Protection of mice from lethal endotoxemia by use of an ornithine-containing lipid or a serine-containing lipid.
The effects of an ornithine-containing lipid [alpha-N-(3-acyloxyacyl)-ornithine (Orn-L)] or a serine-containing lipid [alpha-N-(3-acyloxyacyl)-serine (Ser-L)] from Flavobacterium meningosepticum on lethal endotoxemia in mice were examined. When 500 micrograms of Orn-L was intravenously administered 1 h before intravenous administration of a lethal dose of endotoxin, none of the mice died. The protective effect of Ser-L was weaker than that of Orn-L. Light and electron microscopic studies demonstrated that necrosis of hepatocytes caused by endotoxin was prevented by pretreatment with Orn-L. Furthermore, Kupffer cells were activated morphologically 1 h after the administration of Orn-L or Ser-L, and the liposomes of the lipoamino acids were incorporated into phagolysosomes in activated Kupffer cells. The activity of tumor necrosis factor in sera of endotoxin-treated mice was decreased markedly by pretreatment of mice with Orn-L. In vitro, the lipoamino acids suppressed endotoxin-induced tumor necrosis factor generation but did not suppress tumor necrosis factor generation induced by zymosan and whole cells of Staphylococcus aureus. These results suggested that Orn-L and Ser-L can be used as specific blocking agents against endotoxin. The blocking mechanism may be antagonistic, because of the structural similarities between the lipoamino acids and endotoxin lipid A.
Kawai
Y
Y
Department of Bacteriology, National Institute of Health, Japan.
Kaneda
K
K
Morisawa
Y
Y
Akagawa
K
K
D000818:Animals; D002460:Cell Line; D005417:Flavobacterium / Q000032:analysis; D008055:Lipids / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D009952:Ornithine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D012694:Serine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D012772:Shock, Septic / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008055:Lipids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C051524:ornithine containing aminolipid; C069989:serine containing aminolipid; D012694:Serine; D009952:Ornithine