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LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria
N Lamping1, R Dettmer, N W Schröder
1Institut für Mikrobiologie und Hygiene, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, D-10098, Berlin, Germany.
Abstract:
LPS-binding protein (LBP) recognizes bacterial LPS and transfers it to CD14, thereby enhancing host cell stimulation, eventually resulting in pathogenic states such as septic shock. Recently, LBP also was shown to detoxify LPS by transferring LPS into HDL particles in vitro. Thus, the predominant in vivo function of LBP has remained unclear. To investigate the biological activity of acute phase concentrations of recombinant murine LBP, high concentrations of LBP were investigated in vitro and in vivo. Although addition of low concentrations of LBP to a murine macrophage cell line enhanced LPS-induced TNF-alpha synthesis, acute phase concentrations of LBP blocked this effect in comparison to low-dose LBP. When injected into mice intraperitoneally, LBP inhibited LPS-mediated cytokine release and prevented hepatic failure resulting in a significantly decreased mortality rate in LPS-challenged and D-galactosamine-sensitized mice, as well as in a murine model of bacteremia. These results complement a recent study revealing LBP-deficient mice to be dramatically more susceptible to an intraperitoneal Salmonella infection as compared with normal mice. We conclude that acute phase LBP has a protective effect against LPS and bacterial infection and may represent a physiologic defense mechanism against infection. Despite the limitations of any murine sepsis model, the results shown may imply that LBP could have beneficial effects during gram-negative peritonitis in humans.
Insights
Acute phase concentrations of LPS-binding protein (LBP) protect against LPS and bacterial infection by inhibiting cytokine release and preventing organ failure. This suggests LBP acts as a physiological defense mechanism against infection, potentially benefiting humans with gram-negative peritonitis.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- LPS-binding protein (LBP) typically enhances host cell stimulation by bacterial LPS, potentially leading to septic shock.
- Recent studies suggest LBP may also detoxify LPS in vitro by transferring it to HDL particles.
- The primary in vivo function of LBP, particularly at acute phase concentrations, remained unclear.
Purpose of the Study:
- To investigate the biological activity of acute phase concentrations of recombinant murine LBP.
- To determine the in vivo function of LBP in response to LPS and bacterial challenge.
Main Methods:
- In vitro studies using a murine macrophage cell line treated with varying LBP concentrations.
- In vivo studies involving intraperitoneal injection of LBP into mice subjected to LPS challenge, D-galactosamine sensitization, or bacteremia.
- Assessment of LPS-induced TNF-alpha synthesis, cytokine release, hepatic failure, and mortality rates.
Main Results:
- Acute phase concentrations of LBP inhibited LPS-induced TNF-alpha synthesis in macrophages, contrasting with low-dose LBP effects.
- In vivo, LBP administration significantly reduced LPS-mediated cytokine release and prevented hepatic failure.
- LBP treatment led to a decreased mortality rate in mice challenged with LPS and D-galactosamine, and in a bacteremia model.
Conclusions:
- Acute phase LBP exhibits a protective effect against LPS and bacterial infection.
- LBP may function as a physiological defense mechanism against infection.
- These findings suggest potential beneficial effects of LBP in human gram-negative peritonitis.