Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation
To Resolve or Not?
Correspondence information about the author Charles N. Serhan
Email the author Charles N. Serhan
Figure 1
Decision paths in acute inflammation: resolution or chronic inflammation? Lipid mediators such as prostaglandins and leukotrienes play specific roles in the physiology of the acute inflammatory response. They can regulate many of the cardinal signs of inflammation. Self-limited inflammatory exudates permitted the identification and study of specialized pro-resolving mediators that stimulate the return to homeostasis.
Figure 2
Ideal outcome of acute inflammation: complete resolution. Using a systems approach to mapping resolution, temporal and spatial dissociation of eicosanoids was uncovered, which is termed lipid mediator class switching. Prostaglandins and leukotrienes are generated early in the response. Prostaglandins E2 and D2 stimulate the transcriptional regulation in human leukocytes for the production of enzymes required for lipoxin biosynthesis. Unresolved acute inflammation is associated with increased prostaglandin and leukotriene production and chronic inflammation. Inset: Experimental acute inflammation shows the temporal theoretical events in edema formation and its decline as well as leukocyte trafficking with nonphlogistic recruitment of PMNs.1x1Cotran, RS, Kumar, V, and Collins, T. in: RS Cotran, V Kumar, T Collins
(Eds.)
Robbins Pathologic Basis of Disease. W.B. Saunders Co.,
Philadelphia; 1999
Google ScholarSee all References, 4x4Winyard, PG and Willoughby, DA. in: PG Winyard, DA Willoughby
(Eds.)
Inflammation Protocols. Humana,
Totowa NJ; 2003
Crossref | Google ScholarSee all References During the decline of PMNs, specialized proresolving mediators are temporally produced in vivo in inflammatory exudates; see text for details.
Figure 3
The genus of specialized proresolving mediators: structures and actions. The SPM genus is defined by reduction or limiting further PMN infiltration and reduction of lipid mediators and cytokines. SPM also stimulate the nonphlogistic recruitment of mononuclear cells and the stimulation of macrophages to phagocytose apoptotic PMN microbes and microbial particles. The family precursors are substrates for their respective conversion to lipoxins, E-series resolvins, D-series resolvins, and protectins. The main structures of key SPM genus members are depicted; the complete stereochemistry of each has been determined, and their physical properties and bioactions have been confirmed by total organic synthesis; see text for details.
Figure 4
SPM-regulated processes in resolution and a new role for edema in delivering essential fatty acids. This illustration depicts a self-limited evolving exudate with the key roles of specialized proresolving mediators (SPM), substrate delivery, and leukocyte trafficking. i) Lower right-hand corner: microbial invasion in injury initiates chemotactic signals that initially summon neutrophils from postcapillary venules. Neutrophils arrive to the site via diapedesis and chemotaxis. A key chemoattractant of the eicosanoids in the process is leukotriene B4. There is also a wide range of cytokines and chemokines that stimulate neutrophil recruitment in this important and fundamental process. ii) As neutrophils congregate in the contained inflammatory exudate, cell–cell interactions (eg, with platelets in transcellular biosynthesis generated between PMN and platelets) initiate the transcellular biosynthesis of lipoxins. Newly arrived and older PMN within the exudate interact to produce resolvins and protectins via transcellular biosynthesis. During this process, edema carries the ω-3 essentially fatty acids EPA and DHA from the blood into the exudate for their utilization. iii) Once resolvins and protectins are produced, these SPM stimulate macrophages to take up apoptotic PMN and cellular debris. Additionally, the corpses of apoptotic PMN can serve to bind chemokines and cytokines for their disposal. SPM enhance macrophage uptake and clearance. iv) Macrophages phagocytose apoptotic PMN. This process is stimulated by SPM and is an anti-inflammatory and nonphlogistic process. Rather than producing proinflammatory mediators during phagocytosis, such as LTB4, TNF, and IL-1, these macrophages produce lipoxins, resolvins, and NPD1/PD1 that, in turn, inhibit further edema through a feedback mechanism. This hypothetical course of events and time course help the contained inflammatory exudate to resolve as well as efficiently combat infection and return to homeostasis from local tissue injury.
Article Outline
- New Solution for Resolution of Acute Inflammation
- Programmed Resolution of Acute Inflammation: Active Resolution versus Collateral Damage?
- Specialized Anti-Inflammatory and Pro-resolving Mediators (SPM) in Programmed Resolution
- Resolvins and Protectins
- Edema: A New Functional Role in Substrate Delivery for Resolution
- GPCR and Not Nuclear Receptors for SPM in Resolution
- Proresolving Receptor Distribution
- RvD2: Resolution and Sepsis
- Targeted Lipidomics in Late Phase, Self-Limited, Resolving Exudates Maresins
- Too Much of a Good Thing? Bugs and SPM
- Resolution Indices and Toxicity
- Are All SPM the Same?
- Conclusion
- References
Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid–derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that anti-inflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies.
New Solution for Resolution of Acute Inflammation
Surgical interventions, tissue injury, and microbial invasion each evoke acute inflammation that is ideally protective for the host and should be “self-limited.” Resolution of this inflammatory response was believed to be passive and defined earlier by histopathology.1x1Cotran, RS, Kumar, V, and Collins, T. in: RS Cotran, V Kumar, T Collins
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Programmed Resolution of Acute Inflammation: Active Resolution versus Collateral Damage?
