Abstract
Background Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.
Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.
Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.
Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.
Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.
Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.
Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.
| Original language | English |
|---|---|
| Pages (from-to) | 193-201 |
| Number of pages | 9 |
| Journal | British Journal of Anaesthesia |
| Volume | 107 |
| Issue number | 2 |
| Early online date | 9 Jun 2011 |
| DOIs | |
| Publication status | Published - Aug 2011 |
Keywords
- antioxidants
- cells, cultured
- endothelium, vascular
- glutathione
- humans
- inflammation
- interleukin-6
- interleukin-8
- melatonin
- membrane potential, mitochondrial
- mitochondria
- NF-kappa B
- oxidative stress
- sepsis
- signal transduction