IN-VIVO PROTECTION AGAINST ENDOTOXIN BY PLASMA HIGH-DENSITY-LIPOPROTEIN

Overwhelming bacterial infection is accompanied by fever, hypotension, disseminated intravascular coagulation, and multiple organ failure le ading to death in 30-80% of cases. These classical symptoms of septic shock are caused by potent cytokines that are produced in response to endotoxin released from Gram-negative bacteria. Treatments with antibo dies and receptor antagonists to block endotoxin or cytokine mediators have given mixed results in clinical trials. High density lipoprotein (HDL) is a natural component of plasma that is known to neutralize en dotoxin in vitro. We report here that raising the plasma HDL concentra tion protects mice against endotoxin in vivo. Transgenic mice with 2-f old-elevated plasma HDL levels had more endotoxin bound to HDL, lower plasma cytokine levels, and improved survival rates compared with low- HDL mice. Intravenous infusion of HDL also protected mice, but only wh en given as reconstituted HDL prepared from phospholipid and either HD L apoprotein or an 18-amino acid peptide synthesized to mimic the stru cture of apolipoprotein A-I of HDL. Intact plasma HDL was mildly toxic , and HDL apoprotein was ineffective. The effectiveness of the reconst ituted peptide renders very unlikely any significant contribution to p rotection by trace proteins in apo-HDL. These data suggest a simple le aflet insertion model for binding and neutralization of lipopolysaccha ride by phospholipid on the surface of HDL. Plasma HDL may normally ac t to protect against endotoxin; this protection may be augmented by ad ministration of reconstituted HDL or reconstituted peptides.