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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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n-3 DPA-derived products display potent anti-inflammatory and tissue protective actions in vivo that are comparable to RvD1.(a) Structures of DHA and n-3 DPA. (b) Ischemia was induced by applying tourniquets to the hind limb of 6-8-week-old male FvB mice. After 1 h, tourniquets were removed and reperfusion ensued for 3 h. 10 min prior to reperfusion, vehicle (saline containing 0.1% EtOH), RvD1 (500 ng) or a mixture of n-3 DPA-derived products (see Methods for details) were administered intravenously. At the end of reperfusion, lungs were collected; (c) tissue histology by H&E staining (x200) and (d) MPO levels were assessed. (e) Blood was collected, incubated with rat anti-mouse Ly6G and rat anti-mouse CD41 antibodies and neutrophil leukocyte aggregates were assessed by flow cytometry. (f) Plasma prostanoid and (g) leukotriene levels were assessed by lipid mediator metabololipidomics. Results c are representative n = 4. Results d–e are mean ± SEM. n = 4. * P < 0.05, ** P < 0.01 vs. vehicle mice.
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f1: n-3 DPA-derived products display potent anti-inflammatory and tissue protective actions in vivo that are comparable to RvD1.(a) Structures of DHA and n-3 DPA. (b) Ischemia was induced by applying tourniquets to the hind limb of 6-8-week-old male FvB mice. After 1 h, tourniquets were removed and reperfusion ensued for 3 h. 10 min prior to reperfusion, vehicle (saline containing 0.1% EtOH), RvD1 (500 ng) or a mixture of n-3 DPA-derived products (see Methods for details) were administered intravenously. At the end of reperfusion, lungs were collected; (c) tissue histology by H&E staining (x200) and (d) MPO levels were assessed. (e) Blood was collected, incubated with rat anti-mouse Ly6G and rat anti-mouse CD41 antibodies and neutrophil leukocyte aggregates were assessed by flow cytometry. (f) Plasma prostanoid and (g) leukotriene levels were assessed by lipid mediator metabololipidomics. Results c are representative n = 4. Results d–e are mean ± SEM. n = 4. * P < 0.05, ** P < 0.01 vs. vehicle mice.

Mentions: Since even minor changes in the structural properties of EFA are of functional significance22, we first investigated whether n-3 DPA, products that contain one fewer double bond than those derived from DHA (Fig. 1a), produced by exudate leukocytes exerted protective actions during acute inflammation. For this purpose, we employed a model of surgery-induced second organ injury, the murine hind limb ischemia reperfusion model (Fig. 1b)9. Administration of an isolated mixture obtained via solid-phase extraction (see Methods) of the n-3 DPA products 10 min prior to onset of reperfusion led to protection from secondary organ injury as evidenced by reduction in lung tissue damage (Fig. 1c) and decrease in the number of infiltrated leukocytes into the lungs (~45%, p < 0.05). These actions were comparable to protection afforded by the DHA-derived pro-resolving mediator RvD1 (Fig. 1c, d).


Novel n-3 immunoresolvents: structures and actions.

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

n-3 DPA-derived products display potent anti-inflammatory and tissue protective actions in vivo that are comparable to RvD1.(a) Structures of DHA and n-3 DPA. (b) Ischemia was induced by applying tourniquets to the hind limb of 6-8-week-old male FvB mice. After 1 h, tourniquets were removed and reperfusion ensued for 3 h. 10 min prior to reperfusion, vehicle (saline containing 0.1% EtOH), RvD1 (500 ng) or a mixture of n-3 DPA-derived products (see Methods for details) were administered intravenously. At the end of reperfusion, lungs were collected; (c) tissue histology by H&E staining (x200) and (d) MPO levels were assessed. (e) Blood was collected, incubated with rat anti-mouse Ly6G and rat anti-mouse CD41 antibodies and neutrophil leukocyte aggregates were assessed by flow cytometry. (f) Plasma prostanoid and (g) leukotriene levels were assessed by lipid mediator metabololipidomics. Results c are representative n = 4. Results d–e are mean ± SEM. n = 4. * P < 0.05, ** P < 0.01 vs. vehicle mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: n-3 DPA-derived products display potent anti-inflammatory and tissue protective actions in vivo that are comparable to RvD1.(a) Structures of DHA and n-3 DPA. (b) Ischemia was induced by applying tourniquets to the hind limb of 6-8-week-old male FvB mice. After 1 h, tourniquets were removed and reperfusion ensued for 3 h. 10 min prior to reperfusion, vehicle (saline containing 0.1% EtOH), RvD1 (500 ng) or a mixture of n-3 DPA-derived products (see Methods for details) were administered intravenously. At the end of reperfusion, lungs were collected; (c) tissue histology by H&E staining (x200) and (d) MPO levels were assessed. (e) Blood was collected, incubated with rat anti-mouse Ly6G and rat anti-mouse CD41 antibodies and neutrophil leukocyte aggregates were assessed by flow cytometry. (f) Plasma prostanoid and (g) leukotriene levels were assessed by lipid mediator metabololipidomics. Results c are representative n = 4. Results d–e are mean ± SEM. n = 4. * P < 0.05, ** P < 0.01 vs. vehicle mice.
Mentions: Since even minor changes in the structural properties of EFA are of functional significance22, we first investigated whether n-3 DPA, products that contain one fewer double bond than those derived from DHA (Fig. 1a), produced by exudate leukocytes exerted protective actions during acute inflammation. For this purpose, we employed a model of surgery-induced second organ injury, the murine hind limb ischemia reperfusion model (Fig. 1b)9. Administration of an isolated mixture obtained via solid-phase extraction (see Methods) of the n-3 DPA products 10 min prior to onset of reperfusion led to protection from secondary organ injury as evidenced by reduction in lung tissue damage (Fig. 1c) and decrease in the number of infiltrated leukocytes into the lungs (~45%, p < 0.05). These actions were comparable to protection afforded by the DHA-derived pro-resolving mediator RvD1 (Fig. 1c, d).

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