Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X.
Lipid X, a precursor of lipid A (the toxic moiety of endotoxin), has been shown to protect animals from the lethal effects of endotoxin challenge. We investigated the mechanism of action of lipid X and 3-aza-lipid X, a diamino-analogue, in vitro, using the ability of lipopolysaccharide (LPS) to prime neutrophils for an enhanced release of toxic oxygen radicals. Lipid X and 3-aza-lipid X inhibited LPS-induced neutrophil priming in a concentration-dependent manner. At high concentrations, 3-aza-lipid X was a partial agonist of priming. Lipid X was found to inhibit LPS-induced priming by directly interacting with the neutrophil in contrast to polymyxin B, which neutralized LPS by binding to it. Increasing concentrations of lipid X shifted the LPS dose response curve of neutrophils rightward but did not prevent maximum priming at higher LPS concentrations, a finding consistent with competitive inhibition. These results suggest that lipid X, a compound structurally related to lipid A, may block neutrophil priming by competing with LPS for cellular binding sites. Lipid X appears to have a novel mechanism of inhibiting LPS effect and may have efficacy in the treatment of gram-negative sepsis.
D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006017:Glycolipids / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D009994:Osmolar Concentration; D012475:Salmonella
D004731:Endotoxins; D006017:Glycolipids; D008070:Lipopolysaccharides; C053474:3-aza-lipid X; C044283:lipid X