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Monophosphoryl lipid A attenuates the effects of endotoxic shock in pigs
C M Carpati1, M E Astiz, E C Rackow
1Department of Medicine, St. Vincent's Hospital and Medical Center of New York, NY 10011.
Abstract:
Monophosphoryl lipid A (MPL) is a nontoxic lipid A derivative that maintains many of the beneficial immunomodulatory activities of the parent lipopolysaccharide molecule, including the induction of tolerance to endotoxin. The hemodynamic effects of Salmonella minnesota MPL (300 mg/kg) and S. minnesota lipopolysaccharide (300 micrograms/kg) were compared in 20 minipigs. Decreases in cardiac output and arterial pressure and increases in pulmonary artery pressure and lactic acidosis were significantly greater in animals treated with lipopolysaccharide. These changes were associated with peak tumor necrosis factor (TNF) levels of 1373 +/- 79 U/ml in animals treated with LPS and 157 +/- 31 U/ml in animals treated with MPL. Ten minipigs were subsequently randomized to receive S. minnesota MPL (30 micrograms/kg) or diluent intravenously 48 hours before receiving S. minnesota lipopolysaccharide (300 micrograms/kg IV). MPL significantly attenuated lipopolysaccharide-induced decreases in mean arterial pressure, cardiac index, stroke volume index, and mixed venous oxygen saturation. At baseline, no significant difference could be seen in TNF levels between diluent and MPL pigs. TNF levels peaked 2 hours after LPS infusion at 1190 +/- 156 U/ml in diluent pigs and at 539 +/- 126 U/ml in MPL pigs (p less than 0.05). Each of the pigs pretreated with MPL survived endotoxic shock, whereas only one of the five diluent pigs survived. These observations are consistent with the induction of endotoxin tolerance by pretreatment with MPL.
Insights
Monophosphoryl lipid A (MPL) induces endotoxin tolerance by attenuating lipopolysaccharide (LPS) effects. MPL pretreatment improved survival rates and reduced LPS-induced shock symptoms in minipigs.
Area of Science:
- Immunology
- Pharmacology
- Toxicology
Background:
- Monophosphoryl lipid A (MPL) is a derivative of lipopolysaccharide (LPS) with retained immunomodulatory properties but reduced toxicity.
- Lipopolysaccharide (LPS) is a potent endotoxin that can induce severe physiological responses, including shock.
- Endotoxin tolerance is a state of reduced responsiveness to LPS following prior exposure.
Purpose of the Study:
- To compare the hemodynamic effects of Monophosphoryl lipid A (MPL) and lipopolysaccharide (LPS) in minipigs.
- To investigate the potential of MPL to induce endotoxin tolerance against LPS challenge.
- To evaluate the impact of MPL pretreatment on survival and physiological parameters during LPS-induced endotoxemia.
Main Methods:
- Hemodynamic parameters and tumor necrosis factor (TNF) levels were measured in minipigs after administration of Salmonella minnesota MPL or LPS.
- A separate group of minipigs received MPL or diluent pretreatment 48 hours before LPS challenge.
- Survival rates and physiological responses, including mean arterial pressure, cardiac index, and TNF levels, were assessed post-LPS challenge.
Main Results:
- LPS administration caused significantly greater decreases in cardiac output, arterial pressure, and increased pulmonary artery pressure and lactic acidosis compared to MPL.
- MPL pretreatment significantly attenuated LPS-induced hemodynamic instability and reduced peak TNF levels.
- All MPL-pretreated minipigs survived endotoxic shock, whereas only one of five diluent-pretreated pigs survived.
Conclusions:
- Monophosphoryl lipid A (MPL) exhibits significantly reduced toxicity compared to lipopolysaccharide (LPS).
- MPL pretreatment effectively induces endotoxin tolerance, protecting against lethal LPS challenge.
- MPL demonstrates potential as an agent for modulating immune responses and preventing endotoxic shock.