Different efficacy of soluble CD14 treatment in high- and low-dose LPS models.
BACKGROUND
About 50% of septic shock cases are attributed to Gram-negative bacteria or their cell wall compound lipopolysaccharide (LPS, endotoxin). An attractive therapeutic strategy could target the binding of LPS to its cellular receptors. In vitro the soluble form of the endotoxin receptor CD14 (sCD14) competitively prevents binding of LPS to membrane-bound CD14 and inhibits LPS-stimulated macrophage responses.


METHODS
We tested the in vivo endotoxin-neutralizing capacity of human recombinant sCD14 using a mouse model of shock induced by 8 micrograms g-1 of LPS from Salmonella abortus equi.


RESULTS
In this model, treatment with sCD14 reduced mortality if administered before or simultaneously with LPS. However, application of sCD14 had no effect on the secretion of early proinflammatory cytokines and did not protect the animals against the development of apparent shock symptoms and liver injury. sCD14 also failed to prevent LPS-inducible (7.5 ng g-1) liver injury in galactosamine-sensitized mice.


CONCLUSIONS
In line with these findings, sCD14 did not block LPS-induced activation of Kupffer cells in vitro, which might explain why the compound only partially protected in vivo.
Stelter
F
F
Ernst-Moritz-Arndt-University, Greifswald, Germany.
Witt
S
S
Fürll
B
B
Jack
R S
RS
Hartung
T
T
Schütt
C
C
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000209:etiology / Q000517:prevention & control*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma