Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 103, Issue 6, Pages 995-1010Publisher
WILEY
DOI: 10.1002/JLB.3MI0617-254R
Keywords
anti-inflammatory; essential fatty acids; ischemia; leukocytes; oxidoreductase; reperfusion injury; resolvins; specialized proresolving mediators
Categories
Funding
- National Institutes of Health [P01GM095467]
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Local production and downstream metabolism of specialized proresolving lipid mediators (SPMs) are pivotal in regulating their biological actions during resolution of inflammation. Resolvin D4 (RvD4: 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z hexaenoic acid) is one of the more recently elucidated SPMs with complete stereochemistry biosynthesized from docosahexaenoic acid. Here, we report a new multimilligram commercial synthesis that afforded enough material for matching, validation, and further evaluation of RvD4 functions. Using LC-MS-MS profiling, RvD4 was identified at bioactive amounts in human (1 pg/mL) and mouse bone marrow (12 pg/femur and tibia). In mouse bone marrow, ischemia increased the formation of RvD4>37-fold (455 pg/femur and tibia). Two separate mouse ischemic injury models were used, where RvD4 reduced second organ reperfusion lung injury>50%, demonstrating organ protection. Structure-function relationships of RvD4 demonstrated>40% increase in neutrophil and monocyte phagocytic function in human whole blood in comparison with 2 separate trans-containing double bond isomers that were inactive. These 2 isomers were prepared by organic synthesis: 4S,5R,17S-trihydroxydocosa-6E,8E,10E,13Z,15E,19Z-hexaenoic acid (10-trans-RvD4), a natural isomer, and 4S,5R,17S-trihydroxydocosa-6E,8E,10E,13E,15E,19Z-hexaenoic acid (10,13-trans-RvD4), a rogue isomer. Compared to leukotriene B-4, D-series resolvins (RvD1, RvD2, RvD3, RvD4, or RvD5) did not stimulate human neutrophil chemotaxis monitored via real-time microfluidics chambers. A novel 17-oxo-containing-RvD4 product of eicosanoid oxidoreductase was identified with human bone marrow cells. Comparison of 17-oxo-RvD4 to RvD4 demonstrated that with human leukocytes 17-oxo-RvD4 was inactive. Together, these provide commercial-scale synthesis that permitted a second independent validation of RvD4 complete stereochemical structure as well as evidence for RvD4 regulation in tissues and its stereoselective phagocyte responses.
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