HMGB1在MC-LR介导的黄颡鱼肝脏损伤中的作用机制研究

炎症反应在微囊藻毒素（MCs）致肝损伤中发挥重要作用。我们前期研究表明MC-LR能够诱导黄颡鱼重要促炎因子HMGB1的表达，而其阻断剂HMGB1 A box和丙酮酸乙酯都能有效缓解MC-LR的肝细胞毒性，说明HMGB1可能参与了MC-LR介导的肝损伤，但其具体作用机制未见报道。本项目拟以黄颡鱼为动物模型，使用MC-LR及HMGB1阻断剂处理，检测不同处理组肝脏组织病理学损伤程度，以确定HMGB1在MC-LR致肝损伤中的作用；检测肝脏原代细胞和白细胞增殖/凋亡/坏死，白细胞比例、白细胞亚型比例、白细胞中炎症介质释放和炎症相关基因的表达，以确定HMGB1在MC-LR介导的肝脏炎症反应中的作用；分析HMGB1的表达和定位，以确定MC-LR对HMGB1的影响。从动物、细胞、分子三个层次研究HMGB1在MC-LR介导的肝脏炎症损伤中的作用机制，从而为利用其阻断剂缓解MC-LR的肝毒性提供理论依据。

Inflammation plays an important role in the liver injury caused by microcystins (MCs). According to our previous study, MC-LR induced the mRNA expression of a vital proinflammatory factor HMGB1 of yellow catfish, and the HMGB1 blockers (HMGB1 A box and Ethyl Pyruvate) attenuated MC-LR hepatotoxicity. These results suggest that HMGB1 may participate in the liver injury caused by MC-LR. However, there is no report about its effect mechanism. This study aims to monitor the liver histopathological lesion using MC-LR and HMGB1 blockers to reveal the HMGB1 effects on the liver damage caused by MC-LR, using yellow catfish as an animal model; the proliferation/apoptosis/necrosis of liver primary cells and leukocytes, leukocyte percentages, leukocyte subtype percentages, inflammatory mediator release and inflammation-related gene expression in leukocytes to identify the HMGB1 effects on the inflammation caused by MC-LR; the HMGB1 expression and location to determine the MC-LR effects on HMGB1. These results will reveal the HMGB1 effect mechanism on MC-LR mediating liver inflammatory injury at animal, cell and molecule levels, which may serve as a theoretical underpinning for applying HMGB1 blockers to alleviate MC-LR hepatotoxicity.