If the ideal outcome of acute inflammation is complete resolution,1x1Cotran, RS, Kumar, V, and Collins, T. in: RS Cotran, V Kumar, T Collins
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| SPM | Disease model | Cellular mechanism of action | References |
|---|---|---|---|
| Resolvin E1 | Skin | Stops neutrophil recruitment in dorsal pouch | Serhan et al.8x8Serhan, CN, Clish, CB, Brannon, J, Colgan, SP, Chiang, N, and Gronert, K. 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. 2000;
192: 1197–1204 Crossref | PubMed | Scopus (422) | Google ScholarSee all References |
| Oral inflammation, periodontitis | Reduces neutrophil infiltration; prevents connective tissue and bone loss; promotes healing of diseased tissues; regenerates lost soft tissue and bone | Hasturk et al.53x53Hasturk, H, Kantarci, A, Ohira, T, Arita, M, Ebrahimi, N, Chiang, N, Petasis, NA, Levy, BD, Serhan, CN, and Van Dyke, TE. RvE1 protects from local inflammation and osteoclast mediated bone destruction in periodontitis. FASEB J. 2006;
20: 401–403 PubMed | Google ScholarSee all References | |
| Peritonitis | Stops neutrophil recruitment; regulates chemokine/cytokine production | Bannenberg et al.40x40Bannenberg, GL, Chiang, N, Ariel, A, Arita, M, Tjonahen, E, Gotlinger, KH, Hong, S, and Serhan, CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;
174: 4345–4355 PubMed | Google ScholarSee all References; Arita et al.54x54Arita, M, Bianchini, F, Aliberti, J, Sher, A, Chiang, N, Hong, S, Yang, R, Petasis, NA, and Serhan, CN. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005; 201: 713–722 Crossref | PubMed | Scopus (358) | Google ScholarSee all References; Schwab et al.55x55Schwab, JM, Chiang, N, Arita, M, and Serhan, CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007; 447: 869–874 Crossref | PubMed | Scopus (387) | Google ScholarSee all References | |
| Promotes lymphatic removal of phagocytes | |||
| Asthma | Reduces airway inflammation; stimulates LXA4; reduces SRS-A | Haworth et al.49x49Haworth, O, Cernadas, M, Yang, R, Serhan, CN, and Levy, BD. Resolvin E1 regulates interleukin-23, interferon-gamma and lipoxin A4 to promote resolution of allergic airway inflammation. Nat Immunol. 2008;
9: 873–879 Crossref | PubMed | Scopus (153) | Google ScholarSee all References | |
| Ocular | Regulates neovascularization, angiogenesis | Connor et al.51x51Connor, KM, SanGiovanni, JP, Lofqvist, C, Aderman, CM, Chen, J, Higuchi, A, Hong, S, Pravda, EA, Majchrzak, S, Carper, D, Hellstrom, A, Kang, JX, Chew, EY, Salem, NN Jr, Serhan, CN, and Smith, LEH. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007;
13: 868–873 Crossref | PubMed | Scopus (260) | Google ScholarSee all References; Jin et al.56x56Jin, Y, Arita, M, Zhang, Q, Saban, DR, Chauhan, SK, Chiang, N, Serhan, CN, and Dana, MR. Novel anti-inflammatory and pro-resolving lipid mediators block inflammatory angiogenesis. Invest Ophthalmol Vis Sci. 2009; 50: 4743–4752 Crossref | PubMed | Scopus (57) | Google ScholarSee all References; Tian et al.57x57Tian, H, Lu, Y, Sherwood, AM, Hongqian, D, and Hong, S. Resolvins E1 and D1 in choroid-retinal endothelial cells and leukocytes: biosynthesis and mechanisms of anti-inflammatory actions. Invest Ophthalmol Vis Sci. 2009; 50: 3613–3620 Crossref | PubMed | Scopus (35) | Google ScholarSee all References | |
| Colitis | Limits PMN recruitment and proinflammatory gene expression; improves survival; reduces weight loss | Arita et al.47x47Arita, M, Yoshida, M, Hong, S, Tjonahen, E, Glickman, JN, Petasis, NA, Blumberg, RS, and Serhan, CN. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci USA. 2005;
102: 7671–7676 Crossref | PubMed | Scopus (269) | Google ScholarSee all References; Ishida et al.58x58Ishida, T, Yoshida, M, Arita, M, Nishitani, Y, Nishiumi, S, Masuda, A, Mizuno, S, Takagawa, T, Morita, Y, Kutsumi, H, Inokuchi, H, Serhan, CN, Blumberg, RS, and Azuma, T. Resolvin E1, an endogenous lipid derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2010; 16: 87–95 Crossref | PubMed | Scopus (39) | Google ScholarSee all References | |
| Resolvin E2 | Peritonitis | Reduces PMN infiltration | Tjonahen et al.59x59Tjonahen, E, Oh, SF, Siegelman, J, Elangovan, S, Percarpio, KB, Hong, S, Arita, M, and Serhan, CN. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem Biol. 2006;
13: 1193–1202 Abstract | Full Text | Full Text PDF | PubMed | Scopus (75) | Google ScholarSee all References; Ogawa et al.60x60Ogawa, S, Urabe, D, Yokokura, Y, Arai, H, Arita, M, and Inoue, M. Total synthesis and bioactivity of resolvin E2. Org Lett. 2009; 11: 3602–3605 Crossref | PubMed | Scopus (34) | Google ScholarSee all References |
| Resolvin D1 | Peritonitis | Limits PMN recruitment | Hong et al.20x20Hong, S, Gronert, K, Devchand, P, Moussignac, R-L, and Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J Biol Chem. 2003;
