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Pentoxifylline differentially regulates migration and respiratory burst activity of the neutrophil
S Dunzendorfer1, P Schratzberger, N Reinisch
1Department of Internal Medicine, Medical Faculty, University of Innsbruck, Austria.
Abstract:
TNF is produced by monocytes/macrophages in response to endotoxin, which may lead to septic shock. TNF stimulates neutrophil adherence, degranulation, and superoxide production, but inhibits neutrophil migration. A mitigating anti-inflammatory effect can be experimentally induced in septic shock by TNF blockers, such as pentoxifylline, and is also suggested for treatment with hrG-CSF. With regard to the combination of pentoxifylline and hrG-CSF, the purpose of this investigation was to explore whether and in what way the effects of hrG-CSF and pentoxifylline interact with each other in neutrophils. To this end, we studied the effects of pentoxifylline on TNF- and G-CSF-induced modulation of neutrophil chemotaxis and O2 release. TNF and G-CSF decreased directed migration of neutrophils to FMLP or IL-8. High-dose pentoxifylline (1 mM) was able to counteract the effect of TNF but not that of G-CSF on neutrophil migration. In the presence of pentoxifylline, TNF and G-CSF were unable to stimulate respiratory burst. In contrast, pre-exposure of cells to pentoxifylline followed by washing increased the priming effect of TNF or hrG-CSF on neutrophil respiratory burst activity. The methylxanthine derivative by itself showed no effect on spontaneous and fMLP-stimulated O2 release by neutrophils. Stimulation of neutrophil respiratory burst by pentoxifylline may not be detectable in the presence of pentoxifylline due to its known oxygen-radical scavenging function. Results suggest that by blocking the inflammatory action of TNF on neutrophils, pentoxifylline may diminish endothelial cell damage caused by inhibited neutrophil chemotaxis. On the other hand, since transiently present pentoxifylline may enhance the respiratory burst activity of TNF- or hrG-CSF-primed neutrophils, concomitant administration of pentoxifylline and hrG-CSF to patients with SIRS/sepsis might diminish beneficial effects of the latter and additional deleterious effects might occur.
Insights
Pentoxifylline blocks tumor necrosis factor (TNF) effects on neutrophils, but its interaction with granulocyte-colony stimulating factor (G-CSF) requires careful consideration in sepsis treatment.
Area of Science:
- Immunology
- Pharmacology
Background:
- Tumor necrosis factor (TNF) contributes to septic shock by affecting monocyte/macrophage activity and neutrophil function.
- TNF blockers like pentoxifylline and human recombinant G-CSF (hrG-CSF) show potential in mitigating inflammatory responses.
- The interaction between pentoxifylline and hrG-CSF in neutrophils is not fully understood.
Purpose of the Study:
- To investigate the interaction between pentoxifylline and hrG-CSF in neutrophils.
- To determine how pentoxifylline affects TNF- and G-CSF-induced neutrophil chemotaxis and superoxide release.
Main Methods:
- Studied the effects of pentoxifylline on TNF- and G-CSF-modulated neutrophil chemotaxis and O2 release.
- Assessed neutrophil migration inhibition by TNF and G-CSF.
- Evaluated the impact of pentoxifylline on TNF/G-CSF-stimulated respiratory burst.
Main Results:
- Pentoxifylline (1 mM) counteracted TNF's effect on neutrophil migration but not G-CSF's.
- In the presence of pentoxifylline, TNF and G-CSF failed to stimulate neutrophil respiratory burst.
- Transient exposure to pentoxifylline enhanced TNF/hrG-CSF-primed neutrophil respiratory burst.
Conclusions:
- Pentoxifylline may reduce endothelial damage by blocking TNF-induced neutrophil chemotaxis.
- Concomitant use of pentoxifylline and hrG-CSF in sepsis could potentially reduce beneficial G-CSF effects and cause harm.