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 leading 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 antibodies 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 endotoxin in vitro. We report here that raising the plasma HDL concentration protects mice against endotoxin in vivo. Transgenic mice with 2-fold-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 when given as reconstituted HDL prepared from phospholipid and either HDL apoprotein or an 18-amino acid peptide synthesized to mimic the structure of apolipoprotein A-I of HDL. Intact plasma HDL was mildly toxic, and HDL apoprotein was ineffective. The effectiveness of the reconstituted peptide renders very unlikely any significant contribution to protection by trace proteins in apo-HDL. These data suggest a simple leaflet insertion model for binding and neutralization of lipopolysaccharide by phospholipid on the surface of HDL. Plasma HDL may normally act to protect against endotoxin; this protection may be augmented by administration of reconstituted HDL or reconstituted peptides.
Levine
D M
DM
Rogosin Institute, New York Hospital-Cornell Medical Center, NY 10021.
Parker
T S
TS
Donnelly
T M
TM
Walsh
A
A
Rubin
A L
AL
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004926:Escherichia coli; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis; D011485:Protein Binding; D012475:Salmonella; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001053:Apolipoproteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha