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Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice

Authors

  • Mohamed A. Hammad,

    1. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA
    2. Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, USA
    3. Center for Engineering in Medicine and Surgical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
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    • The first two authors contributed equally to this work.

  • Mohamed Sadek Abdel-Bakky,

    1. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA
    2. Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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    • The first two authors contributed equally to this work.

  • Larry A. Walker,

    1. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA
    2. Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, USA
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  • Mohammad K. Ashfaq

    Corresponding author
    • National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, USA
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Correspondence to: Mohammad K. Ashfaq, Thad Cochran Research Center, School of Pharmacy, University of Mississippi, Room 2047, University, MS 38677, USA.

E-mail: mkashfaq@olemiss.edu

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 (5.6 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.

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