In situ expression of fibrogenic growth factors and their receptors in biliary atresia: comparison between early and late stages

Abstract

Progressive fibrosis, despite successful surgical treatment, is one of the serious complications of biliary atresia. To understand the mechanism of this fibrosis, the in situ expression of fibrogenic growth factors (TGF-beta and PDGF) and their corresponding receptors was studied by immunohistochemistry using frozen sections. The results were compared between the early (n=12) and late (n=6) stages. The early stage was characterized by abundant expression of all ligands and receptors, together with type I procollagen (PC-I). The major cellular sources were activated fibroblasts/myofibroblasts distributed mostly in the portal tracts. Macrophages also expressed all the ligands and the receptors, but to a lesser degree. Bile duct cells strongly expressed TGF-beta RI and RII and PDGF AA and BB, but focally expressed TGF-beta. All of these decreased in the late stage of biliary atresia. These results suggest that TGF-beta and PDGF play important roles in the fibrogenesis of biliary atresia, especially in its early stage, acting either by autocrine or paracrine mechanisms involving activated fibroblasts/myofibroblasts, bile duct cells, and macrophages.

Serum and tissue tumor growth factor β1 in children with biliary atresia

“…The lack of expression of TGFβ1 in liver explants was also observed by Ahmed et al [16] who studied BA patients with early and late-stage fibrosis. They noted a global decrease of TGFβ1 in late-stage BA by immunohistochemistry.…”

“…Ahmed et al [16] found marked TGFβ1 staining in spindle-shaped cells that could represent activated myofibroblasts. In our case, bile duct plugs may have made it difficult to visualize positive myofibroblasts, but as seen in Fig.…”

Epithelial–mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia

“…The histogenesis of another histological feature of BA, sclerosing cholangiopathy, has previously been speculated to be associated with fibrogenic factors such as platelet‐derived growth factor (PDGF) 29 and connective tissue growth factor (CTGF) 30. However, our preliminary study revealed that these fibrogenic factors were not induced by a biliary innate immune response to dsRNA.…”

Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis

“…In biliary atresia, it has been well documented that there is increased production of TGF-β, particularly the isoform TGF-β2, by BECs and surrounding cells in cases with a prominent ductular reaction [28][29][30][31][32][33]. TGF-β2 secretion by activated rat portal fibroblasts is also increased both in isolated cells in vitro and in biliary atresia [30,34].…”