Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

Abstract

Coadministration of nonhepatotoxic doses of the histamine 2-receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN-treated rats. Rats were given either LPS (44.4 ؋ 10 6 EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RANcotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin-antithrombin dimers and in serum concentration of plasminogen activator inhibitor-1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN-cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN-treated rats. In conclusion, the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model. B acterial lipopolysaccharide (endotoxin, LPS) is an outer cell wall component of gram-negative bacteria and a potent inflammagen. Exposure to large doses of LPS can cause extensive damage to the liver and other organs in humans and rodents. 1 Exposure of liver to smaller amounts of LPS is commonplace and occurs through multiple means, including LPS translocation from the intestinal lumen into the portal venous blood. 2 Inflammatory responses triggered by small doses of LPS typically are noninjurious, but several studies have shown they can markedly enhance the hepatotoxicity of a variety of chemicals. 2 Moreover, idiosyncratic hepatotoxicity during drug therapy may arise from coexposure to inflammagens such as LPS. 3 Idiosyncratic liver injury occurs during treatment with numerous drugs, typically in a small fraction of people taking the drug. These responses are seemingly unrelated to dose, and the time of onset relative to beginning of drug therapy is often highly variable. One drug that causes idiosyncratic hepatotoxicity is the histamine 2 receptorantagonist, ranitidine (RAN). RAN is used therapeutically for treatment of duodenal ulcers, gastric hypersecretory diseases, and gastroesophageal reflux disease, and it is estimated to cause liver injury in less than 0.1% of people taking the drug. 4 Mechanisms of RAN idiosyncrasy are not understood, but liver injury might develop in part from a coexisting infl...

Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

“…Lesions in livers of LPS/RAN-treated rats have been described previously (Luyendyk et al, 2003b) and were characterized by midzonal and subserosal hepatocellular oncotic necrosis and neutrophilic infiltrate (data not shown). Previous studies showed that the coagulation system is a critical mediator of LPS/RAN-induced liver injury (Luyendyk et al, 2004a). Confirming these results, serum ALT activity was significantly attenuated by heparin at 6 h (Fig.…”

“…Indeed, liver hypoxia is observed at a time near the onset of hepatotoxicity in this model (Luyendyk et al, 2004a). Although these results are consistent with liver hypoxia as an important downstream deleterious consequence of hemostasis in LPS/RANtreated rats, a direct link between coagulation system activation and hypoxia has not yet been established in this model.…”

“…Coagulation system activation in LPS/RAN-treated rats results in sinusoidal fibrin deposition, one consequence of which is liver hypoxia (Luyendyk et al, 2004a). Indeed, liver hypoxia is observed at a time near the onset of hepatotoxicity in this model (Luyendyk et al, 2004a).…”

“…Accordingly, cross-talk between coagulation and PMNs can occur during liver injury. In LPS/RAN-treated rats, coagulation system activation and fibrin deposition occurred before the onset of hepatotoxicity, and the ensuing liver injury was prevented by administration of the anticoagulant heparin (Luyendyk et al, 2004a). Accordingly, interaction between accumulated PMNs and the coagulation system might occur in LPS/RAN-treated rats.…”

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…Bacterial LPS (100 µg/kg, i.p), 28,29 was administered 2 hours before antimalarial drugs. Methyl palmitate (2 g/kg, i.v) was applied as an effective kupffer cells inhibitor and administered 44 hours before LPS.…”