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.

为了鉴定肝脏炎症慢性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小鼠中的几种肝功能障碍模型。＃1。我们证明了干扰素（IFN）-γ调节促炎性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，从而有助于脂多糖（LPS）诱导的急性肝损伤的脂肪症状脂肪症和抗激素的脂肪肌酸脂蛋白效应。我们获得了证据表明，白介素（IL）-6在四氯化碳诱导的慢性肝纤维化中具有两类角色。通过上调潜在的纤维化因子的表达，分别转化生长因子-β_1和肝细胞生长因子，诱导纤维化过程和肝细胞能力来产生血清蛋白（例如白蛋白）。我们提供了证据表明肿瘤坏死因子受体p55介导的信号调节了库普弗和ITO细胞的积累，从而诱导了肝纤维化。＃4。我们观察到肿瘤内胞内注射诱导的TNF-α表达和随后在肝脏正弦内皮细胞中的血管粘附分子1表达，从而诱导肝转移。＃5。我们观察到，由内源性产生的IL-1诱导的CCL3可能与其特定的接收器CCR1相互作用，在人肝癌组织中，在肝癌细胞上组成性表达。慢性肝感染的发展。