Adaptative bile duct proliferative response in experimental bile duct ischemia

Abstract

A rat model of bile duct ischemia was established and used to examine the potential of bile duct proliferation to provide an adaptative response in cholestatic disorders. Rats underwent partial or complete arterial deprivation of the liver. Serum biochemical tests, histological analyses and bile secretion measurements were performed at different time points up to 6 weeks after surgery. Rats developed biochemical signs of cholestasis exclusively after complete arterial deprivation. Within 4h, cholangiocytes in these rats showed morphological signs of cell damage. After 48h, they displayed VEGF expression and became proliferative. The proportion of Ki67-labeled cholangiocytes ( approximately 30%) was similar in interlobular bile ducts and periportal ductules. A ductular reaction made of well-formed bile ducts confined to portal tracts developed within 1 week. Bile flow which was initially decreased, was restored at 3 weeks, while the biochemical signs of cholestasis completely resolved at 6 weeks. At this time, the number of bile duct sections was maximal. Fibrosis intensity was also maximal, although moderate (<F2 METAVIR staging) as assessed by Sirius-red staining morphometry. In the present model of bile duct ischemia, ductular reaction derives from bile ducts of all anatomical compartments, and provides a poorly fibrogenic functional response to biliary dysfunction.