In vivo protection against endotoxin by plasma high density lipoprotein.

Abstract

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-foldelevated 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.

Apolipoprotein A-I Exerts Bactericidal Activity against Yersinia enterocolitica Serotype O:3

“…2D), suggesting that the previously observed interaction between the purified LPS YeO3 and apoA-I ( Fig. 2A) occurred most likely via the lipid A portion of LPS, as suggested earlier (26,27). In summary, apoA-I interaction with Y. enterocolitica is not direct and seems to require preexposure of the bacteria to serum proteins.…”

Membrane Permeabilization by Trypanosome Lytic Factor, a Cytolytic Human High Density Lipoprotein

“…Recently Samanovic et al (4) reported that TLF effectively kills Leishmania promastigotes within the parasitophorous vacuole of macrophages. Additionally, it is known that apoA-1 binds the bacterial outer membrane component lipopolysaccharide (38 -40), protects against the toxic effects of this molecule in vivo (41), and inhibits the growth of Escherichia coli in vitro (42). Thus it is intriguing to consider the possibility that the membrane-destabilizing activity of TLF is also an effective mechanism of combating bacterial infection.…”

Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

“…In addition to the decrease in CETP levels, a decrease in hepatic lipase activity (7-10) may also serve to maintain HDL cholesterol levels by decreasing formation of remnant HDL 2 and thus decreasing clearance of HDL. Preserving HDL cholesterol levels during infection and inflammation may be important because of the ability of HDL to prevent the toxic effects of endotoxin (41)(42)(43) and reduce oxidative stress (44,45). Maintaining HDL cholesterol levels may also be important for delivery of cholesterol to peripheral tissues that may have increased needs for cholesterol during infection and inflammation.…”