title: Antagonism of lipopolysaccharide-induced priming of human neutrophils by lipid A analogs.
abstract: Lipid X, a monosaccharide precursor of the lipid A component of LPS, has been found to antagonize LPS-induced priming of human neutrophils in a manner consistent with competitive inhibition. In this investigation, the inhibition of neutrophil priming by lipid A analogs was found to be specific for LPS-induced priming. Priming of neutrophils by TNF, IL-8, and C5a were all unaffected by increasing concentrations of 3-aza-lipid X-4-phosphate (compound 3), a monosaccharide LPS-antagonist. Unlike lipid X, the pattern of antagonism exhibited by some monosaccharide LPS-antagonists was noncompetitive-like. The relationship between the chemical structure and inhibition pattern was found to be complex and not simply related to the type of acyl linkage at the C-3 position of the glucosamine backbone. Lipid A analogs were found to antagonize calcium ionophore A23187-stimulated leukotriene B4 (LTB4) production from LPS-primed neutrophils in a pattern of inhibition qualitatively similar to that seen with FMLP-stimulated O2- production. Resting and FMLP-stimulated (peak) cytosolic-free calcium levels did not differ significantly between unprimed and LPS-primed neutrophils, (p = 0.67 and p = 0.97, respectively). Furthermore, antagonism of LPS-mediated priming by 3-aza-lipid X-4-phosphate (compound 3) could not be explained by changes in intracellular calcium flux despite marked inhibition of O2- production (p less than 0.0001). Thus, lipid A analogs antagonize only LPS-induced priming and the pattern of inhibition is dependent on the chemical structure. Inhibition of LPS-induced priming by lipid A analogs may involve an early step in the signal transduction pathway common to both O2- and LTB4 generation, but independent of intracellular calcium concentration.
authors.affiliation: Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: A L
authors.initials: AL
authors.lastname: Van Dervort
authors.forename: M E
authors.initials: ME
authors.lastname: Doerfler
authors.forename: P
authors.initials: P
authors.lastname: Stuetz
authors.forename: R L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D002118:Calcium / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D008050:Lipid A / Q000737:chemistry / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D015394:Molecular Structure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D016897:Respiratory Burst; D015290:Second Messenger Systems; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D013481:Superoxides; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium