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From the The Hepatic Fibrosis Group,*
Clinical Sciences
Unit, The Queensland Institute of Medical Research, and the Department
of Pediatrics and Child Health,
Royal
Children's Hospital, Brisbane, Queensland, Australia
Extrahepatic biliary atresia is a severe neonatal liver
disease resulting from a sclerosing cholangiopathy of unknown etiology.
Although biliary obstruction may be surgically corrected by a
"Kasai" hepatoportoenterostomy, most patients still develop
progressive hepatic fibrosis, although the source of increased
collagen deposition is unclear. This study examined the role of hepatic
stellate cells (HSCs) and assessed the source of transforming growth
factor-ß (TGF-ß) production in hepatic fibrogenesis in patients
with biliary atresia. Liver biopsies from 18 biliary atresia patients
(including 5 pre- and post-Kasai) were subjected to
immunohistochemistry for 
-smooth muscle actin and in
situ hybridization for either procollagen 1 (I)
mRNA or TGF-ß1 mRNA. Sections were also subjected to
immunohistochemistry for active TGF-ß1 protein. The role
of Kupffer cells in TGF-ß1 production was assessed by
immunohistochemistry for CD68. Procollagen 1 (I) mRNA
was colocalized to -smooth muscle actin-positive HSCs within the
region of increased collagen protein deposition in fibrotic septa and
surrounding hyperplastic bile ducts. The number of activated HSCs was
decreased in only one post-Kasai biopsy. TGF-ß1 mRNA
expression was demonstrated in bile duct epithelial cells and activated
HSCs and in hepatocytes in close proximity to fibrotic septa. Active
TGF-ß1 protein was demonstrated in bile duct epithelial
cells and activated HSCs. This study provides evidence that activated
HSCs are responsible for increased collagen production in patients with
biliary atresia and therefore play a definitive role in the fibrogenic
process. We have also shown that bile duct epithelial cells,
HSCs, and hepatocytes are all involved in the production of the
profibrogenic cytokine, TGF-ß1.
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