BACTERIAL LIPOPOLYSACCHARIDE BINDS AND STIMULATES CYTOKINE-PRODUCING CELLS BEFORE NEUTRALIZATION BY ENDOGENOUS LIPOPROTEINS CAN OCCUR

Lipoproteins are able to bind to lipopolysaccharide (LPS) and neutrali ze its deleterious effects. However, it is not clear why the LPS-bindi ng capacity of circulating lipoproteins, which is 10- to 10 000-fold a bove the maximal LPS concentrations found in septic patients, is not s ufficient to inhibit the effects of LPS during an infection, whereas i nfusion of exogenous lipoproteins has a potent inhibitory action. In t his study, the kinetics of LPS-neutralization bal VLDL, LDL, and HDL w ere investigated, at lipoprotein-to-LPS ratios found in severe Gram-ne gative sepsis, At least 4-8-h preincubation of LPS with either LDL or HDL were necessary to inhibit 50% of the LPS-induced TNF-alpha product ion by human peripheral blood mononuclear cells (PBMC), whereas after 24 h of preincubation LDL or HDL strongly inhibited the TNF-a synthesi s (70-90%, P < 0.01), VLDL was the least effective lipoprotein fractio n. In contrast, FITC-LPS bound to PBMC much more rapidly, with 70% of the total binding after 30 min, and 90% after l-lh incubation. The inc rease of LDL or HDL concentrations up to 10-fold las in experimental m odels of hyperlipoproteinaemia) was able not only to further decrease TNF-alpha production after long LPS-lipoproteins preincubation periods , but also to improve the kinetics of LPS neutralization. In conclusio n, LPS binds and stimulates the mononuclear cells in circulation befor e neutralization by endogenous lipoproteins can occur. Additional incr ease in the lipoprotein-to-LPS molar ratio (e,g, by infusion of exogen ous lipoproteins) accelerates the kinetics of LPS neutralization, and may be useful as adjunctive therapy in severe Gram-negative infections , (C) 1998 Academic Press.