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Monophosphoryl lipid A blocks the hemodynamic effects of lethal endotoxemia
E C Rackow1, M E Astiz, Y B Kim
1Department of Medicine, University of Health Sciences, Chicago Medical School, IL 60064.
Abstract:
Monophosphoryl lipid A (MPL) is a "nontoxic" derivative of lipid A. We hypothesized that, because of the structural similarity between MPL and the lipid A portion of lipopolysaccharide (a "toxic" moiety of endotoxin), hemodynamic events occurring during endotoxemia could be attenuated by administration of MPL. Lipopolysaccharide (LPS) from Salmonella minnesota wild type S and MPL from S. minnesota R595 were used for the study. Fifteen Sprague-Dawley rats were randomized to receive either (1) 0.50 mg LPS per 100 gm body weight intravenously, (2) 0.50 mg MPL per 100 gm body weight intravenously, or (3) 0.5 mg MPL per 100 gm body weight intravenously followed in 15 minutes by 0.50 mg LPS per 100 gm body weight intravenously. Arterial pressure, thermodilution cardiac output, and central venous oxygen saturation were measured before and 30 and 60 minutes after LPS administration. In LPS-treated animals, cardiac output decreased from 448 +/- 28 ml/kg/min to 336 +/- 15 ml/kg/min (p less than 0.02), and central venous oxygen saturation decreased from 71% +/- 1% to 62% +/- 2% (p less than 0.05). Mean arterial pressure decreased from 134 +/- 5 mm Hg to 90 +/- 6 mm Hg (p less than 0.01). In MPL-treated and MPL + LPS-treated animals, no significant changes were observed in cardiac output, central venous oxygen saturation, or arterial pressure. These data indicate that MPL is not associated with the adverse cardiovascular responses observed after LPS administration. Furthermore, administration of MPL blocks the development of acute circulatory failure during endotoxemia.
Insights
Monophosphoryl lipid A (MPL) administration prevented adverse cardiovascular changes during endotoxemia. MPL treatment blocked the development of circulatory failure caused by lipopolysaccharide (LPS).
Area of Science:
- Immunology
- Pharmacology
- Physiology
Background:
- Lipid A is the toxic component of lipopolysaccharide (LPS), a bacterial endotoxin.
- Monophosphoryl lipid A (MPL) is a detoxified derivative of lipid A.
- Structural similarity suggests MPL may mitigate LPS-induced endotoxemia.
Purpose of the Study:
- To investigate if MPL can attenuate hemodynamic alterations during endotoxemia.
- To evaluate the protective effects of MPL against LPS-induced circulatory collapse.
Main Methods:
- Lipopolysaccharide (LPS) and Monophosphoryl lipid A (MPL) from Salmonella minnesota were used.
- Sprague-Dawley rats received LPS, MPL, or MPL followed by LPS.
- Hemodynamic parameters including arterial pressure, cardiac output, and central venous oxygen saturation were measured.
Main Results:
- LPS administration significantly decreased cardiac output, mean arterial pressure, and central venous oxygen saturation.
- MPL administration alone did not cause significant hemodynamic changes.
- MPL pretreatment completely blocked the adverse cardiovascular effects of LPS.
Conclusions:
- Monophosphoryl lipid A (MPL) does not induce adverse cardiovascular responses.
- MPL effectively prevents acute circulatory failure associated with endotoxemia.
- MPL demonstrates potential as a therapeutic agent against endotoxic shock.