Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment

Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, United States.
Toxicology (Impact Factor: 3.62). 04/2010; 272(1-3):32-8. DOI: 10.1016/j.tox.2010.03.015
Source: PubMed


Among currently prescribed nonsteroidal anti-inflammatory drugs, sulindac (SLD) is associated with the greatest incidence of idiosyncratic hepatotoxicity in humans. Previously, an animal model of SLD-induced idiosyncratic hepatotoxicity was developed by cotreating rats with a nonhepatotoxic dose of LPS. Tumor necrosis factor-alpha (TNF) was found to be critically important to the pathogenesis. In this study, the mechanism of liver injury induced by SLD/LPS cotreatment was further explored. Protein carbonyls, products of oxidative stress, were elevated in liver mitochondria of SLD/LPS-cotreated rats. The results of analyzing gene expression in livers of rats before the onset of liver injury indicated that genes associated with oxidative stress were selectively regulated by SLD/LPS cotreatment. Antioxidant treatment with either ebselen or dimethyl sulfoxide attenuated SLD/LPS-induced liver injury. The role of oxidative stress was further investigated in vitro. SLD sulfide, the toxic metabolite of SLD, enhanced TNF-induced cytotoxicity and caspase 3/7 activity in HepG2 cells. SLD sulfide also increased dichlorofluorescein fluorescence, suggesting generation of reactive oxygen species (ROS). Hydrogen peroxide and TNF cotreatment of HepG2 cells caused greater cytotoxicity than either treatment alone. Either antioxidant tempol or a pancaspase inhibitor Z-VAD-FMK decreased cell death as well as caspase 3/7 activity induced by SLD sulfide/TNF coexposure. These results indicate that SLD/LPS treatment causes oxidative stress in livers of rats and suggest that ROS are important in SLD/LPS-induced liver injury in vivo. Furthermore, ROS contribute to the cytotoxic interaction of SLD and TNF by activating caspase 3/7.

Download full-text


Available from: Lyle D Burgoon, Dec 29, 2014
  • Source
    • "Compared to the complete protection by neutrophil depletion, eglin C substantially but incompletely reduced liver injury; thus, the proteases released from PMNs might not be the only PMN-derived mediators contributing to the pathogenesis. Antioxidants attenuated PMN-mediated hepatotoxicity in numerous inflammatory liver injury models (Liu et al., 1995; Jaeschke and Smith, 1997), including SLD/LPS-induced liver injury (Zou et al., 2010), supporting the possibility that both reactive oxygen species and proteases released by PMNs contribute to SLD/LPS-induced liver injury. TNF neutralization significantly attenuated liver injury induced by SLD/LPS in vivo (Zou et al., 2009a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies indicated that lipopolysaccharide (LPS) interacts with the nonsteroidal anti-inflammatory drug sulindac (SLD) to produce liver injury in rats. In the present study, the mechanism of SLD/LPS-induced liver injury was further investigated. Accumulation of polymorphonuclear neutrophils (PMNs) in the liver was greater in SLD/LPS-cotreated rats compared to those treated with SLD or LPS alone. In addition, PMN activation occurred specifically in livers of rats cotreated with SLD/LPS. The hypothesis that PMNs and proteases released from them play critical roles in the hepatotoxicity was tested. SLD/LPS-induced liver injury was attenuated by prior depletion of PMNs or by treatment with the PMN protease inhibitor, eglin C. Previous studies suggested that tumor necrosis factor-α (TNF) and the hemostatic system play critical roles in the pathogenesis of liver injury induced by SLD/LPS. TNF and plasminogen activator inhibitor-1 (PAI-1) can contribute to hepatotoxicity by affecting PMN activation and fibrin deposition. Therefore, the role of TNF and PAI-1 in PMN activation and fibrin deposition in the SLD/LPS-induced liver injury model was tested. Neutralization of TNF or inhibition of PAI-1 attenuated PMN activation. TNF had no effect on PAI-1 production or fibrin deposition. In contrast, PAI-1 contributed to fibrin deposition in livers of rats treated with SLD/LPS. In summary, PMNs, TNF and PAI-1 contribute to the liver injury induced by SLD/LPS cotreatment. TNF and PAI-1 independently contributed to PMN activation, which is critical to the pathogenesis of liver injury. Moreover, PAI-1 contributed to liver injury by promoting fibrin deposition.
    Full-text · Article · Dec 2011 · Toxicology

  • No preview · Article · Oct 2007
  • [Show abstract] [Hide abstract]
    ABSTRACT: CGX, a traditional herbal drug, has been prescribed for patients suffering from various liver diseases, including hepatitis B, alcoholic liver disease, and fatty liver. We investigated whether CGX has hepatoprotective effects against lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced acute liver injury and its underlying mechanism(s). Mice were administered CGX orally for 7 days prior to an injection of LPS (5 μg/kg)/D-GalN (700 mg/kg). Complete blood count, serum diagnostic markers, antioxidant activities, caspase activity, and histopathological examinations were conducted 8 h after the injection. To evaluate the immunological mechanism of CGX, serum TNF-α and IL-10 were investigated 1.5 h after LPS/D-GalN injection. CGX pretreatment (100, 200, and 400 mg/kg) inhibited the elevation of serum AST and ALT levels as well as histopathological alterations. Moreover, CGX pretreatment inhibited activation of caspase-3/7. CGX attenuated LPS/D-GalN-induced lipid peroxidation with concomitant improvement in total antioxidant activities (superoxide dismutase, catalase, and glutathione peroxidase). CGX elevated the antioxidant capacity of the liver in both the pathological and normal conditions. Furthermore, LPS/D-GalN-induced alterations of neutrophil and lymphocyte populations were ameliorated and serum TNF-α was decreased significantly by CGX. From these data we conclude that CGX protects the liver from LPS/D-GalN-induced hepatitis through antioxidant mechanisms as well as immune modulation.
    No preview · Article · Mar 2011 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association
Show more