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
Cn. Serhan et al., 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, J PHYSL PH, 51(4), 2000, pp. 643-654
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.