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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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Related in: MedlinePlus

Biosynthetic schemes proposed for novel n-3 docosapentaenoic acid products and their actions.At the site of injury, n-3 DPA is converted to (a) 17-HpDPA that undergoes further conversion by lipoxygenation to the n-3 DPA resolvins. 17-HpDPA is also a substrate for enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to the n-3 DPA protectin structures. (b) n-3DPA is also converted to 14-lipoxygenation to yield 14-HpDPA that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to MaR1n-3 DPA and/or MaR2n-3 DPA. 14-HpDPA can also undergo a second oxygenation at the omega −1 position to yield the MaR3n-3 DPA. Note that each product is depicted in the 17S and 14S configuration based on the results obtained from chiral lipidomics that indicated S as the predominate form of each but may also carry 17R as well as 14R chirality from lipoxygenase reactions as these lesser components (see Supplementary Fig. 2 and text for details). The complete stereochemistries of these novel mediators remain to be established and are depicted in their likely configuration based on biogenic synthesis (see Supplementary Figures 3–5 for retention times, UV and MS-MS for each of these mediators).
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f8: Biosynthetic schemes proposed for novel n-3 docosapentaenoic acid products and their actions.At the site of injury, n-3 DPA is converted to (a) 17-HpDPA that undergoes further conversion by lipoxygenation to the n-3 DPA resolvins. 17-HpDPA is also a substrate for enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to the n-3 DPA protectin structures. (b) n-3DPA is also converted to 14-lipoxygenation to yield 14-HpDPA that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to MaR1n-3 DPA and/or MaR2n-3 DPA. 14-HpDPA can also undergo a second oxygenation at the omega −1 position to yield the MaR3n-3 DPA. Note that each product is depicted in the 17S and 14S configuration based on the results obtained from chiral lipidomics that indicated S as the predominate form of each but may also carry 17R as well as 14R chirality from lipoxygenase reactions as these lesser components (see Supplementary Fig. 2 and text for details). The complete stereochemistries of these novel mediators remain to be established and are depicted in their likely configuration based on biogenic synthesis (see Supplementary Figures 3–5 for retention times, UV and MS-MS for each of these mediators).

Mentions: In light of the results from the present studies in conjunction with earlier mechanisms proposed for the biosynthesis of the D-series resolvins, protectins1534 and maresins35, the pathways for the novel n-3 DPA immunoresolvent are illustrated in Fig. 8. In this proposed scheme, n-3 DPA is first converted via 17 lipoxygenation to 17-hydroperoxy-8Z,10Z,13Z,15E,19Z-docosapentaenoic acid (17-HpDPA). This intermediate can next undergo a second lipoxygenation by 5-lipoxygenase-like reaction to yield the 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1n-3DPA), 7, 16, 17-trihydroxy-8,10,12,14E,19Z-docosapentaenoic acid (RvD2n-3DPA) and/or 7,17-trihydroxy-8E,10,13,15E,19Z-docosapentaenoic acid (RvD5n-3DPA). In addition, 17-HpDPA can undergo enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to either 10,17-dihydroxy-7Z,11,13,15,19Z-docosapentaenoic acid (PD1n-3DPA) or 16,17-dihydroxy-7Z,10,13, 14,19Z- docosapentaenoic acid (PD2n-3DPA). In a parallel pathway, the arachidonate 12-lipoxygenase coverts n-3 DPA to 14-hydroperoxy-7Z,10 Z,12E,16Z,19Z-docosapentaenoic acid (14-HpDPA) that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to yield 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1n-3 DPA) or 13,14-dihydroxy-7Z,9,11, 16Z,19Z-docosapentaenoic acid (MaR2n-3 DPA). Alternatively, this 14-HpDPA can undergo a second oxygenation at the omega -1 position to yield 14, 21-dihydroxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid (MaR3n-3 DPA). Of note, since we identified the S isomer of both 17-HDPA and 14-HDPA, the reduction products of 17-HpDPA and 14-HpDPA, as the major products in inflamed tissues (Supplementary Fig. 2), it is highly likely that the stereochemistry at these positions is retained in the biosynthesis of the novel n-3 DPA-derived resolvins, protectins and maresins. Of note, it is conceivable that the R-containing diastereomers of the n-3 DPA resolvins, protectins and maresins may also be of biological relevance in inflammation-resolution, since they were also obtained via lipoxygenation reaction albeit to lesser proportions than their corresponding R-containing products (see Supplementary Fig. 2).


Novel n-3 immunoresolvents: structures and actions.

