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

为了确定内源性生物活性物质参与肝脏炎症的慢性阶段，我们从分子病理学的角度分析了几种小鼠肝功能障碍模型。我们证明干扰素(IFN)-γ调节促炎细胞因子的产生和包括中性粒细胞和巨噬细胞在内的炎症细胞的浸润，从而促进脂多糖（LPS）诱导的痤疮丙酸杆菌引发的小鼠急性肝损伤和对乙酰氨基酚诱导的急性致死性肝功能障碍的发展。我们获得的证据表明，白细胞介素(IL)-6在四氯化碳诱导的慢性肝纤维化中具有双重作用；通过上调一种有效的纤维化因子，转化生长因子-β_1和肝细胞生长因子的表达，诱导纤维化过程并维持肝细胞产生血清蛋白（如白蛋白）的能力。我们提供的证据表明，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。我们观察到脾内注射肿瘤可诱导肝窦内皮细胞中TNF-α的表达和随后血管粘附分子-1的表达，从而诱导肝转移。我们观察到内源性IL-1诱导的CCL3可能与其特异性受体CCR1相互作用，CCR1在人肝癌组织中组成性表达于肝癌细胞上。我们正在分析上述炎症模型中野生型和各种类型的细胞因子相关基因缺陷小鼠之间的基因表达模式，以确定在慢性肝脏炎症发展中至关重要的分子。

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.