• Martin Roderfeld, Ralf Weiskirchen, Srebrena Atanasova, Axel M Gressner, Klaus T Preissner, Elke Roeb, and Sandip M Kanse.
• Department of Medicine II, Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany.
• Liver Int. 2009 May 1;29(5):686-91.

BackgroundPlatelet-derived growth factor-BB (PDGF-BB) is a profibrotic factor in liver fibrosis through its ability to stimulate hepatic stellate cells (HSC). The liver-derived serine protease factor VII activating protease (FSAP) regulates the activities of PDGF-BB in a cell-specific manner.AimsOur aim was to determine the influence of FSAP on the activation of HSC and to analyse the regulation of FSAP in hepatic fibrogenesis.MethodsThe effect of FSAP on PDGF-stimulated p42/p44 mitogen-activated protein kinase (MAPK) activation in primary rat HSC was determined by Western blotting. Migration and proliferation of HSC was evaluated in Boyden chamber experiments and (3)H-thymidine incorporation assays respectively. Expression of FSAP was analysed in a CCl(4) mouse model of liver fibrosis by Western blot, quantitative real-time polymerase chain reaction and immunohistochemistry.ResultsFSAP inhibited PDGF-BB-stimulated p42/p44 MAPK phosphorylation, proliferation and migration of HSC. FSAP mRNA expression level was increased 3 h after CCl(4) application and decreased after 18 h and, in established fibrosis, after chronic CCl(4) administration. In parallel, there was a decrease in the circulating FSAP protein in chronic fibrosis. Concurrently, the homogenous hepatic expression pattern of FSAP was disturbed. Immunohistochemistry revealed a decrease of FSAP in hepatocytes in inflammatory and fibrotic lesions.ConclusionsOur results demonstrate an inhibitory effect of FSAP on PDGF-mediated activation of HSC. In addition, FSAP expression is transiently increased in acute-phase reaction but decreased during chronic fibrogenesis, which in turn may influence PDGF-BB availability and myofibroblast activity.

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