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Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation
Published on: May 16, 2016
Reduction in endotoxin-induced organ dysfunction and cytokine secretion by a cyclic nitrone antioxidant
T R Downs1, R C Dage, J F French
1Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
International Journal of Immunopharmacology
|July 1, 1995
Summary
This study shows that MDL 101,002, a free radical scavenger, significantly reduced organ dysfunction and mortality in rats challenged with lipopolysaccharide (LPS). The treatment effectively lowered liver and kidney damage, and inhibited tumor necrosis factor-alpha (TNF) secretion.
Area of Science:
- Biomedical Science
- Pharmacology
- Toxicology
Background:
- Multiple organ dysfunction (MOD) is a primary cause of death in septic patients with circulatory shock.
- Overproduction of tumor necrosis factor-alpha (TNF) and oxygen free radicals are implicated in sepsis progression to MOD and mortality.
- Lipopolysaccharide (LPS) administration in rats is a model for studying endotoxin-induced sepsis and organ dysfunction.
Purpose of the Study:
- To investigate the efficacy of MDL 101,002, a free radical scavenger, in mitigating organ dysfunction and cytokine secretion induced by LPS in rats.
- To determine the dose-dependent effects of MDL 101,002 on sepsis-related markers and mortality.
- To elucidate the role of oxygen free radicals in endotoxin-induced organ damage and shock.
Main Methods:
- Administration of MDL 101,002 (10-60 ng/kg, i.p.) 30 minutes prior to LPS challenge in rats.
- Assessment of liver and kidney damage using serum markers: aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine.
- Evaluation of pulmonary edema, leukopenia, thrombocytopenia, and mortality rates post-LPS challenge.
- Measurement of cytokine levels, including interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF).
Main Results:
- MDL 101,002 administration resulted in a dose-dependent reduction in organ dysfunction markers and mortality.
- Significant decrease in LPS-induced liver and kidney damage was observed.
- Prevention of pulmonary edema and partial reduction in thrombocytopenia were noted.
- Marked inhibition (>90%) of TNF secretion, along with a modest decrease in IL-1 alpha and IL-1 beta secretion, was achieved.
Conclusions:
- Oxygen free radicals play a crucial role in the development of endotoxin-induced organ dysfunction and shock.
- Free radical scavengers, such as MDL 101,002, show potential in reducing sepsis-related mortality.
- MDL 101,002's protective effects may be partly mediated by reducing free radical-stimulated cytokine secretion, particularly TNF.
