Plasma concentrations of LDL and HDL rapidly and markedly decline in acutely ill, septic humans with known bacterial infections. This acute phase response is felt to be mediated by inflammatory cytokines such as TNF-alpha and IL6 which are known from animal studies to strongly perturb lipid metabolism. Surprisingly, there have been no previous studies of the effect of endotoxin on human lipid and apolipoprotein metabolism. Our plan is to use an established and safe model of human endotoxemia with intravenous endotoxin and stable isotopic tracers in normal volunteers studied in the controlled setting of the Rockefeller GCRC to understand the mechanism(s) for the declines in LDL and HDL lipoproteins. The role of cytokine mediators produced in response to endotoxin will also be evaluated. Once the magnitude, time course, variability and mediators of the lipoprotein changes are characterized, then the second phase of the study in normal volunteers will be designed using an intravenous phospholipid-rich emulsion infused with and without endotoxin. This lipid emulsion, developed by the Rogosin Institute, is expected to bind endotoxin, raise lipid levels, and reverse the metabolic alterations induced by endotoxin. It may ultimately be used to enhance the host lipoprotein defense against endotoxin and reduce the immense mortality and morbidity associated with septic shock.
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