大麻二酚对小鼠肝纤维化的防治及机制初探

Liver fibrosis has always been a hotspot in liver disease research field，for which no effective treatments are available currently. Oxidative stress is considered critital in the pathogenesis of liver diseases especially liver fibrosis. Peroxisome proliferator activated receptors α(PPARα) and Nuclear factor erythroid 2–related factor 2(Nrf2) are well-documented to be heavily involved in oxidative stess regulation. Cannabidiol (CBD) is the most abundant non-psychoactive constituent of marijuana plant and thus has been extensively studied recently. In addition to the application of anticancer and the treatment of tumor epilepsy, CBD also contribute to preventing from oxidative stress and inflammation through attenuating responses in key inflammatory pathways and oxidative tissue injury. Our previous study indicate that CBD protects against chronic-binge ethanol-induced liver injury by attenuating oxidative stress and liver inflammation. In the current study, we plan to examine the benificial effects of CBD in mice hepatic fibrosis and investigate whether the mechanism is related to the increased antioxidative capability of liver liver and/or the inhibited expression of NF-κB through the activity of PPARα and Nrf2.

肝纤维化的治疗目前尚无有效的方法，寻找预防和逆转肝纤维化的物质有重要意义。氧化应激是肝纤维化的重要发病机制之一，过氧化物酶体增殖物激活受体（PPARα）对氧化应激具有重要的调控作用，核转录相关因子2(Nrf2) 是细胞调节抗氧化应激反应的重要转录因子。大麻二酚（canabidiol，CBD）属于大麻素非成瘾成份，近年来，CBD的应用研究逐渐被重视，除治疗肿瘤、癫痫外，CBD对氧化应激和炎症相关的疾病具有防治作用，如CBD可通过减轻氧化应激和炎症反应从而减轻小鼠肝脏缺血再灌注损伤。申请人前期实验发现，CBD能通过减轻氧化应激和炎症反应防治小鼠酒精性肝损伤，推测CBD对肝纤维化可能有一定的治疗作用。因此，本课题拟研究CBD对小鼠肝纤维化的作用，并探讨其机制是否与启动肝脏PPARα和Nrf2的激活，诱导抗氧化酶的转录和抑制NF-κB的表达，从而增加抗氧化应激损伤和抗炎反应能力有关。

肝纤维化的治疗目前尚无有效的方法，寻找预防和逆转肝纤维化的物质有重要意义。氧化应激是肝纤维化的重要发病机制之一，过氧化物酶体增殖物激活受体（PPARα）对氧化应激具有重要的调控作用，核转录相关因子2(Nrf2) 是细胞调节抗氧化应激反应的重要转录因子。 大麻二酚（canabidiol，CBD）属于大麻素非成瘾成份，近年来，CBD的应用研究逐渐被重视， 除治疗肿瘤、癫痫外，CBD对氧化应激和炎症相关的疾病具有防治作用，如CBD可通过减轻氧化应激和炎症反应从而减轻小鼠肝脏缺血再灌注损伤。本课题研究了CBD对小鼠急性肝损伤和肝纤维化的作用，以及对大鼠肝星状细胞系HSC-T6氧化应激的干预作用及机制。结果提示CBD对CCl4诱导的小鼠肝纤维化有干预作用，其作用机制可能与调节NF-κB/Nrf2通路相关蛋白表达，减轻机体氧化应激损伤、抑制脂质过氧化，抑制炎症反应从而发挥抗肝纤维化作用有关；CBD可以通过中断NF-κB信号通路抑制HSCs的活化和胶原蛋白的沉积同时降低HSCs炎症的产生；CBD能够减轻CCl4诱导的小鼠急性肝损伤，抑制肝组织过氧化反应及炎症反应，其作用机制可能与CBD上调PPAR-γ及Nrf2的表达，发挥抗炎抗氧化作用有关。