Protection of mice against lethal endotoxemia by lipid X is mediated through inhibition of neutrophil function.
The effects of lipid X and 3-aza-lipid X on in vitro neutrophil function were related to their ability to inhibit the toxicity of endotoxin in galactosamine-sensitized mice. In vitro, lipid X and 3-aza-lipid X (100 ng/ml) blocked completely endotoxin (100 ng/ml)-enhanced neutrophil aggregation, superoxide anion generation, and release of beta-glucuronidase in response to a chemotactic tripeptide, f-met-leu-phe (10(-7) M). In vivo, lipid X at 250 micrograms/mouse (but not 3-aza-lipid X at a similar dose) protected groups of 10 mice from an otherwise lethal dose of endotoxin in galactosamine-sensitized mice when it was administered IV 4 hr or 2 hr before endotoxin challenge. The minimum effective dose of lipid X that could protect 50% of the challenged mice was calculated to be 715 micrograms/kg. However, lipid X failed to suppress neutrophil infiltration into the lungs. The ability of lipid X to inhibit endotoxin-induced neutrophil responses and to protect against lethal endotoxemia may be due to induction of early phase tolerance to endotoxin by the compound.
Lam
C
C
Sandoz Forschungsinstitut Ges.m.b.H., Vienna, Austria.
Schütze
E
E
Walzl
H
H
Basalka
E
E
D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D005688:Galactosamine; D005966:Glucuronidase / Q000097:blood; D006017:Glycolipids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D012772:Shock, Septic / Q000150:complications / Q000517:prevention & control*; D013481:Superoxides / Q000097:blood
D006017:Glycolipids; D008050:Lipid A; D008070:Lipopolysaccharides; C053474:3-aza-lipid X; D013481:Superoxides; D005688:Galactosamine; C044283:lipid X; D005966:Glucuronidase