278: 14677–14687 Crossref | PubMed | Scopus (435) | Google ScholarSee all References; Sun et al.48x48Sun, Y-P, Oh, SF, Uddin, J, Yang, R, Gotlinger, K, Campbell, E, Colgan, SP, Petasis, NA, and Serhan, CN. Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J Biol Chem. 2007; 282: 9323–9334 Crossref | PubMed | Scopus (158) | Google ScholarSee all References |
| Skin | Stops PMN recruitment (air pouch) | Serhan et al.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
196: 1025–1037 Crossref | PubMed | Scopus (601) | Google ScholarSee all References; Hong et al.20x20Hong, S, Gronert, K, Devchand, P, Moussignac, R-L, and Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J Biol Chem. 2003; 278: 14677–14687 Crossref | PubMed | Scopus (435) | Google ScholarSee all References | |
| Kidney ischemia-reperfusion | Protects from ischemia-reperfusion-induced kidney damage and loss of function; regulates macrophages and protects from fibrosis | Duffield et al.61x61Duffield, JS, Hong, S, Vaidya, V, Lu, Y, Fredman, G, Serhan, CN, and Bonventre, JV. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol. 2006;
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| Ocular | Protects against neovascularization | Connor et al.51x51Connor, KM, SanGiovanni, JP, Lofqvist, C, Aderman, CM, Chen, J, Higuchi, A, Hong, S, Pravda, EA, Majchrzak, S, Carper, D, Hellstrom, A, Kang, JX, Chew, EY, Salem, NN Jr, Serhan, CN, and Smith, LEH. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007;
13: 868–873 Crossref | PubMed | Scopus (260) | Google ScholarSee all References | |
| Resolvin D2 | Peritonitis, sepsis | Reduce peritonitis and increase phagocyte reactive oxygen species bacterial killing | Spite et al.42x42Spite, M, Norling, LV, Summers, L, Yang, R, Cooper, D, Petasis, NA, Flower, RJ, Perretti, M, and Serhan, CN. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;
461: 1287–1291 Crossref | PubMed | Scopus (153) | Google ScholarSee all References |
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During natural resolution as well as experimental resolution with a fixed time 0, PMN initially defend the tissue (ie, kill microbes and clear debris) and then are lost from inflammatory sites; mononuclear cells and MΦ are recruited in a nonphlogistic manner; and tissues return to homeostasis.1x1Cotran, RS, Kumar, V, and Collins, T. in: RS Cotran, V Kumar, T Collins
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Figure 3
The genus of specialized proresolving mediators: structures and actions. The SPM genus is defined by reduction or limiting further PMN infiltration and reduction of lipid mediators and cytokines. SPM also stimulate the nonphlogistic recruitment of mononuclear cells and the stimulation of macrophages to phagocytose apoptotic PMN microbes and microbial particles. The family precursors are substrates for their respective conversion to lipoxins, E-series resolvins, D-series resolvins, and protectins. The main structures of key SPM genus members are depicted; the complete stereochemistry of each has been determined, and their physical properties and bioactions have been confirmed by total organic synthesis; see text for details.
Figure 4
SPM-regulated processes in resolution and a new role for edema in delivering essential fatty acids. This illustration depicts a self-limited evolving exudate with the key roles of specialized proresolving mediators (SPM), substrate delivery, and leukocyte trafficking. i) Lower right-hand corner: microbial invasion in injury initiates chemotactic signals that initially summon neutrophils from postcapillary venules. Neutrophils arrive to the site via diapedesis and chemotaxis. A key chemoattractant of the eicosanoids in the process is leukotriene B4. There is also a wide range of cytokines and chemokines that stimulate neutrophil recruitment in this important and fundamental process. ii) As neutrophils congregate in the contained inflammatory exudate, cell–cell interactions (eg, with platelets in transcellular biosynthesis generated between PMN and platelets) initiate the transcellular biosynthesis of lipoxins. Newly arrived and older PMN within the exudate interact to produce resolvins and protectins via transcellular biosynthesis. During this process, edema carries the ω-3 essentially fatty acids EPA and DHA from the blood into the exudate for their utilization. iii) Once resolvins and protectins are produced, these SPM stimulate macrophages to take up apoptotic PMN and cellular debris. Additionally, the corpses of apoptotic PMN can serve to bind chemokines and cytokines for their disposal. SPM enhance macrophage uptake and clearance. iv) Macrophages phagocytose apoptotic PMN. This process is stimulated by SPM and is an anti-inflammatory and nonphlogistic process. Rather than producing proinflammatory mediators during phagocytosis, such as LTB4, TNF, and IL-1, these macrophages produce lipoxins, resolvins, and NPD1/PD1 that, in turn, inhibit further edema through a feedback mechanism. This hypothetical course of events and time course help the contained inflammatory exudate to resolve as well as efficiently combat infection and return to homeostasis from local tissue injury.
