Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow.
The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of cycloxygenases COX-1 and COX-2. During recent years, combined 5-LOX/COX-inhibition, interfering with the biosynthesis of both prostaglandins and leukotrienes (LTs), has emerged as a possibility to avoid side effects related to COX-inhibition. The aim of the present study was to investigate if there is a contribution of mechanisms other than the reduction of inflammatory prostaglandins and leukotrienes to the anti-inflammatory effect of the LOX/COX inhibitor licofelone. In a flow chamber assay, licofelone (10-30 microM) dose-dependently decreased both the rolling and adhesion of leukocytes on endothelial cells (EC). In contrast, no effects were found after treatment of EC with the unselective COX-1/COX-2 inhibitor indomethacin (30 microM), the potent and selective 5-LOX inhibitor, ZD-2138 (30 microM), the mainly COX-2 inhibitor aceclofenac (30 microM), the selective COX-2 inhibitor celecoxib (30 microM) and the combination of ZD-2138 with the selective COX-2 inhibitor celecoxib (30 microM). In the presence of licofelone (30 microM) the expression of E-selectin mRNA in cytokine-stimulated EC was attenuated, whereas no NSAID (30 microM) tested showed any effect on E-selectin expression. Moreover, licofelone treatment (30 microM) attenuated expression of VCAM-1 and ICAM-1 on inflammatory EC. The effect of licofelone on leukocyte recruitment was also evaluated in vivo. Using a mouse peritonitis model it was found that leukocyte accumulation was markedly reduced in licofelone treated animals (100mg/kg) compared to untreated mice. Thus, the novel 5-LOX/COX inhibitor licofelone possesses anti-inflammatory activity that, in addition to COX/LOX inhibition, involves effects on leukocyte-endothelial interactions.
Ulbrich
H
H
Karolinska Institute, Department of Physiology and Pharmacology, von Eulers väg 8, SE-171 77 Stockholm, Sweden. ulbrich@uni-mainz.de <ulbrich@uni-mainz.de>
Soehnlein
O
O
Xie
X
X
Eriksson
E E
EE
Lindbom
L
L
Albrecht
W
W
Laufer
S
S
Dannhardt
G
G
D000085:Acetates / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis
D000085:Acetates; D015815:Cell Adhesion Molecules; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; C088092:licofelone