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TOXICOLOGY

Neutrophil Interaction with the Hemostatic System Contributes to Liver Injury in Rats Cotreated with Lipopolysaccharide and Ranitidine

Departments of Biochemistry and Molecular Biology (X.D., J.L.), Pharmacology and Toxicology (J.P.L., P.E.G., R.A.R.), and Microbiology and Molecular Genetics (W.Z.), Michigan State University, East Lansing, Michigan; and Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria (E.M.)

Cotreatment of rats with nontoxic doses of ranitidine (RAN) and lipopolysaccharide (LPS) causes liver injury, and this drug-inflammation interaction might be a model for idiosyncratic adverse drug responses in humans. Both polymorphonuclear neutrophils (PMNs) and the hemostatic system have been shown to be important in the injury. We tested the hypothesis that PMNs cause liver injury by interacting with the hemostatic system and producing subsequent hypoxia. In rats cotreated with LPS/RAN, PMN depletion by anti-PMN serum reduced fibrin deposition and hypoxia in the liver. PMN depletion also reduced the plasma concentration of active plasminogen activator inhibitor-1 (PAI-1), a major down-regulator of the fibrinolytic system. This suggests that PMNs promote fibrin deposition by increasing PAI-1 concentration. PMNs were activated in the livers of LPS/RAN-cotreated rats as evidenced by increased staining for hypochlorous acid-modified proteins generated by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes. Antiserum against the PMN adhesion molecule CD18 protected against LPS/RAN-induced liver injury. Because CD18 is important for PMN transmigration and activation, these results suggest that PMN activation is required for the liver injury. Furthermore, anti-CD18 serum reduced biomarkers of hemostasis and hypoxia, suggesting the necessity for PMN activation in the interaction between PMNs and the hemostatic system/hypoxia. Liver injury, liver fibrin, and plasma PAI-1 concentration were also reduced by eglin C, an inhibitor of proteases released by activated PMNs. In summary, PMNs are activated in LPS/RAN-cotreated rats and participate in the liver injury in part by contributing to hemostasis and hypoxia.

Address correspondence to: Robert A. Roth, Department of Pharmacology and Toxicology, Michigan State University, Food Safety and Toxicology Building, Michigan State University, Room 221, East Lansing, MI 48824. E-mail: rothr{at}msu.edu

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				X. Deng, J. Lu, L. D. Lehman-McKeeman, E. Malle, D. L. Crandall, P. E. Ganey, and R. A. Roth p38 Mitogen-Activated Protein Kinase-Dependent Tumor Necrosis Factor-{alpha}-Converting Enzyme Is Important for Liver Injury in Hepatotoxic Interaction between Lipopolysaccharide and Ranitidine J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 144 - 152. [Abstract] [Full Text] [PDF]