Mice were sacrificed at various time points and peripheral blood and liver were collected for immunohistochemistry, flow cytometry, real-time PCR and microarray analysis. Results: Chronic oral administration of TAA induced two distinct phases

of liver injury (Figure 1). The first phase (0–7 days) induced a rapid peri-central inflammatory infiltrate in association with MCP-1 production and collagen deposition. This inflammatory infiltrate was enriched in non-phagocytic F4/80+ monocytes (Figure 2A,B), which co-localized INCB024360 with activated fibroblasts (αSMA+) and collagen-1 deposits (Figure 2C). Notably, this early phase of fibrosis occurred in the absence of a significant ductular reaction. A second phase of injury, initiated after 4 weeks treatment, was associated with macrophage accumulation and sequestration to peri-central regions and a surge in collagen deposition. In contrast to the early

phase, this second phase had a prominent ductular reaction which initiated in the portal regions and migrated to the site of injury. Strikingly, the activated progenitor cells co-localized with hepatic tissue macrophages. In the late stages of TAA-induced liver injury (6–12 weeks), the DR and collagen formed large fibrous septa resembling cirrhosis. Conclusions: During the initial stages of liver injury, monocytes are recruited to the tissue resulting in early collagen deposition. However, the interaction between the hepatic progenitor cells and tissues macrophages is required during the later stages of injury for the progression of liver fibrosis the KU-60019 clinical trial development of cirrhosis. 1. Friedman SL. Mac the knife? Macrophages- the double-edged sword of hepatic fibrosis. The Journal of clinical investigation 2005;115:29–32. 2. Clouston AD et al. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 2005;41:809–818. V KNIGHT, J TCHONGUE, D LOURENSZ, A LIU, P TIPPING, W SIEVERT Centre for Inflammatory Diseases, Monash University, Victoria, Australia Tissue factor (TF) has a well-known function in hemostasis but also plays an important role in angiogenesis, sepsis and inflammation. TF has 3 domains, the

cytoplasmic domain 上海皓元医药股份有限公司 acts as a signaling receptor to promote a proinflammatory phenotype in macrophages (Cunningham 1999). Deletion of the TF cytoplasmic domain reduces the severity of inflammatory arthritis in an experimental murine model (Yang 2004). The aim of this study was to investigate whether deletion of the TF cytoplasmic domain protected against fibrogenesis in a model of hepatic inflammation and fibrosis. Methods: 9 week old wildtype (WT) and C57/BL6 mice with deletion of the TF cytoplasmic domain (TF§CT/§CT) received twice weekly intraperitoneal injections of carbon tetrachloride for 8 weeks. Fibrosis was quantified by computer assisted morphometry of Sirius red stained liver sections. Hydroxyproline assay quantified hepatic collagen content.