Pro-resolving lipid mediators are leads for resolution physiology



Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

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Figure 1: Lipid mediators in the acute inflammatory response, resolution and other outcomes.
Figure 2: Production of specialized pro-resolving mediators in resolving inflammatory exudates.


  1. 1

    Flower, R. J. Prostaglandins, bioassay and inflammation. Br. J. Pharmacol. 147, S182–S192 (2006).

  2. 2

    Samuelsson, B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J. Biol. Chem. 287, 10070–10080 (2012).

  3. 3

    Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Rev. Drug Discov. 11, 633–652 (2012).

  4. 4

    Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nature Immunol. 6, 1191–1197 (2005).

  5. 5

    Maderna, P. & Godson, C. Lipoxins: resolutionary road. Br. J. Pharmacol. 158, 947–959 (2009).

  6. 6

    Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

  7. 7

    Serhan, C. N. et al. 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. J. Exp. Med. 192, 1197–1204 (2000).

  8. 8

    Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter pro-inflammation signals. J. Exp. Med. 196, 1025–1037 (2002).

  9. 9

    Lands, W. E. M. Fish, Omega-3 and Human Health 2nd edn (AOCS Press, 2005).

  10. 10

    Serhan, C. N. & Chiang, N. Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 13, 632–640 (2013).

  11. 11

    Malawista, S. E., de Boisfleury Chevance, A., van Damme, J. & Serhan, C. N. Tonic inhibition of chemotaxis in human plasma. Proc. Natl Acad. Sci. USA 105, 17949–17954 (2008).

  12. 12

    Fullerton, J. N., O'Brien, A. J. & Gilroy, D. W. Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol. 35, 12–21 (2014).

  13. 13

    Dalli, J. & Serhan, C. N. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood 120, e60–e72 (2012).

  14. 14

    Serhan, C. N. The resolution of inflammation: the devil in the flask and in the details. FASEB J. 25, 1441–1448 (2011).

  15. 15

    Bailey, R. L., Gahche, J. J., Miller, P. E., Thomas, P. R. & Dwyer, J. T. Why US adults use dietary supplements. JAMA Intern. Med. 173, 355–361 (2013).

  16. 16

    Yates, C. M., Calder, P. C. & Rainger, G. E. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol. Ther. 141, 272–282 (2014). A thoughtful review of the use of omega-3 essential fatty acids in inflammatory diseases and their potential in supplementation, dietary manipulation and pharmacology.

  17. 17

    Serhan, C. N. & Petasis, N. A. Resolvins and protectins in inflammation-resolution. Chem. Rev. 111, 5922–5943 (2011).

  18. 18

    Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).

  19. 19

    Miyahara, T. et al. D-series resolvins attenuate vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury. FASEB J. 27, 2220–2232 (2013).

  20. 20

    Levy, B. D. & Serhan, C. N. Resolution of acute inflammation in the lung. Annu. Rev. Physiol. 76, 467–492 (2014).

  21. 21

    Spite, M., Claria, J. & Serhan, C. N. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab. 19, 21–36 (2014).

  22. 22

    Dalli, J. et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 20, 188–201 (2013).

  23. 23

    Serhan, C. N. et al. Macrophage pro-resolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 26, 1755–1765 (2012).

  24. 24

    Dalli, J. et al. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 27, 2573–2583 (2013).

  25. 25

    Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 11, 889–896 (2010).

  26. 26

    Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001).

  27. 27

    Morris, T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 183, 2089–2096 (2009).

  28. 28

    Takano, T., Clish, C. B., Gronert, K., Petasis, N. & Serhan, C. N. Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues. J. Clin. Invest. 101, 819–826 (1998).

  29. 29

    Chan, M. M.-Y. & Moore, A. R. Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J. Immunol. 184, 6418–6426 (2010).

  30. 30

    Bannenberg, G. L. et al. Molecular circuits of resolution: Formation and actions of resolvins and protectins. J. Immunol. 174, 4345–4355 (2005).

