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Lipoxin A₄ and Aspirin-Triggered 15-epi-Lipoxin A₄ Inhibit Human Neutrophil Migration: Comparisons Between Synthetic 15 Epimers in Chemotaxis and Transmigration with Microvessel Endothelial Cells and Epithelial Cells ¹

Iolanda M. Fierro^2,*, Sean P. Colgan^*, Giovanni Bernasconi, Nicos A. Petasis, Clary B. Clish^*, Makoto Arita^* and Charles N. Serhan^3,*

^* Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; Department of Chemistry, University of Southern California, Los Angeles, CA 90089

Lipoxins (LX) are bioactive eicosanoids that can be formed during cell to cell interactions in human tissues to self limit key responses in host defense and promote resolution. Aspirin treatment initiates biosynthesis of carbon 15 epimeric LXs, and both series of epimers (LX and aspirin-triggered 15-epi-LX) display counter-regulatory actions with neutrophils. In this study, we report that synthetic lipoxin A₄ (LXA₄) and 15-epi-LXA₄ (i.e., 15(R)-LXA₄ or aspirin-triggered LXA₄) are essentially equipotent in inhibiting human polymorphonuclear leukocytes (PMN) in vitro chemotaxis in response to leukotriene B₄, with the maximum inhibition (50% reduction) obtained at 1 nM LXA₄. At higher concentrations, 15-epi-LXA₄ proved more potent than LXA₄ as its corresponding carboxyl methyl ester. Also, exposure of PMN to LXA₄ and 15-epi-LXA₄ markedly decreased PMN transmigration across both human microvessel endothelial and epithelial cells, where 15-epi-LXA₄ was more active than LXA₄ at "stopping" migration across epithelial cells. Differences in potency existed between LXA₄ and 15-epi-LXA₄ as their carboxyl methyl esters appear to arise from cell type-specific conversion of their respective carboxyl methyl esters to their corresponding carboxylates as monitored by liquid chromatography tandem mass spectrometry. Both synthetic LXA₄ and 15-epi-LXA₄ as free acids activate recombinant human LXA₄ receptor (ALXR) to regulate gene expression, whereas the corresponding methyl ester of LXA₄ proved to be a partial ALXR antagonist and did not effectively regulate gene expression. These results demonstrate the potent stereospecific actions shared by LXA₄ and 15-epi-LXA₄ for activating human ALXR-regulated gene expression and their ability to inhibit human PMN migration during PMN vascular as well as mucosal cell to cell interactions.

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