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

By C. Serhan, C. Clish, Jessica Brannon, S. Colgan, Chia Nan, K. Gronert. Journal of Experimental Medicine, 2000

1,245 citations recorded by the source corpus.

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.

Subfields: Biochemistry, Nutrition and Dietetics, Pharmacology

View Paper: https://www.semanticscholar.org/paper/86246fe3705c256e83832ce9fc17775d9bea7d05

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. C. Serhan
2. B. Levy
3. Undurti N. Das
4. N. Petasis
5. Chia Nan
6. M. Perretti
7. D. Gilroy
8. C. Buckley

In Nutrition and Dietetics

1. C. Serhan
2. B. Levy
3. D. Gilroy
4. Undurti N. Das
5. N. Petasis
6. Chia Nan
7. M. Perretti
8. C. Buckley

In Pharmacology

1. C. Serhan
2. B. Levy
3. Undurti N. Das
4. Chia Nan
5. N. Petasis
6. J. Tschopp
7. P. Calder

Citations in the corpus

• Inflammatory Resolution: new opportunities for drug discovery (2004, background): “DHA and EPA — omega-3 fatty-acid constituents of fish oils — were shown recently to be metabolized during the resolving phase of an aspirin-treated TNF-α-induced inflammation to potent anti-inflammatory products, aptly named resolvin”
• Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. (2018, background): “EPA-derived 18-HEPE and 15-HEPE are produced by hypoxic vascular endothelial cells and reduce PMN transendothelial migration, but are less potent than resolvin E1 (RvE1) or 15-epi-LXA 5 (9).”
• Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. (2013, background): “Furthermore, we also found that Alox5 and Alox15 double deficiency or inhibition of COX-2 activity by celecoxib had no impact on the inhibitory activity of DHA on NLRP3 or NLRP1b inflammasome activation (Figures 3D and 3E; Figure S2).”
• Essential fatty acids: biochemistry, physiology and pathology (2006, background): “These results suggest that 5,12,18R-triHEPE suppress LTmediated responses if present in adequate amounts at the sites of inflammation [90].”
• Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1 (2005, methodology): “RvE1 also blocked PMN transendothelial migration in vitro (7) and inhibited migration and IL-12 production from APCs (Fig.”