Mechanisms of the formation of ductular reactions in cholestatic liver disease

几乎所有形式的人类淤胆性肝病都会导致胆管反应(DR)。DR的特征是胆管细胞的增殖导致胆管样结构。DR的病理生理学相关性仍有争议。一些研究得出结论，DR代表了应该被对抗的治疗靶点。其他人将DR解释为对胆汁淤积的适应性反应，从而改善了疾病。我们之前的工作导致了两个假说：DR可能是如何形成的。根据假设1，已经存在的胆管形成新的分支，这些分支延长并渗透到受损的组织区域。然而，我们也获得了证据表明，胆管细胞的囊泡最初形成于延长并最终连接到已经存在的胆道的受损组织(假设2)。在本项目中，我们将阐明DR形成的确切机制。这一知识具有临床意义，因为一个将有毒胆汁酸分泌到其管腔内的孤立囊肿需要不同的治疗策略，因为新形成的导管从一开始就在功能上与现有的胆道系统相连。

Virtually all forms of human cholestatic liver disease lead to ductular reactions (DR). DR are characterized by the proliferation of cholangiocytes leading to bile duct-like structures. The pathophysiological relevance of DR is still discussed controversially. Some studies concluded that DR represent therapeutic targets that should be antagonized. Others interpret DR as an adaptive response to cholestasis that ameliorates the disease. Our previous work resulted in two hypotheses how DR may be formed. According to hypothesis 1, already existing bile ducts form new branches that elongate and infiltrate damaged tissue regions. However, we also obtained evidence that cysts of cholangiocytes are initially formed in damaged tissue that elongate and finally connect to the already existing biliary tract (hypothesis 2). In the present project, we will clarify the exact mechanism by which DR are formed. This knowledge is of clinical relevance, because an isolated cyst that secrets toxic bile acids into its lumen requires different therapeutic strategies as newly formed ducts that from the beginning are functionally linked to the already existing biliary channel system.