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(American Journal of Pathology. 2001;158:1239-1244.)
© 2001 American Society for Investigative Pathology

Short Communications

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

Nicolai Sedlaczek^*, Ji-Dong Jia^*, Michael Bauer, Hermann Herbst, Martin Ruehl^*, Eckhart G. Hahn and Detlef Schuppan

From the Department of Gastroenterology and Hepatology,^*
Klinikum Benjamin Franklin, Free University of Berlin, Berlin, Germany; the Department of Gastroenterology and Hepatology,
Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany; and the Gerhard-Domagk-Institute of Pathology,
University of Muenster, Muenster, Germany

Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-ß1 (TGF-ß1) 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-ß1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl₄) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-ß1 and CTGF mRNA levels 6 hours after injection of CCl₄, with peak levels after 72 hours. In biliary fibrosis TGF-ß1 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-ß1 and that, contrary to a previous report, not solely hepatic stellate cells but activated bile duct epithelial cells are the main source of this profibrogenic factor.

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