What is Proresolving? A New Bioaction for Chemical Mediators
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SPM in Resolution: Agonist of Nonphlogistic Responses
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Abstract | Full Text | Full Text PDF | PubMed | Scopus (23) | Google ScholarSee all References Arachidonate-derived eicosanoids changed from the initial production of prostaglandins and leukotrienes to lipoxins. The appearance of lipoxins within inflammatory exudates was concomitant with the loss of PMN and resolution of inflammation.72x72Levy, BD, Clish, CB, Schmidt, B, Gronert, K, and Serhan, CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;
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Crossref | PubMed | Scopus (521) | Google ScholarSee all References we introduced the concept that “α signals omega.”10x10Serhan, CN and Savill, J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;
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Within exudates, PMN undergo either apoptosis or necrotic cell death. As part of resolution, lipoxins signal macrophages to enhance engulfment of apoptotic PMN.81x81Godson, C, Mitchell, S, Harvey, K, Petasis, NA, Hogg, N, and Brady, HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol. 2000;
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Anti-inflammatory Versus Proresolution
Endogenous anti-inflammation alone is different and only part of the cellular processes linked to proresolution that are regulated by SPM. Proresolving actions can also encompass anti-inflammatory and are newly defined via SPM. For example, SPM stimulate macrophages to clear cytokines-chemokines and cellular debris as well as apoptotic PMN.95x95Ariel, A, Fredman, G, Sun, Y-P, Kantarci, A, Van Dyke, TE, Luster, AD, and Serhan, CN. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution via modulation of CCR5 expression. Nat Immunol. 2006;
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Google ScholarSee all References SPM possess anti-inflammatory actions in that they reduce PMN infiltration, which in turn limits PMN-mediated tissue damage and resulting local amplification of proinflammatory signals (illustrated in Figure 4). Frequently, classic anti-inflammatory compounds do not stimulate phagocytosis. In this regard, SPM are agonists that stimulate cytoskeletal/shape changes in PMN, limiting diapedesis and tissue accumulation but not interfering with their antimicrobial activity (see below). This fundamental difference for SPM actions opened a new appreciation of active resolution as a programmed tissue response that involves separate regulation of PMN and macrophage activities in vivo.55x55Schwab, JM, Chiang, N, Arita, M, and Serhan, CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;
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The molecular terrain of resolution offers new insights into disease pathogenesis and many opportunities for targeting new therapeutics.88x88Gilroy, DW, Lawrence, T, Perretti, M, and Rossi, AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov. 2004;
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As early as 1929, the importance of dietary EFA was demonstrated in maintaining health in rodents and reduced incidence of infection and inflammation.109x109Burr, GO and Burr, MM. A new deficiency disease produced by the rigid exclusion of fat from the diet. J Biol Chem. 1929;
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Resolvins and Protectins
Resolvins are enzymatically biosynthesized within resolving exudates. They were initially identified and elucidated using LC-MS-MS-based lipidomics8x8Serhan, CN, Clish, CB, Brannon, J, Colgan, SP, Chiang, N, and Gronert, K. 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. 2000;
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Crossref | PubMed | Scopus (352) | Google ScholarSee all References). The main biosynthetic route with DHA for Rv and PD proceeds via a 17S-hydro(peroxy)docosahexaenoic intermediate produced by a lipoxygenase (ie, 12/15-LOX in mice and 15-LOX type I in human leukocytes).
We established the complete stereochemistry of RvD1,48x48Sun, Y-P, Oh, SF, Uddin, J, Yang, R, Gotlinger, K, Campbell, E, Colgan, SP, Petasis, NA, and Serhan, CN. Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J Biol Chem. 2007;
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Crossref | PubMed | Scopus (158) | Google ScholarSee all References Genetic deficiency or overexpression of murine 12/15-LOX regulates production of SPM and alters their responses to both thermal injury120x120Gronert, K, Maheshwari, N, Khan, N, Hassan, IR, Dunn, M, and Schwartzman, ML. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense. J Biol Chem. 2005;
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Crossref | PubMed | Scopus (352) | Google ScholarSee all References and include results from our collaborators as well as many recent findings of other groups worldwide. Of interest, DPA (C22:5), an intermediate in humans for DHA, is a substrate for novel Rv-like LM.73x73Dangi, B, Obeng, M, Nauroth, JM, Teymourlouei, M, Needham, M, Raman, K, and Arterburn, LM. Biogenic synthesis, purification, and chemical characterization of anti-inflammatory resolvins derived from docosapentaenoic acid (DPAn-6). J Biol Chem. 2009;
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The first evidence was obtained for the conversion of DHA to unknown DHA-derived products in 1984 in retinal pigment cells using radiolabeled DHA and inhibitors.122x122Bazan, NG, Birkle, DL, and Reddy, TS. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem Biophys Res Commun. 1984;
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Crossref | PubMed | Google ScholarSee all References The structure of 10,17-docosatriene (neuroprotectin D1: NPD1), the founding member of the family of protectins, was first disclosed in a report on the isolation and elucidation of the bioactive resolvins.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
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Crossref | PubMed | Scopus (601) | Google ScholarSee all References Because these DHA-derived compounds were identified in resolving exudates, additional evidence was obtained for their biosynthesis from murine brain and vascular endothelial cells for the new bioactive products.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
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Crossref | PubMed | Scopus (601) | Google ScholarSee all References These studies initially focused on aspirin and its impact in the biosynthesis of 17R-hydroxy-containing resolvins and related structures. Isolates of the novel DHA-derived products reduced cytokine IL-1β production by human glioma cells stimulated with TNFα. Additionally, exudates obtained from mice given DHA, after extraction and transfer to other mice with peritonitis, reduced neutrophil infiltration in vivo, indicating the presence of potent bioactive products within the original inflammatory exudates.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
