title: 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.
abstract: 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 A(4) (LXA(4)) and 15-epi-LXA(4) (i.e., 15(R)-LXA(4) or aspirin-triggered LXA(4)) are essentially equipotent in inhibiting human polymorphonuclear leukocytes (PMN) in vitro chemotaxis in response to leukotriene B(4), with the maximum inhibition ( approximately 50% reduction) obtained at 1 nM LXA(4). At higher concentrations, 15-epi-LXA(4) proved more potent than LXA(4) as its corresponding carboxyl methyl ester. Also, exposure of PMN to LXA(4) and 15-epi-LXA(4) markedly decreased PMN transmigration across both human microvessel endothelial and epithelial cells, where 15-epi-LXA(4) was more active than LXA(4) at "stopping" migration across epithelial cells. Differences in potency existed between LXA(4) and 15-epi-LXA(4) 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 LXA(4) and 15-epi-LXA(4) as free acids activate recombinant human LXA(4) receptor (ALXR) to regulate gene expression, whereas the corresponding methyl ester of LXA(4) proved to be a partial ALXR antagonist and did not effectively regulate gene expression. These results demonstrate the potent stereospecific actions shared by LXA(4) and 15-epi-LXA(4) 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.
authors.affiliation: 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, USA. iolanda@uerj.br
authors.forename: Iolanda M
authors.initials: IM
authors.lastname: Fierro
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernasconi
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000378:metabolism; D002460:Cell Line; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D004952:Esters; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000502:physiology*; D044045:Lipoxins; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D002264:Carboxylic Acids; D004952:Esters; C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; C040527:lipoxin A4; D001241:Aspirin