  31. 31

    Lucas, C. D. et al. Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung. Mucosal Immunol. (2013).

  32. 32

    Navarro-Xavier, R. A. et al. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J. Immunol. 184, 1516–1525 (2010).

  33. 33

    Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012).

  34. 34

    Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009).

  35. 35

    Birnbaum, Y. et al. Augmentation of myocardial production of 15-epi-lipoxin-A4 by pioglitazone and atorvastatin in the rat. Circulation 114, 929–935 (2006). This is the first description of 15-epi-LXA 4 biosynthesis by statins in vivo in rats using a novel pathway and phosphorylated enzymes in the biosynthesis of 15-epi-LXA 4 that mimic the biosynthetic capacity of acetylated COX-2.

  36. 36

    Cooray, S. N. et al. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc. Natl Acad. Sci. USA 110, 18232–18237 (2013). This article reports exciting results indicating that heterodimers and homodimers of ALX/FPR2 signal different responses by activation of distinct intracellular signalling mechanisms.

  37. 37

    Serhan, C. N. et al. Novel proresolving aspirin-triggered DHA pathway. Chem. Biol. 18, 976–987 (2011).

  38. 38

    Morris, T. et al. Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways. Proc. Natl Acad. Sci. USA 107, 8842–8847 (2010).

  39. 39

    Brancaleone, V. et al. A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation. Blood 122, 608–617 (2013).

  40. 40

    Norling, L. V. et al. Cutting edge: humanized nano-proresolving medicines mimic inflammation-resolution and enhance wound healing. J. Immunol. 186, 5543–5547 (2011).

  41. 41

    Stables, M. J. et al. Transcriptomic analyses of murine resolution-phase macrophages. Blood 118, e192–e208 (2011).

  42. 42

    Miki, Y. et al. Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J. Exp. Med. 210, 1217–1234 (2013). This article reports the identification of a secretory phospholipase A2 activated during contact hypersensitive reactions that is specifically involved in the generation of resolvin D1 and protectin D1.

  43. 43

    Levy, B. D. et al. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J. Immunol. 178, 496–502 (2007).

  44. 44

    Miyata, J. et al. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma. J. Allergy Clin. Immunol. 131, 353–360 (2013).

  45. 45

    Yamada, T. et al. Eosinophils promote resolution of acute periotonitis by producing proresolving mediators in mice. FASEB J. 25, 561–568 (2011).

  46. 46

    Isobe, Y. et al. Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3. J. Biochem. 153, 355–360 (2013).

  47. 47

    Arita, M. et al. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005).

  48. 48

    Ohira, T. et al. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J. Biol. Chem. 285, 3451–3461 (2010).

  49. 49

    El Kebir, D., Gjorstrup, P. & Filep, J. G. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc. Natl Acad. Sci. USA 109, 14983–14988 (2012).

  50. 50

    Krishnamoorthy, S., Recchiuti, A., Chiang, N., Fredman, G. & Serhan, C. N. Resolvin D1 receptor stereoselectivity and regulation of inflammation and pro-resolving microRNAs. Am. J. Pathol. 180, 2018–2027 (2012).

  51. 51

    Norling, L. V., Dalli, J., Flower, R. J., Serhan, C. N. & Perretti, M. Resolvin D1 limits polymorphonuclear leukocytes recruitment to inflammatory loci: receptor dependent actions. Arterioscler. Thromb. Vasc. Biol. 32, 1970–1978 (2012).

  52. 52

    Fredman, G., Li, Y., Dalli, J., Chiang, N. & Serhan, C. N. Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA. Sci. Rep. 2, 639 (2012).

  53. 53

    Li, Y. et al. Plasticity of leukocytic exudates in resolving acute inflammation is regulated by microRNA and proresolving mediators. Immunity 39, 885–898 (2013).

  54. 54

    Li, D. et al. Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. Mucosal Immunol. (2013).

  55. 55

    Nelson, J. et al. The ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands. Am. J. Physiol. Cell Physiol. 306, C178–C185 (2014).

