Development of a novel diagnostic method for early detection of chronic liver diseases through the molecular pathological analysis of chronic liver disease models

通过慢性肝病模型的分子病理分析开发一种早期检测慢性肝病的新诊断方法

基本信息

批准号：
11470516
负责人：
MUKAIDA Naofumi
金额：
$ 9.09万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2002
项目状态：
已结题

项目摘要

In order to identify an endogenous bioactive substance(s) which are involved in the chronic phases of inflammation in liver, we analyzed several liver dysfunction models in mice from molecular pathological viewpoints.#1. We proved that interferon (IFN)-γ regulated the production of pro-inflammatory cytokines and the infiltration of inflammatory cells including neutrophils and macrophages, thereby contributing to the development of lipopolysaccharide (LPS)-induced acute liver injury in Propioniobaciterium acnes-primed mice and acetaminophen-induced acute fatal liver dysfunction.#2. We obtained the evidence to suggest that interleukin (IL)-6 have bifacial roles in carbon tetrachloride-induced chronic liver fibrosis; induction of fibrogenic process and maintenance of the hepatocyte capacity to produce serum proteins such as albumin, by up-regulating the expression of a potent fibrogenic factor, transforming growth factor-β_1 and hepatocyte growth factor, respectively.#3. We have provided evidence that tumor necrosis factor receptor p55-mediated signals regulated the accumulation of Kupffer and Ito cells, thereby inducing liver fibrosis.#4. We observed that intrasplenic injection of tumors induced TNF-α expression and subsequent vascular adhesion molecule-1 expression in sinusoidal endothelial cells in liver, thereby inducing liver metastasis.#5. We observed that CCL3, induced by endogenously produced IL-1, might interact with its specific receptor, CCR1, constitutively expressed on hepatoma cells, in human hepatoma tissues.We are in the process to analyze the gene expression patterns between wild-type and various types of cytokine-related gene-deficient mice in the above mentioned inflammation models, in order to identify the molecule(s) which is crucially involved in the development of chronic liver inflammation.

为了确定参与肝脏慢性炎症阶段的内源性生物活性物质，我们从分子病理学角度分析了几种小鼠肝功能障碍模型。#1。促炎细胞因子的产生以及包括中性粒细胞和巨噬细胞在内的炎症细胞的浸润，从而促进丙酸杆菌中脂多糖（LPS）诱导的急性肝损伤的发生痤疮引发的小鼠和对乙酰氨基酚诱导的急性致命性肝功能障碍。我们获得的证据表明白介素 (IL)-6 在四氯化碳诱导的慢性肝纤维化和肝细胞的维持中具有双面作用；通过分别上调有效的纤维形成因子、转化生长因子-β_1 和肝细胞生长因子的表达来产生血清蛋白（例如白蛋白）。#3。肿瘤坏死因子受体 p55 介导的信号调节 Kupffer 和 Ito 细胞的积累，从而诱导肝纤维化。#4。肝脏，从而诱导肝转移。#5。我们观察到，内源性产生的 IL-1 诱导的 CCL3 可能与其特异性受体 CCR1 相互作用。在人类肝癌组织中的肝癌细胞上组成型表达。我们正在分析上述炎症模型中野生型和各类细胞因子相关基因缺陷小鼠之间的基因表达模式，以鉴定该分子(s) 与慢性肝脏炎症的发展密切相关。