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Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide)
1Division of Molecular Medicine, North Shore University Hospital/Cornell University Medical College, Manhasset, NY 11030, USA.
Abstract:
Endotoxic shock is a life-threatening condition mediated by cytokines released after exposure to bacterial LPS/endotoxin. Activation of monocytes and neutrophils by the binding of LPS to the membrane receptor, CD14, plays a key role in this response. Furthermore, a soluble form of the CD14 receptor enhances the endothelial cell response to LPS. We show here that despite the agonist effects of soluble CD14 on the endothelial cell response to LPS, recombinant soluble CD14 is able to protect mice from LPS-induced lethality. This protection appears to be associated with the inhibition of TNF-alpha release. These results suggest that the soluble CD14 receptor may represent a new form of therapy for endotoxic shock in humans.
Insights
Recombinant soluble CD14 protects mice from lethal endotoxic shock by inhibiting tumor necrosis factor-alpha. This suggests soluble CD14 (sCD14) may be a novel therapy for endotoxic shock in humans.
Area of Science:
- Immunology
- Pathophysiology
- Biochemistry
Background:
- Endotoxic shock is a critical condition driven by cytokines released following bacterial lipopolysaccharide (LPS) exposure.
- Monocyte and neutrophil activation via LPS binding to the CD14 receptor is central to this response.
- Soluble CD14 (sCD14) amplifies the endothelial cell response to LPS.
Purpose of the Study:
- To investigate the therapeutic potential of recombinant soluble CD14 in a mouse model of LPS-induced endotoxic shock.
- To determine the mechanism by which sCD14 influences LPS-mediated lethality.
Main Methods:
- Administration of recombinant soluble CD14 to mice challenged with LPS.
- Monitoring of survival rates and measurement of cytokine levels, specifically TNF-alpha.
Main Results:
- Recombinant soluble CD14 administration significantly protected mice against LPS-induced lethality.
- Protection was correlated with a marked inhibition of TNF-alpha release.
- Despite sCD14's agonist effect on endothelial cells, it conferred protection in vivo.
Conclusions:
- Soluble CD14 demonstrates a protective effect in experimental endotoxic shock.
- Inhibition of TNF-alpha appears to be a key mechanism for sCD14-mediated protection.
- Soluble CD14 represents a promising therapeutic candidate for human endotoxic shock.