  56. 56

    Jones, C. N. et al. Microfluidic chambers for monitoring leukocyte trafficking and humanized nano-proresolving medicines interactions. Proc. Natl Acad. Sci. USA 109, 20560–20565 (2012).

  57. 57

    Kasuga, K. et al. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J. Immunol. 181, 8677–8687 (2008).

  58. 58

    Simiele, F. et al. Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity. FASEB J. 26, 1323–1333 (2012).

  59. 59

    Serhan, C. N. et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J. Immunol. 171, 6856–6865 (2003).

  60. 60

    Hasturk, H. et al. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J. Immunol. 179, 7021–7029 (2007).

  61. 61

    Oh, S. F., Pillai, P. S., Recchiuti, A., Yang, R. & Serhan, C. N. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest. 121, 569–581 (2011).

  62. 62

    Walker, J. et al. Lipoxin A4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock 36, 410–416 (2011).

  63. 63

    Prescott, D. & McKay, D. M. Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G487–G497 (2011).

  64. 64

    Divangahi, M. et al. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nature Immunol. 10, 899–906 (2009).

  65. 65

    Tobin, D. M. et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012). This systematic analysis of tuberculosis in infections in zebrafish identified the host gradation response to producing excess LTB 4 or excess LXA 4 , each having different outcomes for the host and the clearance of tuberculosis infections.

  66. 66

    Rajasagi, N. K., Reddy, P. B., Mulik, S., Gjorstrup, P. & Rouse, B. T. Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology. Invest. Ophthalmol. Vis. Sci. 54, 6269–6279 (2013).

  67. 67

    Rajasagi, N. K. et al. Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J. Immunol. 186, 1735–1746 (2011). This is an exciting first report demonstrating that resolvin E1 protects the eye from Herpes simplex virus infection and stimulates clearance of the virus.

  68. 68

    Cilloniz, C. et al. Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection. J. Virol. 84, 7613–7624 (2010).

  69. 69

    Morita, M. et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153, 112–125 (2013).

  70. 70

    Tam, V. C. et al. Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. Cell 154, 213–227 (2013).

  71. 71

    Haas-Stapleton, E. J. et al. Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1. PLoS ONE 2, e1316 (2007).

  72. 72

    Baillie, J. K. & Digard, P. Influenza–time to target the host? N. Engl. J. Med. 369, 191–193 (2013).

  73. 73

    Pouliot, M., Clish, C. B., Petasis, N. A., Van Dyke, T. E. & Serhan, C. N. Lipoxin A4 analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 39, 4761–4768 (2000).

  74. 74

    Shen, J. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208 (1996).

  75. 75

    Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N. & Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 22, 3595–3606 (2008).

  76. 76

    Merched, A. J., Serhan, C. N. & Chan, L. Nutrigenetic disruption of inflammation-resolution homeostasis and atherogenesis. J. Nutrigenet. Nutrigenomics 4, 12–24 (2011).

  77. 77

    Hasturk, H. et al. RvE1 protects from local inflammation and osteoclast mediated bone destruction in periodontitis. FASEB J. 20, 401–403 (2006).

  78. 78

    Lima-Garcia, J. F. et al. The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br. J. Pharmacol. 164, 278–293 (2011). The authors of this article demonstrate that 17-HDHA and aspirin-triggered RvD1 have potent protective actions in adjuvant-induced arthritis and reduce pain in this model of arthritis.

  79. 79

    Kowal-Bielecka, O., Kowal, K., Distler, O. & Gay, S. Mechanisms of disease: leukotrienes and lipoxins in scleroderma lung disease–insights and potential therapeutic implications. Nature Clin. Pract. Rheumatol. 3, 43–51 (2007).

  80. 80

    Martins, V. et al. ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis. J. Immunol. 182, 5374–5381 (2009).

  81. 81

    Börgeson, E. et al. Lipoxin A(4) and benzo-lipoxin A(4) attenuate experimental renal fibrosis. FASEB J. 25, 2967–2979 (2011). This article reported that expediting resolution and counter-regulation of pro-inflammatory mediators by administration of LXA 4 or its analogues can prevent organ fibrosis and renal fibrosis.

