DIPHOSPHORYL LIPID-A FROM RHODOPSEUDOMONAS-SPHAEROIDES INDUCES TOLERANCE TO ENDOTOXIC-SHOCK IN THE RAT

Objectives: To examine the hemodynamic effects of diphosphoryl lipid A from Rhodopseudomonas sphaeroides and to examine the ability of this substance to induce tolerance to endotoxic shock. Design: Randomized, prospective, controlled study comparing the hemodynamic actions of R. sphaeroides diphosphoryl lipid A to those effects of lipopolysaccharid e from Salmonella minnesota, followed by a prospective, randomized, co ntrolled study comparing pretreatment with R. sphaeroides diphosphoryl lipid A and phosphate-buffered saline in the induction of tolerance t o endotoxic shock. Setting. Laboratory of the Section of Critical Care Medicine at a University Hospital. Subjects: Male Sprague-Dawley rats . Interventions: Eight rats were randomized to receive intravenous R. sphaeroides diphosphoryl lipid A, 0.5 mg/100 g body weight or S. minne sota lipopolysaccharide, 0.5 mg/100 g body weight. Ten rats were then randomized to receive R. sphaeroides diphosphoryl lipid A, 0.5 mg/100 g body weight, or phosphate-buffered saline intravenously 48 hrs befor e receiving S. minnesota lipopolysaccharide, 5 mg/100 g body weight, b y intravenous infusion. Measurements and Main Results: Cardiac index w as significantly decreased from baseline in rats treated with lipopoly saccharide; there was no significant change in the R. sphaeroides diph osphoryl lipid A group. Peak circulating tumor necrosis factor (TNF) c oncentrations in the lipopolysaccharide-treated rats were higher than in R. sphaeroides diphosphoryl lipid A-treated rats (3.1 +/- 1.0 vs. 1 .5 /- 0.4 ng/mL). R. sphaeroides diphosphoryl lipid A significantly at tenuated lipopolysaccharide-induced changes in mean arterial pressure and cardiac index. At baseline, there was no significant difference in serum TNF concentrations between rats pretreated with R. sphaeroides diphosphoryl lipid A and those rats pretreated with phosphate-buffered saline. TNF levels peaked at 1 hr post-lipopolysaccharide infusion at 4.3 +/- 0.6 ng/mL in the phosphate-buffered saline group and at 2.0 /- 0.5 ng/mL in the R. sphaeroides diphosphoryl lipid A group (p < .02 ). Four of five rats pretreated with R. sphaeroides diphosphoryl lipid A survived endotoxic shock, whereas none of the phosphate-buffered sa line-pretreated rats survived (p = .05). Conclusions: These observatio ns are consistent with previous reports of the limited toxic effects o f R. sphaeroides diphosphoryl lipid A and suggest that this molecule r etains the ability to induce tolerance to endotoxic shock.