Comparison of the induction of endotoxin tolerance in endotoxemia and peritonitis by monophosphoryl lipid A and lipopolysaccharide.

Abstract

We compared the induction of endotoxin tolerance with Salmonella minnesota monophosphoryl lipid A (MPL), a nontoxic derivative of lipid A, and S. minnesota endotoxin (LPS) in lethal endotoxemia and peritonitis. Lethal endotoxemia was induced by injecting 750 micrograms/mouse LPS intravenously. Cecal ligation and perforation was used to induce peritonitis. Tumor necrosis factor (TNF) was measured by immunoassay at 2 hr after lethal endotoxin infusion and 24 hr after peritonitis. A dose of 0.1 micrograms/mouse of MPL or LPS significantly reduced endotoxin mortality from 100% to 50% and 27%, respectively (P < 0.05). The LD50 for a 0.1 micrograms dose of MPL was 750 micrograms of LPS and the LD50 for a 0.1 micrograms dose of LPS was 1150 micrograms of endotoxin (P < 0.05). TNF levels decreased linearly when increasing doses of MPL and LPS were used to induce tolerance. At higher pretreatment doses of LPS, survival benefits were attenuated despite the reduction in TNF levels. A 25 micrograms dose of LPS reduced mortality from peritonitis from 93% to 45% (P < 0.05). Although MPL reduced short-term mortality, overall mortality was not significantly reduced despite using large doses of MPL. TNF levels peaked at 24 hr and were significantly lower than those following lethal endotoxemia. The induction of endotoxin tolerance by LPS and MPL is dose dependent, and LPS is modestly more effective in inducing endotoxin tolerance than MPL. Both LPS and MPL are significantly less effective in protecting against lethality from peritonitis.