  82. 82

    Qu, X. et al. Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J. Pathol. 228, 506–519 (2012).

  83. 83

    Hsiao, H. M. et al. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS ONE 8, e58258 (2013).

  84. 84

    Wang, S. B. et al. Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea. FASEB J. 26, 1506–1516 (2012).

  85. 85

    Menon, R. The Effect of Resolvins on Dermal Wound Healing. MS thesis, Rutgers Univ. (2012).

  86. 86

    Tang, Y. et al. Proresolution therapy for the treatment of delayed healing of diabetic wounds. Diabetes 62, 618–627 (2013). In this article, the authors demonstrate that pro-resolving mediators such as RvD1 can expedite healing of wounds encountered in diabetes.

  87. 87

    Ramon, S., Gao, F., Serhan, C. N. & Phipps, R. P. Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J. Immunol. 189, 1036–1042 (2012).

  88. 88

    Hong, S. et al. Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms. J. Am. Soc. Mass Spectrom. 18, 128–144 (2007).

  89. 89

    Ariel, A. et al. The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering. J. Biol. Chem. 280, 43079–43086 (2005).

  90. 90

    Ariel, A. et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution via modulation of CCR5 expression. Nature Immunol. 7, 1209–1216 (2006).

  91. 91

    Settimio, R., Clara, D. F., Franca, F., Francesca, S. & Michele, D. Resolvin D1 reduces the immunoinflammatory response of the rat eye following uveitis. Mediators Inflamm. 2012, 318621 (2012).

  92. 92

    Tian, H., Lu, Y., Sherwood, A. M., Hongqian, D. & Hong, S. Resolvins E1 and D1 in choroid-retinal endothelial cells and leukocytes: biosynthesis and mechanisms of anti-inflammatory actions. Invest. Ophthalmol. Vis. Sci. 50, 3613–3620 (2009). The authors of this report demonstrate the endogenous biosynthesis of RvE1 and RvD1 in the retina and the role of cell–cell interactions in this organ.

  93. 93

    Vassiliou, E. K., Kesler, O. M., Tadros, J. H. & Ganea, D. Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells. J. Immunol. 181, 4534–4544 (2008).

  94. 94

    Kim, T. H., Kim, G. D., Jin, Y. H., Park, Y. S. & Park, C. S. Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice. Int. Immunopharmacol. 14, 384–391 (2012).

  95. 95

    Hong, S., Gronert, K., Devchand, P., Moussignac, R.-L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).

  96. 96

    Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783 (2005).

  97. 97

    Marcheselli, V. L. et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807–43817 (2003). This is an important first report of the production and actions of NPD1 in the mouse brain and its neural function by reducing inflammation.

  98. 98

    Bazan, N. G., Calandria, J. M. & Serhan, C. N. Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. J. Lipid Res. 51, 2018–2031 (2010). An authoritative, critical review of the bioactivity and actions of NPD1 in the eye and brain.

  99. 99

    Sheets, K. G. et al. Microglial ramification and redistribution concomitant with the attenuation of choroidal neovascularization by neuroprotectin D1. Mol. Vis. 19, 1747–1759 (2013). The article is the first description of NPD1 action in regulating neovascularization by targeting microglia.

  100. 100

    Bazan, N. G. et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp. Neurol. 236, 122–130 (2012).

  101. 101

    Wang, X. et al. Resolution of inflammation is altered in Alzheimer's disease. Alzheimers Dement. (2014).

  102. 102

    Mizwicki, M. T. et al. 1α,25-Dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients. J. Alzheimers Dis. 34, 155–170 (2013).

  103. 103

    Svensson, C. I., Zattoni, M. & Serhan, C. N. Lipoxins and aspirin-triggered lipoxin stop inflammatory pain processing. J. Exp. Med. 204, 245–252 (2007).

