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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.
Conclusion:
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.
Insights
Soluble CD14 (sCD14) reduced mortality in a mouse model of septic shock caused by lipopolysaccharide (LPS). However, sCD14 did not prevent shock symptoms or liver injury, indicating limited therapeutic efficacy.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Septic shock is often caused by Gram-negative bacteria and lipopolysaccharide (LPS).
- Targeting LPS-receptor interactions is a potential therapeutic strategy.
- Soluble CD14 (sCD14) inhibits LPS binding to cellular receptors in vitro.
Purpose of the Study:
- To evaluate the in vivo efficacy of human recombinant sCD14 in neutralizing endotoxin.
- To assess sCD14's protective effects against LPS-induced shock and liver injury in a mouse model.
Main Methods:
- A mouse model of septic shock was induced using Salmonella abortus equi LPS.
- Mice were treated with sCD14 before or simultaneously with LPS administration.
- LPS-induced liver injury was assessed in galactosamine-sensitized mice.
Main Results:
- sCD14 treatment reduced mortality when given before or with LPS.
- sCD14 did not affect early proinflammatory cytokine secretion.
- sCD14 failed to protect against shock symptoms, liver injury, or LPS-inducible liver injury.
Conclusions:
- sCD14 demonstrated partial protection against LPS-induced mortality in vivo.
- The compound did not prevent LPS-induced shock or liver damage.
- sCD14's failure to block Kupffer cell activation in vitro may explain its limited in vivo efficacy.