Hepatic fibrosis and cirrhosis are the common endpoint of a variety of liver diseases and represent a major global health burden. The current model for hepatic fibrosis development is that progressive injurious stimuli lead to dysregulation of extracellular matrix (ECM) turnover. Activation of the hepatic stellate cell (HSC) has been identified as the key cellular event resulting in the accumulation of extracellular matrix (Friedman 2008) and therefore there is considerable interest in factors

more »

... hat regulate HSC activation and collagen expression. There is a strong linkage between inflammation, coagulation and fibrosis (Tacke, Luedde et al. 2009). One proposed mechanism for this linkage is signalling by coagulation factors through their cellular receptors protease-activated receptors (PARs) to activate stellate cells (Anstee, Wright et al. 2009). This thesis has explored the role of PAR-1, PAR-2 and the cytoplasmic domain of tissue factor in the development of hepatic fibrosis. The close relationship between the coagulation cascade and the inflammatory response led to the hypothesis that coagulation factors and their receptors may play an important role in hepatic fibrogenesis. In order to mimic human liver disease processes, a mouse model was studied using carbon tetrachloride administration to generate liver fibrosis. Mice with deletion of the PAR-1 gene, PAR-2 gene, with deletion of the cytoplasmic domain of TF and with dual deletion of PAR-2 gene and TF cytoplasmic domain were individually studied and compared to wildtype. Common fibrosis endpoints were studied in vivo. In vitro experiments were performed with a line of human hepatic stellate cells. Initial experiments demonstrate PAR-1 deficiency protects against liver fibrosis with reduced histological fibrosis, hydroxyproline content, TGF β gene and protein expression seen. This adds evidence to support the view that PAR-1 is involved in hepatic fibrogenesis. PAR-2 deficiency was also found to afford protection from hepatic fibrosis. PAR-1 and PAR-2 activat [...]