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 lipopolysaccharide form Salmonella minnesota, followed by a prospective, randomized, controlled study comparing pretreatment with R. sphaeroides diphosphoryl lipid A and phosphate-buffered saline in the induction of tolerance to 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. minnesota 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 before receiving S. minnesota lipopolysaccharide, 5 mg/100 g body weight, by intravenous infusion.

MEASUREMENTS AND MAIN RESULTS

Cardiac index was significantly decreased from baseline in rats treated with lipopolysaccharide; there was no significant change in the R. sphaeroides diphosphoryl lipid A group. Peak circulating tumor necrosis factor (TNF) concentrations 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 attenuated 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 saline-pretreated rats survived (p = .05).

CONCLUSIONS

These observations are consistent with previous reports of the limited toxic effects of R. sphaeroides diphosphoryl lipid A and suggest that this molecule retains the ability to induce tolerance to endotoxic shock.