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In parallel, experiments with isolated human cells were carried out to reconstruct potential biosynthetic routes. Human endothelial cells held in a hypoxic environment followed by inflammatory stimuli used DHA and EPA, converting each to intermediates taken up by human leukocytes and further transformed to bioactive products.8x8Serhan, CN, Clish, CB, Brannon, J, Colgan, SP, Chiang, N, and Gronert, K. 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. 2000;
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201: 713–722
Crossref | PubMed | Scopus (358) | Google ScholarSee all References Without aspirin treatment, 17S-HDHA and corresponding 17S-hydroxy-containing dihydroxy and tri-hydroxy products were identified in murine exudates and isolated human cells.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
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DHA is well known for its essential role in neuronal development123x123Salem, N Jr, Litman, B, Kim, H-Y, and Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids. 2001;
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Crossref | PubMed | Google ScholarSee all References and, along with arachidonic acid, is a major PUFA found in the retina.122x122Bazan, NG, Birkle, DL, and Reddy, TS. Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem Biophys Res Commun. 1984;
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Crossref | PubMed | Google ScholarSee all References As a family within the SPM genus, protectins are distinguished by the presence of a conjugated, triene-containing structure and enzymatic additions at carbon positions 10 and 17.115x115Serhan, CN, Gotlinger, K, Hong, S, Lu, Y, Siegelman, J, Baer, T, Yang, R, Colgan, SP, and Petasis, NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006;
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PubMed | Google ScholarSee all References The name “protectins” was coined from the observed anti-inflammatory and organ-protective actions and systems.20x20Hong, S, Gronert, K, Devchand, P, Moussignac, R-L, and Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J Biol Chem. 2003;
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Crossref | PubMed | Scopus (435) | Google ScholarSee all References, 115x115Serhan, CN, Gotlinger, K, Hong, S, Lu, Y, Siegelman, J, Baer, T, Yang, R, Colgan, SP, and Petasis, NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006;
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PubMed | Google ScholarSee all References In studies in collaboration with Bazan et al,52x52Mukherjee, PK, Marcheselli, VL, Serhan, CN, and Bazan, NG. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA. 2004;
101: 8491–8496
Crossref | PubMed | Scopus (378) | Google ScholarSee all References the prefix neuroprotectin, such as neuroprotectin D1 (NPD1), was used, giving the tissue location of their biosynthesis and local actions.115x115Serhan, CN, Gotlinger, K, Hong, S, Lu, Y, Siegelman, J, Baer, T, Yang, R, Colgan, SP, and Petasis, NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006;
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Edema: A New Functional Role in Substrate Delivery for Resolution
The mechanism of ω-3 fatty acid mobilization in vivo during inflammation-resolution had not been addressed. Recently, we reported evidence for new mechanisms that indicate that unesterified or free ω-3 fatty acids rapidly appear within exudates moving directly from the circulation to the site of inflammation.124x124Kasuga, K, Yang, R, Porter, TF, Agrawal, N, Petasis, NA, Irimia, D, Toner, M, and Serhan, CN. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J Immunol. 2008;
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PubMed | Google ScholarSee all References The movement of EPA and DHA parallels those of both plasma albumin proteins and trafficking leukocytes (Figure 4).
After ingestion, EPA and DHA are distributed throughout the human body.125x125Lands, B. A critique of paradoxes in current advice on dietary lipids. Prog Lipid Res. 2008;
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PubMed | Google ScholarSee all References Of note, DHA is esterified in phospholipids of microglial cells in culture and on activation of these cells, DHA is released from the phospholipids for enzymatic processing.20x20Hong, S, Gronert, K, Devchand, P, Moussignac, R-L, and Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J Biol Chem. 2003;
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Crossref | PubMed | Scopus (402) | Google ScholarSee all References The availability of unesterified EPA and DHA for processing during inflammation-resolution was of interest. The level of total fatty acids in human blood is approximately 343 mg/100 ml plasma.127x127Patil, VS and Magar, NG. Fatty acids of human blood. Biochem J. 1960;
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Although native DHA and EPA themselves are thought to be anti-inflammatory, the specific mechanisms responsible are still evolving. The ω-3 fatty acids are thought to replace the sn-2 position in phospholipid stores that are usually the positional sites of esterified ω-6 fatty acids, such as arachidonic acid.125x125Lands, B. A critique of paradoxes in current advice on dietary lipids. Prog Lipid Res. 2008;
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Crossref | PubMed | Scopus (49) | Google ScholarSee all References The sn-2 position of phospholipids can become substituted with ω-3 fatty acids (eg, DHA and EPA) and is currently thought to simply “compete” for these enzymatic reactions, thus blocking or preventing the utilization of arachidonate and production of specific eicosanoids that are proinflammatory and prothrombotic mediators. This view is consistent with results from both cultured and isolated cells in vitro when ω-3 fatty acids are supplied.125x125Lands, B. A critique of paradoxes in current advice on dietary lipids. Prog Lipid Res. 2008;
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To address these points in a pathophysiological setting,124x124Kasuga, K, Yang, R, Porter, TF, Agrawal, N, Petasis, NA, Irimia, D, Toner, M, and Serhan, CN. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J Immunol. 2008;
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PubMed | Google ScholarSee all References we monitored both deuterium-labeled d5-EPA and d5-DHA levels from the circulation as well as increases in protein levels within exudates. Both d5-EPA and d5-DHA were identified in exudates within 1 hour of challenge, and levels were maintained up to 48 hours. At 48 hours, both d5-EPA and d5-DHA levels were significantly greater within the exudates than their levels at 24 hours. Thus, the initial or first peak of deuterium-labeled fatty acids was directly delivered from the circulation. The second peak at 48 hours likely reflects recirculation and expression of specific PLA2 during resolution.
