Mechanisms of the formation of ductular reactions in cholestatic liver disease

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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.