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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zou, W; Roth, RA; Younis, HS; Malle, E; Ganey, PE.
Neutrophil-cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injury.
TOXICOLOGY. 2011; 290(2-3): 278-285.
Doi: 10.1016/j.tox.2011.10.005
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- Co-Autor*innen der Med Uni Graz
- Malle Ernst
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- 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-á (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.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. - Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anti-Inflammatory Agents, Non-Steroidal - toxicity
- Cytokines - metabolism
- Drug-Induced Liver Injury - etiology
- Fibrin - metabolism
- Lipopolysaccharides - toxicity
- Male -
- Neutrophils - drug effects
- Plasminogen Activator Inhibitor 1 - metabolism
- Proteins - pharmacology
- Rabbits -
- Rats -
- Rats, Sprague-Dawley -
- Sulindac - toxicity
- Tumor Necrosis Factor-alpha - metabolism
- Find related publications in this database (Keywords)
- Idiosyncratic drug-induced liver injury
- Sulindac
- Lipopolysaccharide
- Tumor necrosis factor-alpha
- Plasminogen activator inhibitor-1
- Polymorphonuclear neutrophils