Proliferating Bile Duct Epithelial Cells Are a Major Source of Connective Tissue Growth Factor in Rat Biliary Fibrosis

Abstract

Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-␤1 (TGF-␤1)and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-␤1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl 4 ) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-␤1 and CTGF mRNA levels 6 hours after injection of CCl 4 , with peak levels after 72 hours. In biliary fibrosis TGF-␤1 and CTGF mRNA levels increased fourfold and sevenfold, respectively (P < 0.001). In situ hybridization combined with cell-specific markers revealed CTGF transcripts in desmin-positive cells after a single dose of carbon tetrachloride, whereas no transcripts were found in normal livers. In biliary fibrosis, however, proliferating bile duct epithelial cells were the predominant source of CTGF mRNA. We conclude that in rat liver fibrogenesis CTGF is up-regulated in close association with TGF-␤1 and that, contrary to a previous report, not solely hepatic stellate cells but ac- Connective tissue growth factor (CTGF) is a cysteine-rich polypeptide identified originally in human umbilical vein endothelial cells by its chemotactic and mitogenic effects on fibroblasts.

Effects of selective bile duct ligation on liver parenchyma in young animals: histologic and molecular evaluations

“…The formation of bile ducts collaterals could lead to a diminution in the ductular reaction after the second week and, as a consequence, a decrease in collagen deposition during the fourth and eighth weeks. In fact, proliferating colangiocytes secrete profibrogenic factors, leading to the activation of fibroblasts and hepatic stellate cells [23,24]. Moreover, the cholangiocytes may acquire phenotypic characteristics of mesenchymal cells, a process called ephitelial-mesenchymal transition [25,26].…”

Targeting Liver Fibrosis

“…TGF␤2, connective tissue growth factor (CTGF), and platelet-derived growth factor (PDGF)-BB that drive the activation of HSC, [13][14][15][16] de novo express profibrogenic integrin ␣v␤6 17 , produce ECM components such as basement membrane proteins, 18 and induce early programs of ductal plate formation by releasing Hedgehog ligands that stimulate HSC. 19 Activated HSC, in turn, produce growth and survival factors for adjacent cholangiocytes, creating a positive fibrogenic feedback loop (Fig.…”

Laser‐induced thermotherapy (LITT) elevates mRNA expression of connective tissue growth factor (CTGF) associated with reduced tumor growth of liver metastases compared to hepatic resection

“…Antisense and sense (negative control) RNA probes were prepared by in vitro transcription with [ 35 S]-UTP (NEN, Cologne, Germany) and used for in-situ hybridization as described somewhere else before [16,19]. Briefly, 5-mm frozen sections were mounted onto 3-aminopropyl triethoxysilane-coated slides and fixed in 4% paraformaldehyde/ phosphate-buffered saline (PBS) for 20 minutes, followed by washes in PBS, dehydration in graded ethanol, and airdrying.…”

“…It was selectively induced in fibroblasts after activation with TGFb [14]. In the liver, CTGF expression is associated with hepatic fibrosis in both human subjects and animal models [15,16]. The aim of the study was to evaluate the growth of residual intrahepatic tumor tissue and changes of intrahepatic mRNA levels of HGF and CTGF after LITT in comparison to hepatic resection.…”