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

TLDR

Aspirin acetylates COX‑2, blocking prostaglandin synthesis while generating 15‑epi‑lipoxins (aspirin‑triggered LXs). The study investigates whether inflammatory exudates from mice treated with ω‑3 fatty acids and aspirin produce novel bioactive lipid signals. Human endothelial cells overexpressing COX‑2 treated with aspirin convert C20:5 ω‑3 to 18R‑HEPE and 15R‑HEPE, and acetaminophen or indomethacin similarly promote these conversions with recombinant COX‑2 and additional ω‑5/ω‑9 oxygenations. These metabolites, including 5‑series 15R‑LX5 and 5,12,18R‑triHEPE, potently inhibit neutrophil transendothelial migration, revealing new COX‑2/NSAID‑dependent transcellular pathways that may underlie the anti‑inflammatory, anti‑neoplastic, and vascular benefits of ω‑3 supplementation.

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 ω-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 ω-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-LX5 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 ω-5 and ω-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 ω-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.