Trafficking of monocytes and their differentiation to dendritic cells and macrophages in the human liver

大多数肝脏疾病的发生是由于血液中的白细胞进入肝脏而导致炎症失控所致。白细胞通过被称为内皮细胞的特殊细胞排列的通道或血窦进入肝脏，在进入肝脏组织之前，白细胞必须与这些细胞结合并在其间迁移。我们认为，这一过程将a)确定招募的细胞的性质，b)确定这些细胞如何被激活，从而决定肝损伤的结果。我们已经开发了复杂的试管模型，其中人类肝细胞的组合在特定条件下生长，模拟患病肝窦内的环境。我们将使用这些模型来研究白细胞是如何招募的，以及与正弦细胞的相互作用如何定义细胞在招募过程中的激活状态。了解这一过程将解释为什么在某些情况下，白细胞可以促进受损肝脏的修复，而在另一些情况下，它们会放大肝脏损伤。我们希望利用这些信息开发新的治疗方法，以操纵肝脏中的白细胞，有利于修复而不是持续的肝脏损伤，从而逆转炎症性肝病和预防肝硬变。

Most liver diseases occur as a consequence of uncontrolled inflammation mediated by white blood cells recruited into the liver from the blood. White blood cells enter the liver via channels or sinusoids that are lined by specialised cells called endothelial cells which the white cells must bind to and migrate between before they can enter liver tissue. We propose that this process will a) determine the nature of the cells recruited and b) determine how those cells become activated and thereby the outcome of liver injury. We have developed complex test tube models in which combinations of human liver cells are grown under particular conditions that mimic the environment within the diseased liver sinusoids. We will use these models to investigate how white cells are recruited and how interactions with sinusoidal cells can define the activation status of the cells during their recruitment. Understanding this process will elucidate why in some circumstances white blood cells can promote the repair of the damaged liver whereas in other circumstances they amplify liver injury. We hope to use this information to develop new therapies to manipulate white blood cells in the liver in favour of repair rather than continuing liver damage and thereby to reverse inflammatory liver disease and prevent liver cirrhosis.