交感神经过度兴奋调控kupffer细胞相关炎症微环境促肝细胞恶性转化的分子机制

There is a proceeding of hepatitis-hepatic cirrhosis-hepatocellular carcinoma in HCC patients, although the mechanism is still unknown from hepatic cirrhosis to HCC. Chronic inflammatory microenvironment and superactivity of sympathetic nerves are often observed in liver cirrhosis, and both of them is related to carcinogenesis. Our previous study showed that superactivity of sympathetic nerves rendered activity of Kupffer cell to enhance liver inflammation. Hepatocarcinogenesis can be inhabited by depletion of Kupffer cell or regulation of sympathetic nerves. On this background, we suppose that superactivity of sympathetic nerves may change hepatic inflammatory microenvironment, so as to promote hepatocarcinogenesis. In this study, it will be determined on how to change the hepatic inflammatory microenvironment by superactivity of sympathetic nerves and activity of adrenorecepter in animal model, and how to lead to carcinogenesis. The influence of inflammatory mediators on hepatocellular oncogenesis will be also examined by genome and protome techniques. The expression and activity of specific integrins regulated by inflammatory mediators in carcinogenesis will be evaluated meanwhile. In conclusion, the mechanism of hepatocarcinogenesis induced by superactivity of sympathetic nerves would be clarified in this study.

肝癌的发病常表现为"肝炎-肝硬化-肝癌"的模式，但肝硬化导致癌变的机制至今仍不明确。研究发现肝硬化使肝内形成慢性炎症微环境并使肝脏内交感神经呈现过度兴奋状态，而炎症微环境和交感神经递质去甲肾上腺素与癌变密切相关。我们的前期研究已证实交感神经兴奋可通过活化Kupffer细胞启动和放大肝内的炎症反应，同时还发现阻断交感神经或去除Kupffer细胞可显著降低实验性肝癌的成癌率。由此可推断交感神经过度兴奋有可能通过调控肝脏内炎症微环境的变化而促发癌变。本课题应用肝癌动物模型探讨不同交感神经兴奋状态和神经递质受体兴奋途径如何诱导肝内炎症微环境的改变以及对肝癌形成的影响；同时借助组学方法等前沿技术明确交感神经调控Kupffer细胞活化后炎症介质的异常表达对肝细胞癌前期转化的影响，及其诱导特定Integrins亚型表达和活化导致癌变形成的分子机制；旨在揭示交感神经促肝癌形成的通路，为肝癌防治提供新理论。

我国是肝癌大国，肝癌致死率居肿瘤第二位。我们的前期研究，已证实交感神经调控影响肿瘤的进展，同时肝硬化进程中，交感神经兴奋性呈持续性升高。本项目旨在阐明交感神经兴奋激活特定神经递质受体调控kupffer 细胞活化诱导肝内炎症微环境改变促进肝癌发生的分子机制，为探索肝癌的诊治新策略提供理论依据。.本项目主要利用肝癌动物模型，探讨交感神经兴奋状态与肝癌的进程的相关性，并检测不同节段阻断交感神经和应用不同交感神经递质受体α、β亚型拮抗剂对诱导实验性肝硬化肝癌形成的影响；明确交感神经调控kupffer细胞活化后相关炎症介质IL-6和TGF-β等的表达变化；研究交感神经递质作用于kupffer 细胞特定肾上腺素能受体的亚型，以及活化kupffer 细胞后促进肝癌发生的分子机制。.通过本课题的研究发现肝癌的形成过程中，交感神经呈过度兴奋状态。高密度的交感神经纤维预示着肝癌患者较差的临床预后。阻断交感神经和阻滞α1受体后能够抑制DEN诱导的肝癌进程。进一步研究发现，交感神经兴奋后释放的去甲肾上腺素等神经递质能够通过激活α1肾上腺素能受体促进kupffer 细胞的活化，调控炎症因子的释放进而促进肝癌的发生。本项目揭示交感神经促发肝硬化状态下肝癌形成的神经调控新理论，阻断交感神经和阻滞α-1A肾上腺素能受体可能为探索肝癌诊治的新策略提供潜在靶点。