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.
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.
Schroeder
Torsten Hans
TH
Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.
Krueger
Wolfgang Artur
WA
Dieterich
Hans-Jürgen
HJ
Nohé
Boris
B
Shock. 2002 Sep;18(3):217-22
12353921
Nat Med. 2004 Sep;10(9):966-73
15322539
J Med Chem. 1991 May;34(5):1560-70
1903450
Life Sci. 1996 May 24;58(26):2377-87
8691982
Crit Care Med. 2000 Jul;28(7):2507-14
10921586
J Leukoc Biol. 1997 Jun;61(6):647-53
9201255
Int J Microcirc Clin Exp. 1993 Aug;13(1):13-26
8262718
FASEB J. 2000 Jan;14(1):48-54
10627279
Biol Neonate. 1999 Aug;76(2):84-91
10393992
Life Sci. 1996;58(23):2167-81
8649201
Arch Gerontol Geriatr. 2004 May-Jun;38(3):201-12
15066307
EMBO J. 1995 Aug 1;14(15):3731-40
7641692
Cardiovasc Res. 2003 Oct 15;60(1):49-57
14522406
J Biol Chem. 2004 Mar 5;279(10):9440-50
14676201
J Immunol. 1997 Apr 1;158(7):3401-7
9120300
Blood. 1997 Apr 15;89(8):3009-18
9108422
Shock. 1997 Jul;8(1):16-25
9249908
Anesth Analg. 2003 Jul;97(1):216-21, table of contents
12818969
N Engl J Med. 2004 Jan 1;350(1):4-7
14702420
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7562-7
9636189
Trends Mol Med. 2003 Jun;9(6):263-8
12829015
J Biol Chem. 1995 Jan 13;270(2):933-43
7822333
J Biol Chem. 1998 Feb 20;273(8):4616-21
9468519
Chest. 1992 Jun;101(6):1644-55
1303622
Mol Cell Biol. 1994 Sep;14(9):5820-31
7520526
J Immunol. 1996 May 15;156(10):3961-9
8621937
J Biol Chem. 1995 Feb 24;270(8):3710-9
7533155
J Clin Invest. 1988 Mar;81(3):939-44
3278007
Intensive Care Med. 2004 Oct;30(10):1935-43
15241586
Acta Pharmacol Sin. 2004 May;25(5):672-7
15132836
Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2301-7
16166569