2). Because the KTFR peptide inhibits the ADAMTS1-dependent activation of TGF-β in HSCs (Fig. 6), we then asked whether this peptide might also prevent the progression of hepatic damage in the mouse model. We assayed blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in C57Bl/6 mice treated with CCl4 and the KTFR peptide for 1 week and sacrificed 48 hours after the last CCl4 administration. Fig. 7B shows that the increase in plasma AST and ALT levels observed upon CCl4 administration was significantly reduced when mice were simultaneously
treated with the KTFR peptide, compared to the TKFR scrambled peptide (1.49-fold versus 5.07-fold and 3.89-fold versus 52.4-fold for AST and ALT, respectively). We also compared the amounts of collagen deposited in hepatic
tissues after oral administration of CCl4 for 1 week, using second harmonic generation (SHG) analysis, which allows for the direct detection learn more and quantification, without staining, of fibrillar collagen. The increase in collagen deposits observed upon CCl4 administration was significantly Lumacaftor mouse reduced when mice were simultaneously treated with the KTFR peptide, compared to the TKFR scrambled peptide (Fig. 8; P < 0.001). Similar results were observed with the LSKL peptide that was previously shown to reduce liver fibrosis after several weeks of CCl4 administration in rats.27 Taken together, these results support our conclusion that ADAMTS1 is implicated in the early events of liver fibrosis, and suggest that the KTFR peptide helps prevent hepatic fibrosis induced by CCl4. ECM remodeling MCE公司 is pivotal to liver fibrosis and is associated with increases in the synthesis of ECM components as well as proteases. In this study, we undertook a screening approach combined with integrated array-data analysis to create a meaningful
landscape of proteases that are deregulated in chronic liver disease. We first generated an interactive graph, and the resulting network was used as a framework for interpreting gene contribution to remodeling. Unexpectedly, the aggrecanase, ADAMTS1, emerged as a central node, together with MMP2, a well-known protease involved in chronic liver diseases, suggesting that ADAMTS1 might play a key role in the fibrosis process. Whereas MMPs have been widely implicated in liver fibrosis remodeling,28 growing interest has come more recently from the observation that members of the ADAM family are up-regulated in chronic liver diseases.29 In addition to ADAMTS1, we also observed the up-regulation of ADAMTS2 and ADAMTS13, two metallopeptidases recently implicated in liver fibrosis. ADAMTS13 is required for the proteolysis of von Willebrand factor and has been observed to be present in HSCs.30 Inactivation of ADAMTS2, a procollagen aminopeptidase, has been shown to reduce liver fibrosis in CCl4-induced mouse models.