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Novel n-3 immunoresolvents: structures and actions.

Dalli J, Colas RA, Serhan CN - Sci Rep (2013)

Bottom Line: The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products.Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion.Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
Resolution of inflammation is now held to be an active process where autacoids promote homeostasis. Using functional-metabololipidomics and in vivo systems, herein we report that endogenous n-3 docosapentaenoic (DPA) acid is converted during inflammation-resolution in mice and by human leukocytes to novel n-3 products congenerous to D-series resolvins (Rv), protectins (PD) and maresins (MaR), termed specialized pro-resolving mediators (SPM). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products. Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion. The n-3 DPA-SPM, including RvD1(n-3 DPA) and MaR1(n-3 DPA), each exerted potent leukocyte directed actions in vivo. With human leukocytes each n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis. Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.

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Identification of novel endogenous n-3 DPA pro-resolving mediators.Mice were subjected to ischemia reperfusion injury (see Methods and Fig. 2 for details). Two h into reperfusion, blood was collected and lipid mediators identified by lipid mediator metabololipidomics. (a) Representative chromatographs obtained by Multiple Reaction Monitoring of the parent ion (Q1) and a diagnostic daughter ion (Q3) in the MS-MS of n3-DPA resolvins, protectins and maresins. Representative MS-MS spectra used for identification of (b) RvD1n-3 DPA, (c) RvD5n-3 DPA, and (d) PD1n-3 DPA. Results are representative of n = 4.
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f3: Identification of novel endogenous n-3 DPA pro-resolving mediators.Mice were subjected to ischemia reperfusion injury (see Methods and Fig. 2 for details). Two h into reperfusion, blood was collected and lipid mediators identified by lipid mediator metabololipidomics. (a) Representative chromatographs obtained by Multiple Reaction Monitoring of the parent ion (Q1) and a diagnostic daughter ion (Q3) in the MS-MS of n3-DPA resolvins, protectins and maresins. Representative MS-MS spectra used for identification of (b) RvD1n-3 DPA, (c) RvD5n-3 DPA, and (d) PD1n-3 DPA. Results are representative of n = 4.

Mentions: Having found that n-3 DPA is converted in vivo to yield monohydroxy acids that predominantly possess the S chirality, we next investigated whether these n-3 DPA monohydroxy products were precursors and/or pathway markers for the biosynthesis of bioactive mediators. To this end, we employed targeted LM metabololipidomics with plasma from mice subjected to ischemia reperfusion injury. Multiple reaction monitoring of m/z 377 in Q1 and m/z 143 in Q3 yielded two peaks, the first at RT = 11.6 min and the second at RT = 12.1 min (Fig. 3a). Inspection of the MS-MS spectrum for the product eluting in peak at RT = 11.6 min demonstrated that this material corresponded to RvD2n-3 DPA with the following characteristic ions assigned: m/z 307, m/z 279, m/z 249, m/z 233, and m/z 143 (c.f.Supplementary Fig. 3a, b); while assessment of the MS-MS spectrum for the products at RT = 12.1 min demonstrated that this material corresponded to RvD1n-3 DPA (Fig. 3b). Multiple reaction monitoring of m/z 361 in Q1 and m/z 263 in Q3 yielded three peaks, one at RT = 13.6 min, the second peak with RT = 13.7 min and the third peak RT = 14.4 min (Fig. 3a). Assessment of MS-MS spectra for the product with RT = 13.6 min gave characteristic fragmentation corresponding to RvD5n-3 DPA (Fig. 3c). MS-MS fragmentation for the material at RT = 13.7 min demonstrated characteristic fragmentation corresponding to PD1n-3 DPA (Fig. 3d). The peak eluting at RT = 14.4 min was identified as PD2n-3 DPA with the following characteristic ions assigned: m/z 233, m/z 247, m/z 189 (c.f.Supplementary Fig. 4c, d). These findings demonstrate that n-3 DPA is converted to novel products that are cognate to pro-resolving mediators from DHA; therefore, we employed the nomenclature from the DHA bioactive metabolome to describe each of these new structures.


