Endogenous lipoproteins impact the response to endotoxin in humans

Objective: To determine whether endogenous lipoproteins can abrogate the host response to lipopolysaccharide (LPS) in vivo. Design: Randomized, placebo-controlled study. Setting: Urban public hospital with academic affiliation. Subjects: Eighteen healthy, normolipidemic, normal weight volunteers, 21-35 yrs of age. Interventions: Fasting and postprandial (hypertriglyceridemic) subjects were injected with endotoxin (LPS, Lot EC-5, 4 ng/kg = 20 endotoxin units/kg) as either a bolus or following preincubation of the LIPS with autologous whole blood vs. saline. In addition, LPS-induced cytokine production was determined ex vivo to examine the capacity of fasting vs. hypertriglyceridemic whole blood to attenuate the effect of large, potentially lethal concentrations of LPS in humans. Measurements: Vital signs were recorded and serial blood samples analyzed for changes in white blood cell count, cytokine, and stress hormone levels over 24 hrs. The distribution of lipoproteins in fasting and postprandial blood after preincubation was determined using I-125-LPS. Main Results: Endogenous lipoproteins abrogated the host response to LPS in vivo, but only after preincubation with the LPS. Peak oral temperature (p < .05) and white blood cell count (p < .05), and plasma tumor necrosis factor (TNF)-alpha-(p < .01) and adrenocorticotropic hormone levels (p < .03) were significantly reduced in volunteers injected with LPS preincubated with whole blood vs. LPS preincubated with saline. Approximately 80% of the LPS was bound to lipoproteins after preincubation with either fasting or hypertriglyceridemic blood. Thus, protection was associated with lipoprotein binding. In addition, hypertriglyceridemic but not fasting blood inhibited the ex vivo TNF-alpha response to large, highly toxic doses of LPS (p < .05). Without the preincubation of lipoproteins with LPS, there was a trend for an exaggerated clinical and TNF-alpha response in the hypertriglyceridemic subjects. Conclusion: Preincubation of LPS with whole blood promotes lipoprotein-LPS binding and is associated with an attenuated response to this toxic macromolecule. Although the clinical relevance of these data requires further elucidation, our results continue to support a lipid-based therapeutic strategy to combat Gram-negative sepsis.