Abstract
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.
Footnotes
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This work was supported by the National Institutes of Health (Grant DK061315) and by the Austrian Science Fund (Grants FWF P17013 and P19074-B05).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.122069.
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ABBREVIATIONS: LPS, lipopolysaccharide; RAN, ranitidine; PMN, polymorphonuclear neutrophil; PA, plasminogen activator; PAI-1, plasminogen activator inhibitor-1; Veh, vehicle; ALT, alanine aminotransferase; PBS, phosphate-buffered saline; CS, control normal rabbit serum; NAS, rabbit anti-rat PMN antiserum; TAT, thrombin-antithrombin; ELISA, enzyme-linked immunosorbent assay; PIM, pimonidazole; HOCl, hypochlorous acid; PAGE, polyacrylamide gel electrophoresis; ANOVA, analysis of variance.
- Received February 28, 2007.
- Accepted May 10, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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