Anti-microinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygenase-2 and transcellular processing: A novel mechanism for NSAID and N-3PUFA therapeutic actions

Aspirin therapy inhibits prostaglandin biosynthesis; yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered lipoxin or ATL). Here, we rev iew our findings indicating that inflammatory exudates from mice treated wi th omega -3 PUFA and aspirin (ASA) generate a novel array of bioactive lipi d signals. Also, human endothelial cells, both HUVEC and microvascular, wit h upregulated COX-2 and treated with ASA converted C20:5 omega -3 to 18R-hy droxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Human PMN activated with se rum treated zymosan (STZ) utilized each of these R-HEPEs to generate novel classes of trihydroxy-containing mediators including 5-series 15R-LX and 5, 12,18R-triHEPE. The novel products were potent inhibitors of human PMN tran sendothelial migration and infiltration of PMN in dorsal air pouches in viv o. In addition to ASA, both acetaminophen and indomethacin also permitted 1 8R-HEPE and 15R-HEPE generation with recombinant human COX-2 as well as ome ga -5 and omega -9 oxygenations of other fatty acids that act on leukocytes , platelets and endothelial cells. These findings establish new transcellul ar routes for producing arrays of lipid mediators via COX-2-NSAIDs and cell -cell interactions that impact microinflammation. Moreover, they provide no vel mechanism(s) that could underlie the many reported therapeutic benefits of omega -3 dietary supplementation of interest in inflammation, cancer, a nd vascular disorders.