A rationale for the prophylactic use of monophosphoryl lipid A in sepsis and septic shock.
Monophosphoryl lipid A (MLA), a substructure of bacterial lipopolysaccharide (LPS), is being developed as a prophylactic for sepsis and septic shock. In the present study it was shown that MLA induced a rapid accumulation of IFN-gamma in mice that correlated with an in vivo priming of macrophages. Primed macrophages could be induced in vitro to synthesize nitric oxide, a key mediator of macrophage cytotoxicity. Due to its rapid clearance, MLA was not present in circulation at the time when IFN-gamma accumulated, suggesting that MLA could not synergize with IFN-gamma to systemically activate macrophages in vivo. MLA treatment tolerized mice against the IFN-gamma response--ie., treatment of mice with MLA on day 1 blocked LPS from inducing IFN-gamma on days 2-4. The significance of these results in relation to MLA's ability to enhance non-specific resistance and block LPS lethality in animals is discussed.
Gustafson
G L
GL
Ribi ImmunoChem Research, Inc., Hamilton, MT 59840.
Rhodes
M J
MJ
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007371:Interferon-gamma / Q000097:blood*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D009573:Nitrites / Q000378:metabolism; D012475:Salmonella; D018805:Sepsis / Q000517:prevention & control*; D012772:Shock, Septic / Q000517:prevention & control*
D008050:Lipid A; D008070:Lipopolysaccharides; D009573:Nitrites; D007371:Interferon-gamma; C048436:monophosphoryl lipid A