Congenital hepatic fibrosis (CHF) and
Caroli's disease are though to result from ductal plate malformation, and the basal laminar components play important roles in biliary differentiation during development. To clarify the involvement of basal laminar components in the ductal plate malformation, this study examined the immunohistochemical expression of
laminin and
type IV collagen in the livers of CHF and
Caroli's disease. Using the
polycystic kidney (PCK) rat, an animal model of
Caroli's disease with CHF, in vivo and in vitro experiments were also performed. Immunostaining showed that basement membrane expression of
laminin and
type IV collagen around intrahepatic bile ducts was degraded in CHF,
Caroli's disease, and the PCK rats. The degradation of
laminin and
type IV collagen around bile ducts was also observed in foci of
cholangiocarcinoma in situ of
Caroli's disease. In vitro, PCK cholangiocytes were found to overexpress
plasminogen and a
serine proteinase, the
tissue-type plasminogen activator (tPA). When PCK cholangiocytes were cultured in
Matrigel, the amounts of
laminin and
collagen in the gel were significantly reduced, and addition of alpha2-antiplasmin in the culture medium inhibited the degradation of
laminin and
collagen in
Matrigel. These results suggest that biliary overexpression of
plasminogen and tPA leads to the generation of excessive amounts of
plasmin, and subsequent
plasmin-dependent lysis of the extracellular matrix molecules may contribute to the biliary dysgenesis in CHF and
Caroli's disease, including progressive cystic dilatation of the intrahepatic bile ducts in
Caroli's disease. In addition, it is suggested that once
cholangiocarcinoma in situ develops in the biliary epithelium of CHF and
Caroli's disease, it tends to transform into invasive
carcinoma, due to instability of the basement membrane of the bile ducts.