The first two authors contributed equally to this work.
Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice
Article first published online: 9 MAR 2012
Copyright © 2012 John Wiley & Sons, Ltd.
Journal of Applied Toxicology
Volume 33, Issue 8, pages 774–783, August 2013
How to Cite
Hammad, M. A., Abdel-Bakky, M. S., Walker, L. A. and Ashfaq, M. K. (2013), Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice. J. Appl. Toxicol., 33: 774–783. doi: 10.1002/jat.2728
- Issue published online: 21 JUN 2013
- Article first published online: 9 MAR 2012
- Manuscript Accepted: 30 DEC 2011
- Manuscript Revised: 29 DEC 2011
- Manuscript Received: 22 NOV 2011
- tissue factor;
- oxidized low-density lipoprotein;
- keratinocyte-derived chemokine;
- tissue factor antisense oligodeoxynucleotides
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 (5.6 mg kg−1) was given i.v. to ND4 male mice 30 min after administration of MCT (200 mg kg−1) p.o. followed after 3.5 h by LPS i.p. (6 mg kg−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 © 2012 John Wiley & Sons, Ltd.