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.


METHODS
Randomized, placebo-controlled study.


METHODS
Urban public hospital with academic affiliation.


METHODS
Eighteen healthy, normolipidemic, normal weight volunteers, 21-35 yrs of age.


METHODS
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 LPS 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.


METHODS
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 125I-LPS.


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.


CONCLUSIONS
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.
Harris
Hobart W
HW
UCSF Surgical Research Laboratory at San Francisco General Hospital, University of California, 94110, USA. hharris@sfghsurg.ucsf.edu
Johnson
Jennifer A
JA
Wigmore
Stephen J
SJ
D000209:Acute-Phase Proteins / Q000032:analysis; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D004731:Endotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007958:Leukocyte Count; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000209:Acute-Phase Proteins; D004731:Endotoxins; D008074:Lipoproteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone