巨噬细胞5-HT2B受体介导吡喹酮抗血吸虫病肝纤维化作用和机制研究

血吸虫病及其它病因所致肝纤维化的治疗是临床难题，尚缺乏有效药物。在肝纤维化研究上，促胶原等细胞外基质降解是主要策略之一。已知Ly-6CloCD11bhiF4/80int亚群MΦ来源的MMPs在胶原降解中起主要作用，且PZQ为5-HT2BR的配体。前期在CCl4诱导肝纤维化的研究初步揭示，PZQ能活化5-HT2BR/ERK通路，增加y-6CloCD11bhiF4/80int亚群MΦ比例，并提高MMPs水平。依据已有报道并结合前期研究，提出“PZQ通过活化5-HT2BR/MAPK/ERK通路，促进血吸虫病小鼠肝脏Ly-6ChiCD11bhiF4/80intMΦ向Ly-6CloCD11bhiF4/80intMΦ转化，上调组织MMPs水平，促进胶原纤维降解”的假说。拟在血吸虫病肝纤维化模型和分离细胞上，阐明PZQ降解胶原的作用机制，以期为拓展PZQ适应症用于肝纤维化治疗，提供依据。

The treatment of liver fibrosis caused by schistosomiasis and other causative factors is a difficult clinical problem and is lack of effective therapeutic drugs. In the aspects of research on anti-liver fibrosis, promoting the degradation of collagen and other extracellular matrix is one of the main strategies. Studies have demonstrated that MMPs derived from Ly-6CloCD11bhiF4/80int MΦ plays a major role in collagen degradation of hepatic fibrosis. Also, PZQ has been proved to be a ligand of 5-HT2B receptor. Our previous studies on CCl4-induced liver fibrosis model revealed that PZQ was able to activate 5-HT2B/ERK pathway, then increasing Ly-6CloCD11bhiF4/80int MΦ proportion and the level of MMPs. Based on the previous reports and the studies by us, we hypothesise that PZQ may stimulates 5-HT2B receptor to activate ERK pathway, resulting in transformation of liver Ly-6ChiCD11bhiF4/80int MΦ to Ly-6CloCD11bhiF4/80int MΦ, increasing liver tissue MMPs levels and enhancing collagen degradation. This project is intended to verify the hypothesis on the schistosomiasis model of liver fibrosis and the isolated cells. The expected results will further provide an important experimental basis for expanding the use of PZQ on treatment of liver fibrosis.