GADOLINIUM CHLORIDE TREATMENT ATTENUATES HEPATIC PLATELET ACCUMULATION AFTER LIPOPOLYSACCHARIDE ADMINISTRATION


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Abstract

Intravenous administration of LPS to rats results in the accumulation of both neutrophils and platelets in the liver and the development of midzonal hepatocellular necrosis. The development of liver injury entails contributions from both cellular and soluble mediators, including neutrophils, platelets, Kupffer cells, tumor necrosis factor-± (TNF-±), and components of the coagulation system. Much remains unknown about the interactions among these mediators in the pathogenesis of liver injury in vivo. Accordingly, we conducted studies with gadolinium chloride (GdCI3), an agent that inhibits Kupffer cell phagocytosis, to evaluate the role of Kupffer cells in lipopolysaccharide (LPS)-mediated liver injury, elevation in plasma TNF-± activity, thrombocytopenia, hepatic platelet accumulation, and activation of the coagulation system. Female Sprague-Dawley rats were pretreated with GdCI3-6H2O (10 mg/kg, i.v.) or saline vehicle 24 h before the administration of LPS (4 mg/kg, i.v.) or saline vehicle. In a preliminary study, this GdCI3 treatment regimen decreased the clearance of colloidal carbon from blood, indicating inhibition of Kupffer cell phagocytosis. Pretreatment with GdCI3 attenuated LPS-induced liver injury, monitored as increased plasma alanine aminotransferase and isocitrate dehydrogenase activities and histologic analysis. Electron micrographs of livers from rats treated with LPS revealed platelets within the sinusoids as well as Kupffer cells with phagolysosomes containing material resembling platelets. Pretreatment with GdCI3 attenuated LPS-induced thrombocytopenia and hepatic platelet accumulation, as measured by radiolabeled platelets. Treatment with GdCI3 did not, however, alter the elevation in plasma TNF-± activity or the activation of the coagulation system, as evidenced by a decrease in plasma fibrinogen concentration. These results suggest that Kupffer cells contribute to LPS-induced hepatic platelet accumulation and raise the possibility that protection against LPS-induced hepatic injury by Kupffer cell inactivation may be due at least partly to decreased deposition of platelets within the liver.

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