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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4132-4142
Anti-Inflammatory Actions of Lipoxin A4 Stable Analogs Are
Demonstrable in Human Whole Blood: Modulation of Leukocyte Adhesion
Molecules and Inhibition of Neutrophil-Endothelial Interactions
János G. Filep,
Christine Zouki,
Nicos A. Petasis,
Mohamed Hachicha, and
Charles N. Serhan
From the Research Center, Maisonneuve-Rosemont Hospital, Department
of Medicine, University of Montréal, Montréal,
Québec, Canada; the Department of Chemistry, University of
Southern California, Los Angeles, CA; and the Center for Experimental
Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham
and Women's Hospital and Harvard Medical School, Boston, MA.
We have examined in whole blood the actions of 2 lipoxin
A4 (LXA4) stable analogs,
15-R/S-methyl-LXA4 and 16-phenoxy-LXA4, for
their impact on the expression of adhesion molecules on human leukocytes and coronary artery endothelial cells (HCAEC) and on neutrophil adhesion to HCAEC in vitro. Both LXA4 analogs in
nanomolar to micromolar concentrations prevented shedding of L-selectin and downregulated CD11/CD18 expression on resting neutrophils, monocytes, and lymphocytes. Changes in CD11/CD18 expression were blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. The LXA4 analogs also attenuated changes in
L-selectin and CD11/CD18 expression evoked by platelet-activating
factor (PAF), interleukin-8, or C-reactive protein-derived peptide
201-206 with IC50 values of 0.2 to 1.9 µmol/L, whereas
they did not affect lipopolysaccharide (LPS)- or tumor necrosis
factor- -stimulated expression of E-selectin and intercellular
adhesion molecule-1 on HCAEC. These LXA4
analogs markedly diminished adhesion of neutrophils to LPS-activated
HCAEC. Inhibition of adhesion was additive with function blocking
anti-E-selectin and anti-L-selectin antibodies, but was not additive
with anti-CD18 antibody. Combining LXA4 analogs with
dexamethasone (100 nmol/L) almost completely inhibited PAF-induced changes in adhesion molecule expression on leukocytes and gave additive
inhibition of neutrophil adhesion to HCAEC. Culture of HCAEC with
dexamethasone, but not with LXA4 analogs, also decreased neutrophil attachment. Together, these results indicate that
LXA4 stable analogs modulate expression of both L-selectin
and CD11/CD18 on resting and immunostimulated leukocytes and
inhibit neutrophil adhesion to HCAEC by attenuating CD11/CD18
expression. These actions are additive with those of glucocorticoids
and may represent a novel and potent regulatory mechanism by which
LXA4 and aspirin-triggered 15-epi-LXA4 modulate
leukocyte trafficking.
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