Both cytosolic PLA2 and secretory PLA2 are highly expressed during the resolution phase.128x128Gilroy, DW, Newson, J, Sawmynaden, P, Willoughby, DA, and Croxtall, JD. A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J. 2004;
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Crossref | PubMed | Scopus (102) | Google ScholarSee all References The second peak at 48 hours, well within the resolution phase, could be from esterified d5-EPA and d5-DHA and released by PLA2 mechanisms. The main protein component in exudates from zymosan-initiated peritonitis is serum albumin as demonstrated by 2D-gel electrophoresis and proteomics40x40Bannenberg, GL, Chiang, N, Ariel, A, Arita, M, Tjonahen, E, Gotlinger, KH, Hong, S, and Serhan, CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;
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PubMed | Google ScholarSee all References; albumin is a well-known carrier of lipids, fatty acids, and particularly DHA.129x129Huang, BX, Dass, C, and Kim, HY. Probing conformational changes of human serum albumin due to unsaturated fatty acid binding by chemical cross-linking and mass spectrometry. Biochem J. 2005;
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Crossref | PubMed | Scopus (48) | Google ScholarSee all References These results in mice suggest that EPA and DHA are directly mobilized for resolvin production from the circulation via albumin as the most abundant and likely main carrier into sites of inflammation. MΦ phagocytosis of apoptotic PMN releases RvE1, RvE2, PD1, and LXA4.55x55Schwab, JM, Chiang, N, Arita, M, and Serhan, CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;
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Crossref | PubMed | Scopus (387) | Google ScholarSee all References LXA4 can then temporally limit edema through a feed-back mechanism (Figure 4), because it is a potent inhibitor of edema.130x130Menezes-de-Lima, O Jr, Kassuya, CA, Nascimento, AF, Henriques, MG, and Calixto, JB. Lipoxin A4 inhibits edema in mice: implications for the anti-edematogenic mechanism induced by aspirin. Prostaglandins Oth Lipid Mediat. 2006;
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Single-Cell Responses to DHA versus Resolvins
Using a new microfluidic chamber approach to rapidly isolate human PMN within 5 minutes directly from circulating whole blood (only 5–10 μl) via capture on P-selectin-coated surfaces, we assessed the direct actions of both precursor DHA versus one of its products, RvD1, on single neutrophil chemotaxis. Earlier procedures required the time-consuming isolation of PMN from whole blood before in vitro analyses. These methods involved several steps of centrifugation and red blood cell lysis that usually required several hours to perform and could lead to changes in the characteristics of the isolated cells. This short time interval is ideal for assessing the activation and/or inhibition status of PMN from peripheral blood of both healthy donors and patients. The combination of rapid separation as well as assessment of shape and migration responses within the same chamber is closely akin to in vivo scenarios on the endothelial surfaces via chemotaxis and migration into tissues (see ref. 1x1Cotran, RS, Kumar, V, and Collins, T. in: RS Cotran, V Kumar, T Collins
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Google ScholarSee all References). Another key feature of the microfluidic chamber system is the ability to record real-time changes in morphology of PMN on exposure to chemokines, DHA, and lipid mediators, such as RvD1, as well as to track migration through switches. The fast gradient switches in the chamber allowed visual assessment and recording of the earliest events after exposure of cells to RvD1 or native DHA as well as precise measurement of these changes in migration direction and velocity. The direct assessment of DHA with PMN indicates that DHA itself is not a potent bioactive ‘stop signal’ for PMN but rather requires exudate conversion to RvD1 to evoke its signaling effects on these cells. Hence, following their actions, local tissues inactivate resolvins, permitting organs to return to homeostasis.48x48Sun, Y-P, Oh, SF, Uddin, J, Yang, R, Gotlinger, K, Campbell, E, Colgan, SP, Petasis, NA, and Serhan, CN. Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J Biol Chem. 2007;
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Once formed, resolvins are active on target cells in their immediate milieu and are then locally inactivated by site-specific metabolism.131x131Arita, M, Oh, S, Chonan, T, Hong, S, Elangovan, S, Sun, Y-P, Uddin, J, Petasis, NA, and Serhan, CN. Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem. 2006;
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PubMed | Google ScholarSee all References Ischemia-reperfusion is an event of significant clinical importance. Reperfusion-related tissue injury often occurs during surgical procedures, particularly those involving extremities, causing both local and remote organ injury as well as increasing costs associated with prolonged postoperative recovery.133x133Gelman, S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology. 1995;
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Crossref | PubMed | Google ScholarSee all References Given the clinical importance and pathophysiology of this type of organ injury, we investigated the direct actions of DHA, resolvins, and related stable analogs, that is, directly comparing the actions of RvD1, its 17-(R/S)-methyl analog, RvE1, and its 19-p-fluorophenoxy analog, in ischemia-reperfusion second organ injury. Of interest, at equivalent doses, DHA was not protective, while RvD1 and its analog as well as the stable analog of RvE1 showed potent anti-leukocyte actions, each reducing infiltration into lung tissues.124x124Kasuga, K, Yang, R, Porter, TF, Agrawal, N, Petasis, NA, Irimia, D, Toner, M, and Serhan, CN. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J Immunol. 2008;
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Native RvE1 itself was not able to protect the lung at these low doses, likely because of local inactivation. Both RvD1 and RvE1 undergo site-specific metabolic inactivation.131x131Arita, M, Oh, S, Chonan, T, Hong, S, Elangovan, S, Sun, Y-P, Uddin, J, Petasis, NA, and Serhan, CN. Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem. 2006;
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PubMed | Google ScholarSee all References Thus, the RvD1 and RvE1 analogs that display potent organ protective actions may provide new approaches to reduce organ damage characterized by excessive PMN infiltration.
