Abstract
Tissue factor (TF) is a membranous glycoprotein that functions as a receptor for coagulation factor VII/VIIa and activates the coagulation system when blood vessels or tissues are damaged. TF was upregulated in our monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. We tested the hypothesis that TF-dependent fibrin deposition and lipid peroxidation in the form of oxidized low-density-lipoprotein (ox-LDL) accumulation contribute to liver inflammation induced by MCT/LPS in mice. In the present study, we blocked TF using antisense oligodeoxynucleotides against mouse TF (TF-ASO). TF-ASO (5.6mgkg-1) was given i.v. to ND4 male mice 30min after administration of MCT (200mgkg-1) p.o. followed after 3.5h by LPS i.p. (6mgkg-1). Blood alanine aminotransferase (ALT), TF, ox-LDL, platelets, hematocrit and keratinocyte-derived chemokine (KC) levels were evaluated in different treatment groups. Fibrin deposition and ox-LDL accumulation were also analyzed in the liver sections using immunofluorescent staining. The results showed that TF-ASO significantly restored blood ALT, hematocrit and KC levels, distorted after MCT/LPS co-treatment, as well as preventing the accumulation of ox-LDL and the deposition of fibrin in the liver tissues, and thereby inhibited liver injury caused by MCT/LPS. In a separate experiment, TF-ASO administration significantly prolonged animal survival. The current study demonstrates that TF is associated with MCT/LPS-induced liver injury. Administration of TF-ASO successfully prevented this type of liver injury. Copyright (c) 2012 John Wiley & Sons, Ltd.