Novel n-3 immunoresolvents: structures and actions.

Dalli J, Colas RA, Serhan CN - Sci Rep (2013)

Identification of novel endogenous n-3 DPA pro-resolving mediators.Mice were subjected to ischemia reperfusion injury (see Methods and Fig. 2 for details). Two h into reperfusion, blood was collected and lipid mediators identified by lipid mediator metabololipidomics. (a) Representative chromatographs obtained by Multiple Reaction Monitoring of the parent ion (Q1) and a diagnostic daughter ion (Q3) in the MS-MS of n3-DPA resolvins, protectins and maresins. Representative MS-MS spectra used for identification of (b) RvD1n-3 DPA, (c) RvD5n-3 DPA, and (d) PD1n-3 DPA. Results are representative of n = 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672887&req=5

f3: Identification of novel endogenous n-3 DPA pro-resolving mediators.Mice were subjected to ischemia reperfusion injury (see Methods and Fig. 2 for details). Two h into reperfusion, blood was collected and lipid mediators identified by lipid mediator metabololipidomics. (a) Representative chromatographs obtained by Multiple Reaction Monitoring of the parent ion (Q1) and a diagnostic daughter ion (Q3) in the MS-MS of n3-DPA resolvins, protectins and maresins. Representative MS-MS spectra used for identification of (b) RvD1n-3 DPA, (c) RvD5n-3 DPA, and (d) PD1n-3 DPA. Results are representative of n = 4.
Mentions: Having found that n-3 DPA is converted in vivo to yield monohydroxy acids that predominantly possess the S chirality, we next investigated whether these n-3 DPA monohydroxy products were precursors and/or pathway markers for the biosynthesis of bioactive mediators. To this end, we employed targeted LM metabololipidomics with plasma from mice subjected to ischemia reperfusion injury. Multiple reaction monitoring of m/z 377 in Q1 and m/z 143 in Q3 yielded two peaks, the first at RT = 11.6 min and the second at RT = 12.1 min (Fig. 3a). Inspection of the MS-MS spectrum for the product eluting in peak at RT = 11.6 min demonstrated that this material corresponded to RvD2n-3 DPA with the following characteristic ions assigned: m/z 307, m/z 279, m/z 249, m/z 233, and m/z 143 (c.f.Supplementary Fig. 3a, b); while assessment of the MS-MS spectrum for the products at RT = 12.1 min demonstrated that this material corresponded to RvD1n-3 DPA (Fig. 3b). Multiple reaction monitoring of m/z 361 in Q1 and m/z 263 in Q3 yielded three peaks, one at RT = 13.6 min, the second peak with RT = 13.7 min and the third peak RT = 14.4 min (Fig. 3a). Assessment of MS-MS spectra for the product with RT = 13.6 min gave characteristic fragmentation corresponding to RvD5n-3 DPA (Fig. 3c). MS-MS fragmentation for the material at RT = 13.7 min demonstrated characteristic fragmentation corresponding to PD1n-3 DPA (Fig. 3d). The peak eluting at RT = 14.4 min was identified as PD2n-3 DPA with the following characteristic ions assigned: m/z 233, m/z 247, m/z 189 (c.f.Supplementary Fig. 4c, d). These findings demonstrate that n-3 DPA is converted to novel products that are cognate to pro-resolving mediators from DHA; therefore, we employed the nomenclature from the DHA bioactive metabolome to describe each of these new structures.

Bottom Line: The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products.Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion.Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
Resolution of inflammation is now held to be an active process where autacoids promote homeostasis. Using functional-metabololipidomics and in vivo systems, herein we report that endogenous n-3 docosapentaenoic (DPA) acid is converted during inflammation-resolution in mice and by human leukocytes to novel n-3 products congenerous to D-series resolvins (Rv), protectins (PD) and maresins (MaR), termed specialized pro-resolving mediators (SPM). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products. Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion. The n-3 DPA-SPM, including RvD1(n-3 DPA) and MaR1(n-3 DPA), each exerted potent leukocyte directed actions in vivo. With human leukocytes each n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis. Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.

Show MeSH
Related in: MedlinePlus