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

Biosynthetic schemes proposed for novel n-3 docosapentaenoic acid products and their actions.At the site of injury, n-3 DPA is converted to (a) 17-HpDPA that undergoes further conversion by lipoxygenation to the n-3 DPA resolvins. 17-HpDPA is also a substrate for enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to the n-3 DPA protectin structures. (b) n-3DPA is also converted to 14-lipoxygenation to yield 14-HpDPA that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to MaR1n-3 DPA and/or MaR2n-3 DPA. 14-HpDPA can also undergo a second oxygenation at the omega −1 position to yield the MaR3n-3 DPA. Note that each product is depicted in the 17S and 14S configuration based on the results obtained from chiral lipidomics that indicated S as the predominate form of each but may also carry 17R as well as 14R chirality from lipoxygenase reactions as these lesser components (see Supplementary Fig. 2 and text for details). The complete stereochemistries of these novel mediators remain to be established and are depicted in their likely configuration based on biogenic synthesis (see Supplementary Figures 3–5 for retention times, UV and MS-MS for each of these mediators).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Biosynthetic schemes proposed for novel n-3 docosapentaenoic acid products and their actions.At the site of injury, n-3 DPA is converted to (a) 17-HpDPA that undergoes further conversion by lipoxygenation to the n-3 DPA resolvins. 17-HpDPA is also a substrate for enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to the n-3 DPA protectin structures. (b) n-3DPA is also converted to 14-lipoxygenation to yield 14-HpDPA that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to MaR1n-3 DPA and/or MaR2n-3 DPA. 14-HpDPA can also undergo a second oxygenation at the omega −1 position to yield the MaR3n-3 DPA. Note that each product is depicted in the 17S and 14S configuration based on the results obtained from chiral lipidomics that indicated S as the predominate form of each but may also carry 17R as well as 14R chirality from lipoxygenase reactions as these lesser components (see Supplementary Fig. 2 and text for details). The complete stereochemistries of these novel mediators remain to be established and are depicted in their likely configuration based on biogenic synthesis (see Supplementary Figures 3–5 for retention times, UV and MS-MS for each of these mediators).
Mentions: In light of the results from the present studies in conjunction with earlier mechanisms proposed for the biosynthesis of the D-series resolvins, protectins1534 and maresins35, the pathways for the novel n-3 DPA immunoresolvent are illustrated in Fig. 8. In this proposed scheme, n-3 DPA is first converted via 17 lipoxygenation to 17-hydroperoxy-8Z,10Z,13Z,15E,19Z-docosapentaenoic acid (17-HpDPA). This intermediate can next undergo a second lipoxygenation by 5-lipoxygenase-like reaction to yield the 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1n-3DPA), 7, 16, 17-trihydroxy-8,10,12,14E,19Z-docosapentaenoic acid (RvD2n-3DPA) and/or 7,17-trihydroxy-8E,10,13,15E,19Z-docosapentaenoic acid (RvD5n-3DPA). In addition, 17-HpDPA can undergo enzymatic conversion to an epoxide intermediate that is next enzymatically hydrolyzed to either 10,17-dihydroxy-7Z,11,13,15,19Z-docosapentaenoic acid (PD1n-3DPA) or 16,17-dihydroxy-7Z,10,13, 14,19Z- docosapentaenoic acid (PD2n-3DPA). In a parallel pathway, the arachidonate 12-lipoxygenase coverts n-3 DPA to 14-hydroperoxy-7Z,10 Z,12E,16Z,19Z-docosapentaenoic acid (14-HpDPA) that is further converted to an epoxide intermediate and then enzymatically hydrolyzed to yield 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1n-3 DPA) or 13,14-dihydroxy-7Z,9,11, 16Z,19Z-docosapentaenoic acid (MaR2n-3 DPA). Alternatively, this 14-HpDPA can undergo a second oxygenation at the omega -1 position to yield 14, 21-dihydroxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid (MaR3n-3 DPA). Of note, since we identified the S isomer of both 17-HDPA and 14-HDPA, the reduction products of 17-HpDPA and 14-HpDPA, as the major products in inflamed tissues (Supplementary Fig. 2), it is highly likely that the stereochemistry at these positions is retained in the biosynthesis of the novel n-3 DPA-derived resolvins, protectins and maresins. Of note, it is conceivable that the R-containing diastereomers of the n-3 DPA resolvins, protectins and maresins may also be of biological relevance in inflammation-resolution, since they were also obtained via lipoxygenation reaction albeit to lesser proportions than their corresponding R-containing products (see Supplementary Fig. 2).

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