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Monophosphoryl lipid A induces tolerance to the lethal hemodynamic effects of endotoxemia
M E Astiz1, E C Rackow, Y B Kim
1Department of Medicine, University of Health Sciences, Chicago Medical School, Illinois.
Abstract:
Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipid A. In this study, the induction of tolerance by MPL to the hemodynamic effects of lethal endotoxemia was tested. Ten Sprague-Dawley rats were received either Salmonella minnesota MPL 0.5 mg/100 g intravenously (i.v.) or equivalent volume of diluent (control) i.v. on day zero. On day 3 S. minnesota endotoxin (LPS) 5.0 mg/100 g was administered i.v. Cardiac output (CO), arterial lactate (L), and central venous oxygen saturation (SvO2) were measured before and 3 and 6 hr after LPS administration. Survival was determined at 72 hr. At 6 hr, CO was 217 +/- 11 ml/kg/min in controls, and 435 +/- 28 ml/kg/min in the MPL animals (P less than 0.01). Arterial lactate was 2.6 +/- 0.3 mmol/liter in controls and 1.3 +/- 0.2 mmol/liter in MPL animals at 6 hr (P less than 0.05). The controls died 7.5 +/- 1.3 hr after LPS administration, whereas all the MPL-pretreated animals survived. These data indicate that MPL induces tolerance to the acute hemodynamic effects of LPS and enhances survival from lethal endotoxemia.
Insights
Monophosphoryl lipid A (MPL) pretreatment induces tolerance to lethal endotoxemia in rats. MPL administration significantly improved hemodynamic function and survival following lipopolysaccharide (LPS) challenge.
Area of Science:
- Immunology
- Pharmacology
- Critical Care Medicine
Background:
- Lipid A is a component of endotoxin responsible for toxic effects.
- Monophosphoryl lipid A (MPL) is a detoxified derivative of lipid A.
- Endotoxemia, caused by lipopolysaccharide (LPS), leads to severe hemodynamic compromise and mortality.
Purpose of the Study:
- To investigate the potential of MPL to induce tolerance against the lethal hemodynamic effects of endotoxemia.
- To evaluate the impact of MPL pretreatment on survival rates during lethal endotoxemia.
Main Methods:
- Sprague-Dawley rats were intravenously administered either MPL or a control diluent.
- On day 3, rats received an intravenous injection of Salmonella minnesota endotoxin (LPS).
- Hemodynamic parameters (cardiac output, arterial lactate, central venous oxygen saturation) and survival were monitored.
Main Results:
- MPL-pretreated rats exhibited significantly higher cardiac output (435 ml/kg/min vs. 217 ml/kg/min) at 6 hours post-LPS.
- Arterial lactate levels were significantly lower in MPL-treated animals (1.3 mmol/L vs. 2.6 mmol/L) at 6 hours post-LPS.
- All MPL-pretreated rats survived for 72 hours, while control rats died within 7.5 hours of LPS administration.
Conclusions:
- Monophosphoryl lipid A (MPL) confers tolerance to the acute hemodynamic derangements induced by lethal endotoxemia.
- MPL pretreatment significantly enhances survival rates in a rat model of lethal endotoxemia.
- MPL demonstrates potential as a therapeutic agent to mitigate the effects of LPS-induced shock.