mice from a parent ES line. We also succeed in establishing embryoid bodies prepared from the ES cells that differentiated into not only hepatocytes but also at least two mesodermal lineages : cardiomyocytes that supported liver development and endothelial cells corresponding to sinusoids. The expression of albumin was significantly higher in cardiomyocytes that had arisen in differentiated ES cells than in those that had not. Our in vitro system for liver organogenesis consists of a blood/sinusoid vascular-like network and hepatocyte layers and shows higher levels of hepatic function, such as albumin production and ammonia degradation, than hepatic cell lines and primary cultures of murine adult hepatocytes. This innovative system will lead to the development of second-generation regenerative medicine techniques using ES cells and is expected to be useful for the development of bioartificial liver systems and drug-metabolism assays. Less

1.肝脏和肝移植期间的肝脏温暖缺血 - 再灌注损伤（IRI）是肝功能障碍的主要原因，其中自由基的病理作用是主要问题。为了评估MCI-186（Edaravone）对肝脏IRI的影响，在用媒介物（C组）或MCI-186（M组）预处理后，将雄性Wistar大鼠患有部分肝缺血60分钟。 M组显示出明显低于C组的系列丙氨酸氨基转移酶和肝脂质过氧化水平，而细胞因子，趋化因子和细胞间粘附分子1的mRNA表达水平也明显较低。在M组中，组织单核细胞和中性粒细胞的少于C组。我们的发现表明，MCI-186的治疗在这种大鼠体内模型中减弱了肝IRI。这项临床研究是为了进行屁股……更多的ESS细胞表达FAS-FASL并确定其参与。结果，FHF患者生活中TUNEL-，FASL-和CD68阳性细胞的数量明显大于CH或正常寿命的细胞。双重免疫荧光染色表明，FASL主要在肝巨噬细胞上表达，很少在CD8阳性淋巴细胞上表达。巨噬细胞及其表达FASL可能在FHF的发病机理中起着作用。3。我们选择的subline具有很高的分化能力与收缩心肌细胞的能力，并且还从父级ES系列产生了种系嵌合小鼠。我们还成功地建立了从ES细胞制备的胚胎体，这些ES细胞不仅分化为肝细胞，而且至少有两个中胚层谱系：支持肝脏发育和与正弦曲线相对应的内皮细胞的心肌细胞。在分化的ES细胞中产生的心肌细胞中白蛋白的表达明显高于没有的细胞。我们用于肝脏器官发生的体外系统由血液/正弦血管状的网络和肝细胞层组成，并显示出比肝成年成人肝细胞的肝素细胞系和原发性培养的肝素功能，例如白蛋白产生和氨降解。这种创新的系统将导致使用ES细胞的第二代再生医学技术的发展，并有望有助于生物人工肝脏系统和药物代谢测定法的开发。较少的