以1、3型胶原过度积聚为特征的肝纤维化硬化是各种病因引起的肝脏疾病的共有表现, 属常见病、多发病，目前尚无有效治疗措施。单核巨噬细胞，因其可塑性强，成为细胞治疗首选。有报道：M1型巨噬细胞可显著改善肝纤维化。我们发现：磷酸鞘胺醇可诱导单核巨噬细胞向M1极化，且极显著地上调可降解1、3型胶原的基质金属蛋白酶13。提示：磷酸鞘胺醇极化的M1可逆转肝纤维化硬化。本研究拟①采用不同病因导致的小鼠肝纤维化硬化模型，尾静脉注射移植经磷酸鞘胺醇极化的M1型巨噬细胞，确认其可逆转肝纤维化硬化；②以不同方式制备肝纤维化时产生1、3型胶原的肌成纤维细胞，与磷酸鞘胺醇极化的M1细胞共培养，体外确认其可降解不同来源的肌成纤维细胞产生的1、3型胶原；③采用细胞分子生物学技术，研究磷酸鞘胺醇上调基质金属蛋白酶13的分子机制；④体内确认基质金属蛋白酶13是逆转肝纤维化硬化的关键分子。本研究为肝纤维化硬化治疗提供新策略。

Hepatic fibrosis/cirrhosis characterized by excessive accumulation of type 1 and type 3 collagen is a common manifestation of liver diseases caused by various causes, and is a common disease and frequently-occurring disease. There is currently no effective treatment. Monocytes/macrophages, because of their strong plasticity, have become the first choice for cell therapy. It has been reported that M1 macrophages can significantly improve liver fibrosis. Our study found that sphingosine 1- phosphate induces macrophage polarization to M1 and significantly upregulates matrix metalloproteinase 13 which degrades type 1 and type 3 collagen. The above results suggest that sphingosine 1-phosphate -polarized macrophages might reverse liver fibrosis/cirrhosis. In this study, ① we will use models of liver fibrosis/cirrhosis in mice caused by different causes. The macrophage pretreated with sphingosine 1-phosphate was injected into the tail vein. Then we confirm that the macrophages can reverse liver fibrosis/cirrhosis. ② Hepatic myofibroblasts, which produced type 1 and type 3 collagen during liver fibrosis, were prepared in different ways, co-cultured with sphingosine 1-phosphate -polarized macrophages. Then, we confirm that the type 1 and type 3 collagen produced by myofibroblasts from different sources could be degraded, in vitro. ③ We will carried out research on the molecular mechanism of up-regulation of matrix metalloproteinase 13 by sphingosine 1-phosphate, using cell molecular biology techniques; ④ We will confirm in vivo that matrix metalloproteinase 13 is a key molecule in reversing liver fibrosis/cirrhosis. This study would provide a new strategy for the treatment of liver fibrosis/cirrhosis.