  104. 104

    Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164–174 (2014).

  105. 105

    Xu, Z.-Z. et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Med. 16, 592–597 (2010).

  106. 106

    Bang, S., Yoo, S., Yang, T. J., Cho, H. & Hwang, S. W. 17(R)-resolvin D1 specifically inhibits transient receptor potential ion channel vanilloid 3 leading to peripheral antinociception. Br. J. Pharmacol. 165, 683–692 (2012).

  107. 107

    Park, C. K. et al. Resolving TRPV1 and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072–15085 (2011).

  108. 108

    Abdelmoaty, S. et al. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS ONE 8, e75543 (2013).

  109. 109

    Terrando, N. et al. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J. 27, 3564–3571 (2013). This article reports an exciting discovery demonstrating that RvD1 counter-regulates pro-inflammatory mediators produced during surgery-induced cognitive decline.

  110. 110

    Psychogios, N. et al. The human serum metabolome. PLoS ONE 6, e16957 (2011).

  111. 111

    Mas, E., Croft, K. D., Zahra, P., Barden, A. & Mori, T. A. Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin. Chem. 58, 1476–1484 (2012).

  112. 112

    Serhan, C. N. et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J. Immunol. 176, 1848–1859 (2006).

  113. 113

    Jones, M. L. et al. Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta. J. Lipid Res. 54, 2247–2254 (2013). This article is an important contribution demonstrating that resolvins and protectins are present in placenta and that their levels can be substantially increased with dietary supplementation.

  114. 114

    Weiss, G. A. et al. High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation. Lipids Health Dis. 12, 89 (2013).

  115. 115

    Markworth, J. F. et al. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R1281–R1296 (2013). This article reports exciting new results indicating that strenuous exercise activates acute inflammation and pro-inflammatory eicosanoids, which then transition in humans to pro-resolving mediators present in peripheral blood following a time course consistent with lipid-mediator class switching and resolution of exercise-induced muscle stress or inflammation.

  116. 116

    Wu, S. H., Chen, X. Q., Liu, B., Wu, H. J. & Dong, L. Efficacy and safety of 15(R/S)-methyl-lipoxin A4 in topical treatment of infantile eczema. Br. J. Dermatol. 168, 172–178 (2013). This article reports a paediatric clinical trial that was the first to demonstrate that the topical addition of an aspirin-triggered LXA 4 stable analogue is safe and effective in reducing infantile eczema.

  117. 117

    Raatz, S. K. et al. Baking reduces prostaglandin, resolvin, and hydroxy-fatty acid content of farm-raised Atlantic salmon (Salmo salar). J. Agric. Food Chem. 59, 11278–11286 (2011).

  118. 118

    Clària, J., Nguyen, B. T., Madenci, A., Ozaki, C. K. & Serhan, C. N. Diversity of lipid mediators in human adipose tissue depots. Am. J. Physiol. Cell Physiol. 304, C1141–C1149 (2013).

  119. 119

    Prüss, H. et al. Proresolution lipid mediators in multiple sclerosis - differential, disease severity-dependent synthesis — a clinical pilot trial. PLoS ONE 8, e55859 (2013).

  120. 120

    Giera, M. et al. Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim. Biophys. Acta 1821, 1415–1424 (2012).

  121. 121

    Colas, R., Shinohara, M., Dalli, J., Chiang, N. & Serhan, C.N. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am. J. Physiol Cell Physiol. (2 April, 2014).

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The author thanks S. Orr, J. Dalli and N. Chiang for their critical reading of this manuscript and grants from the US National Institutes of Health (R01GM038765 and P01GM095467) and the Mérieux Foundation (France) for support of the author's research. I also thank our collaborators and investigators contributing to this area whose publications were not cited due to size limitations.

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Correspondence to Charles N. Serhan.

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C.N.S. is an inventor of patents (resolvins) assigned to BWH and licensed to Resolvyx Pharmaceuticals. C.N.S. is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. The interests of C.N.S. were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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Serhan, C. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).

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