Bile duct ligation: step-by-step to cholangiocyte inflammatory tumorigenesis.

Chronic liver inflammation after murine bile duct ligation could evolve according to three interrelated phenotypes, which would have different metabolic, functional and histologic characteristics. Liver injury secondary to extrahepatic cholestasis would induce an early ischemic-reperfusion phenotype with cholangiocyte depolarization, abnormal ion transport, hypometabolism with anaerobic glycolysis and hepatocytic apoptosis. This phenotype, in turn, could trigger the switch to a leukocytic phenotype by the cholangiocytes, with an intense anaplerotic activity, hypermetabolism, extracellular matrix degradation and moderated proliferation to create a pseudotissue with metabolic autonomy and paracrine functions. In the long-term cholestasis-drive tumorigenesis, the tumorous tissue would principally consist of cholangiocyte parenchyma, with an impressive biosynthetic activity through the tricarboxylic cell cycle. In terms of the tumorous stroma, made up by fibroplasia and angiogenesis, it would favor the tumor trophism. In conclusion, the great intensity and persistence in the expression of these phenotypes by the cholestatic cholangiocyte would favor chronic inflammatory tumorigenesis.