GPCR and Not Nuclear Receptors for SPM in Resolution
At least two GPCRs are involved in transducing RvE1 signals, namely ChemR23 and BLT1.54x54Arita, M, Bianchini, F, Aliberti, J, Sher, A, Chiang, N, Hong, S, Yang, R, Petasis, NA, and Serhan, CN. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005;
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Crossref | PubMed | Scopus (158) | Google ScholarSee all References (Figure 3) to identify sites of RvD1 action, we prepared synthetic [3H]-RvD1 and obtained evidence for specific RvD1 surface recognition on human leukocytes and identification of two GPCRs. The presence of RvD1-recognition sites on human phagocytes is of considerable interest in view of the potent actions of this autacoid.9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
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PubMed | Google ScholarSee all References Two GPCRs denoted ALX, a lipoxin A4 receptor, and an orphan, GPR32, were identified as directly interacting with RvD1. In addition, RvD1 regulates phagocytosis by human MΦ in a receptor-dependent manner.135x135Krishnamoorthy, S, Recchiuti, A, Chiang, N, Yacoubian, S, Lee, C-H, Yang, R, Petasis, NA, and Serhan, CN. Resolvin D1 binds human phagocytes with evidence for pro-resolving receptors. Proc Natl Acad Sci USA. 2010;
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We prepared [3H]-RvD1 by total organic synthesis and used it to identify high-affinity, cell-surface recognition sites for RvD1 on human leukocytes, giving a kDa of approximately 0.2 nmol/L (∼75 pg/ml), which is within the range of its levels measured in murine cells and tissues, that is, greater than 75–300 pg,34x34Merched, A, Ko, K, Gotlinger, KH, Serhan, CN, and Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 2008;
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Proresolving Receptor Distribution
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Crossref | PubMed | Google ScholarSee all References Indeed, human and mouse MΦ converted 14S-HpDHA and DHA to new products identified via MS-based LM-lipidomics to novel bioactive 7,14-dihydroxy-containing products.21x21Serhan, CN, Yang, R, Martinod, K, Kasuga, K, Pillai, PS, Porter, TF, Oh, SF, and Spite, M. Maresins: novel macrophage mediators with potent anti-inflammatory and pro-resolving actions. J Exp Med. 2009;
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Crossref | PubMed | Scopus (199) | Google ScholarSee all References Figure 2 illustrates the proposed hypothetical scheme for the maresin pathway and MaR1 biosynthesis. MΦ LOX converts DHA into 14S-HpDHA, followed by epoxidation to a 13(14)-epoxide intermediate that is enzymatically converted to the new bioactive mediator Maresin 1 or reduction of the peroxide intermediate to 14S-HDHA. Either 14S-HpDHA and/or 14S-HDHA is converted via LOX (double dioxygenation) to 7S,14S-diHDHA also identified in exudates.21x21Serhan, CN, Yang, R, Martinod, K, Kasuga, K, Pillai, PS, Porter, TF, Oh, SF, and Spite, M. Maresins: novel macrophage mediators with potent anti-inflammatory and pro-resolving actions. J Exp Med. 2009;
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Crossref | PubMed | Scopus (199) | Google ScholarSee all References In addition to reducing PMN infiltration in vivo, the new MΦ-derived compounds also enhanced phagocytosis. Given its potent actions and novel structure, the potent MΦ product was coined Maresin 1 (MaR1). MaR1 proved to be of comparable potency to synthetic RvE1 and PD1/NPD1.
Too Much of a Good Thing? Bugs and SPM
Certain pathogens have learned to use anti-inflammatory mediators such as LX to evade the host antimicrobial responses.144x144Sacks, D and Sher, A. Evasion of innate immunity by parasitic protozoa. Nat Immunol. 2002;
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Crossref | PubMed | Google ScholarSee all References The LX levels are superphysiologic, which enables the parasite to protect itself from phagocytes by stopping the recruitment. T. gondii carries its own 15-LO that we identified with proteomic analysis of tachyzoite-derived lysates, demonstrating peptides homologous to plant-derived type I LOX.146x146Bannenberg, GL, Aliberti, J, Hong, S, Sher, A, and Serhan, CN. Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J Exp Med. 2004;
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Crossref | PubMed | Scopus (51) | Google ScholarSee all References These findings suggest that the enzyme can interact with substrates from the host to elevate LX. This was also independently observed in a genomic study of Pseudomonas aeruginosa, which carries the first-identified secretable form of 15-LO that can convert host arachidonic acid to its LX precursor.147x147Vance, RE, Hong, S, Gronert, K, Serhan, CN, and Mekalanos, JJ. The opportunistic pathogen Pseudomonas aeruginosa carries a novel secretable arachidonate 15-lipoxygenase. Proc Natl Acad Sci USA. 2004;
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Crossref | PubMed | Scopus (77) | Google ScholarSee all References When 15-LOX is injected into mice, it generates endogenous LX that reduces inflammation and IL-12 production in vivo.146x146Bannenberg, GL, Aliberti, J, Hong, S, Sher, A, and Serhan, CN. Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J Exp Med. 2004;
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Crossref | PubMed | Scopus (51) | Google ScholarSee all References Cystic fibrosis patients have frequent lung infections with P. aeruginosa, and they have a reduced capacity to biosynthesize LX. Uncontrolled accumulation of PMN in the lungs of these patients leads to organ failure.148x148Karp, CL, Flick, LM, Park, KW, Softic, S, Greer, TM, Keledjian, R, Yang, R, Uddin, J, Guggino, WB, Atabani, SF, Belkaid, Y, Xu, Y, Whitsett, JA, Accurso, FJ, Wills-Karp, M, and Petasis, NA. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat Immunol. 2004;
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Candida albicans can produce RvE1 from host nutrients, which enhances phagocytosis, and ROS mediates killing of Candida while blocking the generation of IL-8 from epithelial cells and reducing the recruitment of PMN.91x91Haas-Stapleton, EH, Lu, Y, Hong, S, Arita, M, Favoreto, S, Nigam, S, Serhan, CN, and Agabian, N. Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator Resolvin E1. PLoS ONE. 2007;
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On the other hand, RvD2 reduces the bacterial burden following sepsis from CLP in mice when administered in very low doses.42x42Spite, M, Norling, LV, Summers, L, Yang, R, Cooper, D, Petasis, NA, Flower, RJ, Perretti, M, and Serhan, CN. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;
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Crossref | PubMed | Scopus (153) | Google ScholarSee all References In these cases, the mechanisms of RvD2 action involves increases in bacterial phagocytosis and intracellular ROS-mediated killing of the bacteria. Thus, certain microbes have learned to commandeer chemical mediators, that is, specific SPM, and the resolution mechanisms of the host to create a favorable local environment for their own survival, thus avoiding destruction.
