Apolipoprotein E protects against-bacterial lipopolysaccharide-induced lethality - A new therapeutic approach to treat Gram-negative sepsis

Septic shock is the most common cause of death in intensive care units and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived cytokines. Previously, we showed that apolipoprotein E (apoE), an established modulator of lipid metabolism, can bind LPS, thereby redirecting LPS from macrophages to hepatocytes in vivo. We now report tha t intravenously administered LPS strongly increases the serum levels of apo E. In addition, apoE can prevent the LPS-induced production of cytokines an d subsequent death in rodents. Finally, apoE-deficient mice show a signific antly higher sensitivity toward LPS than control wild-type mice. These find ings indicate that apoE may have a physiological role in the protection aga inst sepsis, and recombinant apoE may be used therapeutically to protect ag ainst LPS-induced endotoxemia.