GADOLINIUM CHLORIDE TREATMENT ATTENUATES HEPATIC PLATELET ACCUMULATION AFTER LIPOPOLYSACCHARIDE ADMINISTRATION

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 enta ils contributions from both cellular and soluble mediators, including neutrophils, platelets, Kupffer cells, tumor necrosis factor-alpha (TN F-alpha), and components of the coagulation system. Much remains unkno wn about the interactions among these mediators in the pathogenesis of liver injury in vivo. Accordingly, we conducted studies with gadolini um chloride (GdCl3), an agent that inhibits Kupffer cell phagocytosis, to evaluate the role of Kupffer cells in lipopolysaccharide (LPS)-med iated liver injury, elevation in plasma TNF-alpha activity, thrombocyt openia, hepatic platelet accumulation, and activation of the coagulati on system. Female Sprague-Dawley rats were pretreated with GdCl3-6H(2) O (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 G dCl3 treatment regimen decreased the clearance of colloidal carbon fro m blood, indicating inhibition of Kupffer cell phagocytosis. Pretreatm ent with GdCl3 attenuated LPS-induced liver injury, monitored as incre ased plasma alanine aminotransferase and isocitrate dehydrogenase acti vities and histologic analysis. Electron micrographs of livers from ra ts treated with LPS revealed platelets within the sinusoids as well as Kupffer cells with phagolysosomes containing material resembling plat elets. Pretreatment with GdCl3 attenuated LPS-induced thrombocytopenia and hepatic platelet accumulation, as measured by radiolabeled platel ets. Treatment with GdCl3 did not, however, alter the elevation in pla sma TNF-alpha activity or the activation of the coagulation system, as evidenced by a decrease in plasma fibrinogen concentration. These res ults suggest that Kupffer cells contribute to LPS-induced hepatic plat elet accumulation and raise the possibility that protection against LP S-induced hepatic injury by Kupffer cell inactivation may be due at le ast partly to decreased deposition of platelets within the liver.