Limits...
Activity of the lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone) and derivatives on the inhibition of adhesion molecule expression on human umbilical vascular endothelial cells.

Schroeder TH, Krueger WA, Dieterich HJ, Nohé B - Biologics (2008)

Bottom Line: TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone.The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry.Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.

ABSTRACT
Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming inflammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-alpha (TNF-alpha) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under flow in vitro. TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone. We tested the inhibition of adhesion molecule expression at different inhibitor concentrations before, during, and after the stimulation of HUVECs. The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry. Rolling and firm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate flow chamber. Phenidone inhibited the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial-leukocyte adhesion molecule-1 on HUVECs when added prior to HUVEC stimulation. The inhibitory effect of phenidone was still observed when added simultaneously, but not when added after HUVEC stimulation. 4-4-dimethyl-phenidone and 5-phenyl-phenidone inhibited the expression of adhesion molecules more effectively than phenidone. The attenuation of leukocyte rolling under flow conditions was also significantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

No MeSH data available.


Related in: MedlinePlus

Inhibition of adhesion molecule expression by phenidone.The decrease of adhesion molecule expression (ICAM-1, VCAM-1, E-selectin) is plotted in a logarithmic dose-response relationship (curve fitting). X-axis: Concentration of phenidone (μM). Y-axis: Per cent inhibition of adhesion molecule expression in relation to maximal TNF-α induced expression. Fine-dotted lines: Pre-incubation – phenidone was added 2 hours before TNF-α stimulation. Coarse-dotted line: Co-incubation – simultaneous application of phenidone and TNF-α. Solid line: Post-incubation – phenidone was added 2 hours after TNF-α stimulation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2727783&req=5

f3-btt-2-151: Inhibition of adhesion molecule expression by phenidone.The decrease of adhesion molecule expression (ICAM-1, VCAM-1, E-selectin) is plotted in a logarithmic dose-response relationship (curve fitting). X-axis: Concentration of phenidone (μM). Y-axis: Per cent inhibition of adhesion molecule expression in relation to maximal TNF-α induced expression. Fine-dotted lines: Pre-incubation – phenidone was added 2 hours before TNF-α stimulation. Coarse-dotted line: Co-incubation – simultaneous application of phenidone and TNF-α. Solid line: Post-incubation – phenidone was added 2 hours after TNF-α stimulation.

Mentions: The expression of ICAM-1, VCAM-1, and E-selectin on HUVECs was stimulated by TNF-α (0.5 ng/mL). We measured the inhibitory effect of phenidone on adhesion molecule expression when added either two hours before (pre-incubation), at the same time as (co-incubation), or two hours after (post-incubation) the stimulation of HUVECs by TNF-α. The experimental setup is shown in Figure 2. Three different phenidone concentrations were tested: 0.5, 1.0, and 2.0 mM. The results are shown in Figures 3A–C. Phenidone significantly decreased the expression of adhesion molecules on the surface of HUVECs when administered two hours before the stimulation of HUVECs by TNF-α (p < 0.01, (n = 4). The inhibition of adhesion molecule expression was still significant when phenidone and TNF-α were co-administered (co-incubation). In contrast, when phenidone was given two hours after the stimulation of HUVECs by TNF-α no decrease in adhesion molecule expression was observed. Furthermore, the inhibition of adhesion molecule expression was concentration-dependent (p < 0.01). The highest phenidone concentration (2.0 mM) led to the greatest inhibition of adhesion molecule expression on HUVECs. There was no statistical difference between the individual inhibitions of the three adhesion molecules tested (p = 0.14).


Activity of the lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone) and derivatives on the inhibition of adhesion molecule expression on human umbilical vascular endothelial cells.

Schroeder TH, Krueger WA, Dieterich HJ, Nohé B - Biologics (2008)

Inhibition of adhesion molecule expression by phenidone.The decrease of adhesion molecule expression (ICAM-1, VCAM-1, E-selectin) is plotted in a logarithmic dose-response relationship (curve fitting). X-axis: Concentration of phenidone (μM). Y-axis: Per cent inhibition of adhesion molecule expression in relation to maximal TNF-α induced expression. Fine-dotted lines: Pre-incubation – phenidone was added 2 hours before TNF-α stimulation. Coarse-dotted line: Co-incubation – simultaneous application of phenidone and TNF-α. Solid line: Post-incubation – phenidone was added 2 hours after TNF-α stimulation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2727783&req=5

f3-btt-2-151: Inhibition of adhesion molecule expression by phenidone.The decrease of adhesion molecule expression (ICAM-1, VCAM-1, E-selectin) is plotted in a logarithmic dose-response relationship (curve fitting). X-axis: Concentration of phenidone (μM). Y-axis: Per cent inhibition of adhesion molecule expression in relation to maximal TNF-α induced expression. Fine-dotted lines: Pre-incubation – phenidone was added 2 hours before TNF-α stimulation. Coarse-dotted line: Co-incubation – simultaneous application of phenidone and TNF-α. Solid line: Post-incubation – phenidone was added 2 hours after TNF-α stimulation.
Mentions: The expression of ICAM-1, VCAM-1, and E-selectin on HUVECs was stimulated by TNF-α (0.5 ng/mL). We measured the inhibitory effect of phenidone on adhesion molecule expression when added either two hours before (pre-incubation), at the same time as (co-incubation), or two hours after (post-incubation) the stimulation of HUVECs by TNF-α. The experimental setup is shown in Figure 2. Three different phenidone concentrations were tested: 0.5, 1.0, and 2.0 mM. The results are shown in Figures 3A–C. Phenidone significantly decreased the expression of adhesion molecules on the surface of HUVECs when administered two hours before the stimulation of HUVECs by TNF-α (p < 0.01, (n = 4). The inhibition of adhesion molecule expression was still significant when phenidone and TNF-α were co-administered (co-incubation). In contrast, when phenidone was given two hours after the stimulation of HUVECs by TNF-α no decrease in adhesion molecule expression was observed. Furthermore, the inhibition of adhesion molecule expression was concentration-dependent (p < 0.01). The highest phenidone concentration (2.0 mM) led to the greatest inhibition of adhesion molecule expression on HUVECs. There was no statistical difference between the individual inhibitions of the three adhesion molecules tested (p = 0.14).

Bottom Line: TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone.The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry.Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.

ABSTRACT
Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming inflammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-alpha (TNF-alpha) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under flow in vitro. TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone. We tested the inhibition of adhesion molecule expression at different inhibitor concentrations before, during, and after the stimulation of HUVECs. The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry. Rolling and firm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate flow chamber. Phenidone inhibited the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial-leukocyte adhesion molecule-1 on HUVECs when added prior to HUVEC stimulation. The inhibitory effect of phenidone was still observed when added simultaneously, but not when added after HUVEC stimulation. 4-4-dimethyl-phenidone and 5-phenyl-phenidone inhibited the expression of adhesion molecules more effectively than phenidone. The attenuation of leukocyte rolling under flow conditions was also significantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

No MeSH data available.


Related in: MedlinePlus