Anti-inflammatory actions of lipoxin A(4) stable analogs are demonstrable in human whole blood: Modulation of leukocyte adhesion molecules and inhibition of neutrophil-endothelial interactions

We have examined in whole blood the actions of 2 lipoxin A(4) (LXA(4)) stab le analogs, 15-R/S-methyl-LXA(4) and 16-phenoxy-LXA(4), for their impact on the expression of adhesion molecules on human leukocytes and coronary arte ry endothelial cells (HCAEC) and on neutrophil adhesion to HCAEC in vitro. Both LXA4 analogs in nanomolar to micromolar concentrations prevented shedd ing of L-selectin and downregulated CD11/CD18 expression on resting neutrop hils, monocytes, and lymphocytes. Changes in CD11/CD18 expression were bloc ked by the mitogen-activated protein kinase kinase inhibitor PD98059, The L XA(4) analogs also attenuated changes in L-selectin and CD11/CD18 expressio n 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 mu mol/L, wh ereas they did not affect lipopolysaccharide (LPS)- or tumor necrosis facto r-alpha-stimulated expression of E-selectin and intercellular adhesion mole cule-1 on HCAEC. These LXA(4) analogs markedly diminished adhesion of neutr ophils to LPS-activated HCAEC. Inhibition of adhesion was additive with fun ction blocking anti-E-selectin and anti-l-selectin antibodies, but was not additive with anti-CD18 antibody. Combining LXA(4) analogs with dexamethaso ne (100 nmol/L) almost completely inhibited PAF-induced changes in adhesion molecule expression on leukocytes and gave additive inhibition of neutroph il adhesion to HCAEC. Culture of HCAEC with dexamethasone, but not with LXA 4 analogs, also decreased neutrophil attachment. Together, these results in dicate 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 a dditive with those of glucocorticoids and may represent a novel and potent regulatory mechanism by which LXA4 and aspirin-triggered 15-epi-LXA(4) modu late leukocyte trafficking. (C) 1999 by The American Society of Hematology.