Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing

Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive Lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates fro m mice treated with omega -3 polyunsaturated fatty acid and aspirin (ASA) g enerate a novel array of bioactive lipid signals. Human endothelial cells w ith upregulated COX-2 treated with ASA converted C20:5 omega -3 to 18R-hydr oxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonu clear leukocytes to generate separate classes of novel trihydroxy-containin g mediators, including 5-series 15R-LX5 and 5,12,18R-triHEPE. These new com pounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18 R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HE PE and 15R-HEPE generation with recombinant COX-2 as well as omega -5 and o mega -9 oxygenations of other fatty acids that act on hematologic cells. Th ese findings establish new transcellular routes for producing arrays of bio active lipid mediators via COX-2-nonsteroidal antiinflammatory drug-depende nt oxygenations and cell-cell interactions that impact microinflammation. T he generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of omega -3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.