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
2000/10/16 by Charles N. Serhan, Clary B. Clish, Jessica Brannon +3 · 1,187 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · Nursing · #Arachidonic acid #Biochemistry #Biology #Chemistry #Cyclooxygenase #Downregulation and upregulation #Eicosanoid #Eicosanoids and Hypertension Pharmacology #Enzyme #Fatty Acid Research and Health #Fatty acid #Immunology #Inflammation #Inflammatory mediators and NSAID effects #Isoprostane #Lipid peroxidation #Lipid signaling #Pharmacology #Polyunsaturated fatty acid #Prostaglandin #Transcellular
paper · pdf · doi:10.1084/jem.192.8.1197
published in The Journal of Experimental Medicine 192(8), 1197-1204 (Rockefeller University Press)
openalex publication_date 2000/10/16 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Abstract
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 from mice treated with omega-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 omega-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX(5) and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as omega-5 and omega-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions that impact microinflammation. The 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.
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