Figure 14.

Suggested sequence of events of cholangiopathy in LCA-fed mice—further evidence for the toxic bile concept. 1) LCA feeding leads to alterations of tight junctions of BECs, resulting in leaky bile ducts and chemotaxis of neutrophil granulocytes. 2) Inflammation and extravasation of toxic bile lead to subepithelial fluid accumulation and concomitant detachment of the biliary epithelium resulting in lifting of the epithelial cell layer. 3) Neutrophil granulocytes invade the bile duct lumina via transmigration and ulcerations of the epithelial cell layer. 4) Ongoing efflux of toxic bile into the portal field together with activation of BECs leads to proliferation and activation of periductal myofibroblasts resulting in rapidly evolving periductal fibrosis.