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

Abstract

Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming infl ammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-α (TNF-α) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under fl ow in vitro. TNF-α 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-dichloro-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 fl ow cytometry. Rolling and fi rm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate fl ow 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 fl ow conditions was also signifi cantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic infl ammation during shock, trauma, and sepsis. © 2008 Schroeder et al, publisher and licensee Dove Medical Press Ltd.