肠肝轴：肝屏障（肝窦内皮细胞）与中性粒细胞在肠源性肝损伤中的作用研究

基于肠肝轴理论：当肠粘膜屏障受损时，肠源性损害因素会导致肝损伤。但大量临床数据和基础研究却显示：肠粘膜屏障严重损伤的炎症性肠病（IBD）却很少伴有明显肝损伤，而只是有基础肝病时，肠粘膜屏障破坏才容易加重肝损伤。这提示，在肠肝轴中可能存在肝屏障，保护肝脏免受肠源性损伤。我们在预实验中建立了7种不同肝损伤模型，发现只有在合并肝窦内皮细胞（LSEC）损伤的肝病中，DSS肠炎才能加重肝损伤；且肝内中性粒细胞明显增多；而清除中性粒细胞后肠炎便无法加重肝损伤。预实验表明LSEC在肠肝轴中起肝屏障作用，而中性粒细胞促进了肠源性肝损伤。本课题拟在此基础上进一步探究LSEC受损后如何募集、激活中性粒细胞？中性粒细胞来自外周血抑或肠道？中性粒细胞如何行使杀伤作用？该研究拓展了肠肝轴学说，提出了肝屏障（LSEC）及中性粒细胞在肠源性肝损伤中均起不可或缺的作用；并为这一特殊类型肝损伤的治疗及寻找干预靶点奠定基础。

Based on the gut-liver-axis theory, when the gut mucosa barrier is damaged, gut-derived pathogenic factors could lead to liver injury. Surprisingly, increasing clinical observations and basic researches suggest that in patients with inflammatory bowel disease (IBD), the damaged gut mucosa seldom leads to severe liver injury independently, but could aggravate existing liver diseases. These evidences suggest that there might be a “hepatic barrier” in the gut-liver axis, protecting the liver against gut-derived injury. In our preliminary animal experiments, we constructed 7 liver disease models with different sorts of liver cell injuries. We found that DSS-colitis could exacerbate liver injury only in 4 liver disease models with significant liver sinusoidal endothelial cell (LSEC) rupture. In contrast, DSS-colitis did not lead to liver damage when there was no LSEC injury in the other 3 liver disease models. For colitis-aggravated liver diseases, increased neutrophils were observed in liver. Furthermore, after neutrophils were depleted, DSS-colitis could no longer aggravate hepatic injury. Our preliminary experiments demonstrated the “hepatic barrier” role of LESC in the gut-liver-axis, as well as the key effect of neutrophils in the development of gut-derived liver injury. In the current study, we aim to further investigate the following questions: 1) how does injured LSEC recruit and activate the neutrophils? 2) the neutrophils are recruited from the peripheral blood or gut? 3) how do the neutrophils induce liver injury? This study will extend the theory of gut-liver-axis, since it proposes a novel role of hepatic barrier (LSEC) and the important effects of neutrophils in the development of gut-derived liver injury. Moreover, it will provide the theoretical basis for the management of gut-derived liver diseases and exploration of new therapeutic targets.