Modulation of collagen XVIII/endostatin expression in lobular and biliary rat liver fibrogenesis

Background/Aims: The liver is the major source of collagen XVIII (C18), the precursor of the angiogenesis inhibitor endostatin. In human liver C18 is mainly expressed by hepatocytes. However, its quantitative and temporospati al expression patterns during liver fibrogenesis are unknown. Methods: We used RNA quantification and in situ hybridization combined with cell-specific markers to study C18 compared to procollagen alpha1(I) and t issue inhibitor of metalloproteinases-1 (TIMP-1) mRNA expression in acute ( single dose Of CCl4) and chronic (biliary) rat liver fibrogenesis. Results: C18 transcripts were only found in hepatocytes and bile duct epith elia of normal and fibrotic livers, and occasionally in arterial myocytes a nd hepatic stellate cells. 72 h after CCl4 injection, C18 mRNA levels remai ned unchanged, while procollagen alpha1(I) mRNA was increased at 72 h and T IMP-1 mRNA peaked at 12 h (P < 0.05). In biliary fibrosis C18 mRNA levels i ncreased 1.8-fold, contrasting with 20- and 4-fold elevated procollagen alp ha1(I) and TIMP-1 transcript levels, respectively. Conclusions: Hepatocytes and bile duct epithelia are the predominant source s of C18 in normal and fibrotic rat liver. Contrary to procollagen alpha1(I ) and TIMP-1, C18 expression remains constant in acute fibrogenesis and is upregulated in biliary fibrosis. Modulation of epithelial C18 expression an d its processing to endostatin could allow a liver-specific anticancer ther apy. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All-rights reserved.