LPS-BINDING PROTEIN PROTECTS MICE FROM SEPTIC SHOCK CAUSED BY LPS OR GRAM-NEGATIVE BACTERIA

LPS-binding protein (LBP) recognizes bacterial LPS and transfers it to CD14, thereby enhancing host cell stimulation, eventually resulting i n 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 inv estigate the biological activity of acute phase concentrations of reco mbinant murine LBP, high concentrations of LBP were investigated in vi tro and in vivo. Although addition of low concentrations of LBP to a m urine macrophage cell line enhanced LPS-induced TNF-alpha synthesis, a cute 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-g alactosamine-sensitized mice, as well as in a murine model of bacterem ia. These results complement a recent study revealing LBP-deficient mi ce to be dramatically more susceptible to an intraperitoneal Salmonell a infection as compared with normal mice. We conclude that acute phase LBP has a protective effect against LPS and bacterial infection and m ay represent a physiologic defense mechanism against infection. Despit e the limitations of any murine sepsis model, the results shown may im ply that LBP could have beneficial effects during gram-negative perito nitis in humans.