The reversibility of hepatic
fibrosis was investigated in an experimental model of
extrahepatic cholestasis in the rat after common bile duct
ligation for 2 weeks, followed by bilioduodenal anastomosis for 3 weeks. Bile duct
ligation resulted in a transitory marked elevation in the serum concentration of
5'-nucleotidase,
alkaline phosphatase, and
bilirubin during the first 3 days. Then these levels decreased to threefold, twofold, and 100-fold the normal values, respectively, during the following 4 weeks. Histologic examination of the liver disclosed extensive bile duct proliferation and the formation of periportal
fibrosis, with only slight
inflammation and
necrosis. The distribution of the major components of the hepatic extracellular matrix was analyzed 2 weeks after bile duct
ligation, using the indirect immunoperoxidase method. Fibrous septa were found to be strongly stained for
collagens I, pro-III, III and IV,
fibronectin, and
laminin. The most intense staining was found in enlarged periportal areas,
collagen IV and
laminin being particularly abundant around newly formed bile ducts. These changes paralleled high steady-state levels of alpha 1(I) and alpha 1(IV)
collagen and B2 chain
laminin mRNAs. Relief of the obstruction for 2 weeks resulted in a shift in the serum concentration of
5'-nucleotidase,
alkaline phosphatase, and
bilirubin toward normal values. A dramatic resorption of bile duct proliferations and periportal
fibrosis were observed. Three weeks after bile duct repermeabilization, immunohistochemical study showed that the pattern of distribution of extracellular matrix components was almost normal, except for
collagen IV, which remained abundant in the sinusoids when compared with the normal liver. In parallel, the steady-state B2-chain
laminin mRNA level became lower than in cholestatic livers, whereas alpha 1(I) and alpha 1(IV) mRNAs were almost undetectable. These results show that hepatic
fibrosis induced by experimental
extrahepatic cholestasis in rat disappears in less than 3 weeks after relief of
bile duct obstruction, suggesting that an active degradation of matrix
protein occurs, except for
collagen IV in the sinusoid.