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Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

These studies were aimed at characterizing an animal model of inflammation-induced hepatotoxicity that would mimic features of idiosyncratic liver toxicity observed in humans. An attempt was made to identify oxidative damage and the involvement of coagulation system in liver after monocrotaline (MCT) administration under the modest inflammatory condition induced by lipopolysaccharide (LPS) exposure. Mice were given MCT (200 mg/kg) or an equivalent volume of sterile saline (Veh.) po followed 4 h later by ip injection of LPS (6 mg/kg) or vehicle. Mice co-treated with MCT and LPS showed increased plasma alanine aminotransferase (ALT), decrease in platelet number, and a reduction in hematocrit. Accumulation of oxidized low-density lipoprotein (ox-LDL) was remarkably higher in the liver sections of mice co-treated with MCT and LPS compared to those given MCT or LPS alone. A similar trend was observed in the expression of CXCL16 receptor in the same liver sections. Elevated expression of tissue factor (TF) and fibrinogen was also observed in the liver sections of MCT/LPS co-treated mice. The in vitro results showed that incubation of HepG2 cells with CXCL16 antibody strongly diminished uptake of ox-LDL. Expression of ox-LDL, CXCL16, and TF represents an early event in the onset of hepatotoxicity induced by MCT/LPS; thus, it may contribute to our understanding of idiosyncratic liver injury and points to potential targets for protection or intervention.

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Acknowledgments

The authors wish to thank the Light Microscopy Core Facility members, Dr. Zia Shariat-Madar and Mr. Noah Osman (School of Pharmacy, University of Mississippi) for their assistance. The Zeiss 510-META confocal microscope service is supported through NSF Grant # MRI 619774 (ZSM). Special thanks are also due to Mrs. Lavanya Madgula, Mrs. Mona Haron and all the vivarium staff at the University of Mississippi for their help to complete the experiments. This work was supported by in part by the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative agreement [58-6408-2-0009] and US Food and Drug Administration [5U01FD002071-09 and 1U01FD003871-011].

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Mohamed A. Hammad & Larry A. Walker

  2. Center for Engineering in Medicine and Surgical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA

    Mohamed A. Hammad

  3. Faculty of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt

    Mohamed Sadek Abdel-Bakky

  4. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Mohamed A. Hammad, Mohamed Sadek Abdel-Bakky, Larry A. Walker & M. K. Ashfaq

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  1. Mohamed A. Hammad
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  2. Mohamed Sadek Abdel-Bakky
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  3. Larry A. Walker
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  4. M. K. Ashfaq
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Correspondence to M. K. Ashfaq.

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M. A. Hammad and M. S. Abdel-Bakky contributed equally to this work.

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Hammad, M.A., Abdel-Bakky, M.S., Walker, L.A. et al. Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity. Arch Toxicol 85, 1079–1089 (2011). https://doi.org/10.1007/s00204-011-0649-6

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