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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

Rolling and adhesion of PMN to TNF-α stimulated HUVECs after pre-incubation with phenidone or 4-4-dimethyl-phenidone.The ability of phenidone and 4-4-dimethyl-phenidone to inhibit rolling and adhesion of PMNs is shown as per cent of rolling and adhesion to untreated HUVECs. *=significant reduction of rolling when the HUVECs were pre-incubated with 4-4-dimethyl-phenidone instead of phenidone (p < 0.01).
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f6-btt-2-151: Rolling and adhesion of PMN to TNF-α stimulated HUVECs after pre-incubation with phenidone or 4-4-dimethyl-phenidone.The ability of phenidone and 4-4-dimethyl-phenidone to inhibit rolling and adhesion of PMNs is shown as per cent of rolling and adhesion to untreated HUVECs. *=significant reduction of rolling when the HUVECs were pre-incubated with 4-4-dimethyl-phenidone instead of phenidone (p < 0.01).

Mentions: Under venular shear forces (2 dynes/cm2) PMN adhesion to untreated endothelial cells was negligible after 10 min of perfusion (not shown). On cytokine-activated HUVECs, total PMN adhesion increased 10-fold (Figures 5A–B). In subsequent experiments, the effect of 4-4-dimethyl-phenidone, which significantly reduced adhesion molecule expression in the static experiments, was compared to phenidone. Pretreatment of endothelial cells with 4-4-dimethyl-phenidone or phenidone (both 400 μM) prior to cytokine-activation significantly reduced total PMN adhesion (p < 0.01; Figures 5C–D) compared with untreated activated HUVECs. When rolling and firm adhesion were examined separately, it became obvious that 4-4-dimethyl-phenidone had a significantly stronger inhibitory effect on rolling interactions than phenidone (p < 0.05). However, the number of adherent PMN was not significantly reduced after preincubation of HUVECs with 4-4-dimethyl-phenidone rather than phenidone (Figure 6).


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)

Rolling and adhesion of PMN to TNF-α stimulated HUVECs after pre-incubation with phenidone or 4-4-dimethyl-phenidone.The ability of phenidone and 4-4-dimethyl-phenidone to inhibit rolling and adhesion of PMNs is shown as per cent of rolling and adhesion to untreated HUVECs. *=significant reduction of rolling when the HUVECs were pre-incubated with 4-4-dimethyl-phenidone instead of phenidone (p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2727783&req=5

f6-btt-2-151: Rolling and adhesion of PMN to TNF-α stimulated HUVECs after pre-incubation with phenidone or 4-4-dimethyl-phenidone.The ability of phenidone and 4-4-dimethyl-phenidone to inhibit rolling and adhesion of PMNs is shown as per cent of rolling and adhesion to untreated HUVECs. *=significant reduction of rolling when the HUVECs were pre-incubated with 4-4-dimethyl-phenidone instead of phenidone (p < 0.01).
Mentions: Under venular shear forces (2 dynes/cm2) PMN adhesion to untreated endothelial cells was negligible after 10 min of perfusion (not shown). On cytokine-activated HUVECs, total PMN adhesion increased 10-fold (Figures 5A–B). In subsequent experiments, the effect of 4-4-dimethyl-phenidone, which significantly reduced adhesion molecule expression in the static experiments, was compared to phenidone. Pretreatment of endothelial cells with 4-4-dimethyl-phenidone or phenidone (both 400 μM) prior to cytokine-activation significantly reduced total PMN adhesion (p < 0.01; Figures 5C–D) compared with untreated activated HUVECs. When rolling and firm adhesion were examined separately, it became obvious that 4-4-dimethyl-phenidone had a significantly stronger inhibitory effect on rolling interactions than phenidone (p < 0.05). However, the number of adherent PMN was not significantly reduced after preincubation of HUVECs with 4-4-dimethyl-phenidone rather than phenidone (Figure 6).

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