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Etoposide attenuates zymosan-induced shock in mice
M Remichkova1, M Yordanov, P Dimitrova
1Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Abstract:
Zymosan-induced generalized inflammation is a convenient model to study the process of acute and chronic inflammatory processes resulting in multiple organ dysfunction syndrome. Macrophages as a source of many pro-inflammatory mediators are the major players in shock and further organ failure. Etoposide is a cytostatic drug known to reduce macrophages and monocytes in blood circulation. In the present study we have investigated whether the ability of etoposide to diminish macrophage number would have an impact on the course of zymosan-induced shock. The drug injected at a dose of 10 mg/kg 1 day before zymosan, significantly reduced the mortality and decreased the organ toxicity in Balb/c mice. Simultaneously, an inhibition of TNF-alpha production by alveolar and peritoneal macrophages was observed. Etoposide administered into mice with severe combined immunodeficiency (SCID) did not change the survival rate and had a little influence on organ toxicity. Our findings suggest that the beneficial action of etoposide might be attributed to the reduction of macrophages and alteration of their functions. Its effect depends on the presence of functional T and B lymphocytes. The results deserve further investigation of etoposide as a perspective therapeutic tool for inhibiting the excessive inflammatory response and to be helpful for revealing mechanisms of shock development.
Insights
Etoposide reduces mortality and organ damage in a mouse model of inflammation by decreasing macrophages. This effect requires functional T and B lymphocytes, suggesting etoposide
Area of Science:
- Immunology
- Pharmacology
- Pathophysiology
Background:
- Zymosan-induced inflammation models acute and chronic inflammatory processes, leading to multiple organ dysfunction syndrome.
- Macrophages are key mediators of inflammation, shock, and organ failure due to their production of pro-inflammatory cytokines.
- Etoposide, a cytostatic drug, is known to reduce circulating macrophages and monocytes.
Purpose of the Study:
- To investigate the impact of etoposide's macrophage-depleting ability on zymosan-induced shock.
- To explore the role of T and B lymphocytes in etoposide's therapeutic effects.
Main Methods:
- Balb/c mice were treated with etoposide (10 mg/kg) one day prior to zymosan challenge.
- Mortality, organ toxicity, and tumor necrosis factor-alpha (TNF-alpha) production by macrophages were assessed.
- Experiments were also conducted in severe combined immunodeficiency (SCID) mice to evaluate lymphocyte dependence.
Main Results:
- Etoposide significantly reduced mortality and organ toxicity in Balb/c mice following zymosan administration.
- A concurrent inhibition of TNF-alpha production by alveolar and peritoneal macrophages was observed.
- In SCID mice, etoposide showed minimal impact on survival and organ toxicity, indicating lymphocyte dependency.
Conclusions:
- Etoposide's beneficial effects in zymosan-induced shock are likely due to macrophage reduction and functional modulation.
- The efficacy of etoposide is dependent on the presence of functional T and B lymphocytes.
- Etoposide warrants further investigation as a potential therapeutic agent for excessive inflammatory responses and shock.
