ALPHA-TOCOPHEROL LIPOSOMES ALLEVIATE LPS-INDUCED HEPATOTOXICITIES

Gram-negative bacteria, in part through lipopolysaccharide (LPS) and t umor necrosis factor-alpha (TNF alpha), activate phagocytes to generat e reactive oxygen species (ROS), which have been known to play a key r ole in the pathogenesis of liver injury. Accordingly, we hypothesized that the susceptibility of the liver to ROS should be reduced by augme nting its antioxidant status. Adult male Sprague-Dawley rats were pret reated with alpha-tocopherol liposomes (20 mg alpha-tocopherol/kg body weight, i.v.), plain liposomes or saline. 24 h after liposomal treatm ent, rats were injected intravenously with LPS (I mg/kg, Escherichia c oli: O111:B4) and killed 2 h later. Livers of saline-pretreated animal s challenged with LPS were damaged as demonstrated by increases in pla sma alanine aminotransferase (ALT) and aspartate aminotransferase (AST ) activities. The hepatic injury appeared to be associated with oxidat ive stress-mediated mechanisms as evidenced by increases in lipid pero xidation and decreases in glutathione concentration in the liver, both indices of oxidative stress. Also, LPS injection resulted in increase s in plasma TNF alpha and thromboxane B-2 (TXB(2)) levels, as well as increases in hepatic myeloperoxidase (MPO) activity and chloramine con centration, suggestive of activation of the inflammatory response. Pre treatment of rats with plain liposomes, 24 h prior to LPS challenge, f ailed to protect against the LPS-induced liver injury. Although pretre atment of animals with a-tocopherol liposomes was not effective in pre venting the LPS-induced inflammatory response, it conferred a partial protection against the LPS-induced changes in plasma AST and ALT activ ities as well as in hepatic levels of lipid peroxidation, glutathione and chloramine concentrations. These data appear to suggest that augme ntation of the hepatic antioxidant status is effective in alleviating the LPS-induced fiver injury.