Resolution Indices and Toxicity
To permit quantitative assessment of initiation and the most relevant parameters of resolution, quantifiable resolution indices were introduced.40x40Bannenberg, GL, Chiang, N, Ariel, A, Arita, M, Tjonahen, E, Gotlinger, KH, Hong, S, and Serhan, CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;
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Crossref | PubMed | Scopus (387) | Google ScholarSee all References These indices track neutrophilic infiltration, their maxima, and the duration of their presence at inflammatory sites and within exudates. The use of these indices permitted the first evidence for demonstrating that resolvins and protectins reduce the amplitude of neutrophilic infiltration, but also shortened the resolution interval, which reflects the duration of the resolution phase. The use of these resolution intervals also permits assessments between species and organ systems for given agents.27x27Seki, H, Fukunaga, K, Arita, M, Arai, H, Nakanishi, H, Taguchi, R, Miyasho, T, Takamiya, R, Asano, K, Ishizaka, A, Takeda, J, and Levy, BD. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J Immunol. 2010;
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This is indeed the case with COX-2 inhibitors154x154Gilroy, DW, Colville-Nash, PR, Willis, D, Chivers, J, Paul-Clark, MJ, and Willoughby, DA. Inducible cycloxygenase may have anti-inflammatory properties. Nat Med. 1999;
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Crossref | PubMed | Scopus (384) | Google ScholarSee all References which block prostaglandin formation, which is relevant to resolution with several sites of action, as well as the traditional view of these substances in the initiation of inflammation. We introduced resolution indices to assess the impact of SPM and other agents on anti-inflammation and resolution.40x40Bannenberg, GL, Chiang, N, Ariel, A, Arita, M, Tjonahen, E, Gotlinger, KH, Hong, S, and Serhan, CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;
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Crossref | PubMed | Scopus (855) | Google ScholarSee all References which can be rescued by administering LXA4, RvE1, or PD1.55x55Schwab, JM, Chiang, N, Arita, M, and Serhan, CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;
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Crossref | PubMed | Scopus (387) | Google ScholarSee all References Stable analogs of natural glucocorticoids do stimulate MΦ uptake of apoptotic PMN155x155Heasman, SJ, Giles, KM, Ward, C, Rossi, AG, Haslett, C, and Dransfield, I. Glucocorticoid-mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation. J Endocrinol. 2003;
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Crossref | PubMed | Scopus (88) | Google ScholarSee all References but are ultimately immunosuppressive. Thus, the use of resolution indices permits evaluation of endogenous mediators as in the case of SPM and their ability to shorten the resolution interval as well as screening of pharmacological agents for their impact in resolution, whether deleterious or beneficial.23x23Navarro-Xavier, RA, Newson, J, Silveira, VLF, Farrow, SN, Gilroy, DW, and Bystrom, J. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J Immunol. 2010;
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PubMed | Google ScholarSee all References It appears that taking resolution into account in the development of new pharmacological agents will be valuable. The use of the resolution indices can also screen for agents that are toxic to resolution.55x55Schwab, JM, Chiang, N, Arita, M, and Serhan, CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;
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Recently, Navarro-Xavier surveyed a number of agents in zymosan-induced peritonitis and assessed resolution indices. They were also able to identify agents with proresolving properties. In addition to RvE1 and aspirin-triggered 15-epi-lipoxin A4, a prostaglandin D2 receptor agonist appeared to possess proresolving actions in this proresolution, drug-screening strategy.23x23Navarro-Xavier, RA, Newson, J, Silveira, VLF, Farrow, SN, Gilroy, DW, and Bystrom, J. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J Immunol. 2010;
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Crossref | PubMed | Scopus (32) | Google ScholarSee all References The use of this type of system also permits discrimination between the actions of resolving macrophages and processes, such as efferocytosis. Thus, it is possible that many of the current therapeutics could be toxic to resolution. Interference within resolution mechanisms should be taken into account when considering new therapeutic approaches.
Are All SPM the Same?
By definition, SPM: i) are generated and/or accumulate within the resolution phase in vivo, ii) limit and reduce neutrophilic infiltration, iii) enhance phagocytic activity of macrophages toward apoptotic leukocytes, cellular debris, and microbes, and iv) stimulate the clearance of PMN from mucosal surfaces and their anti-microbial actions. If a mediator fulfills each of these and is produced in vivo, it then belongs to the genus of proresolving mediators. Each endogenous lipid mediator produced, such as lipoxins, resolvins, and protectins (as well as their aspirin-triggered forms), possesses additional compound-specific actions along with their general SPM properties uncovered both in vivo and in vitro that likely reflect target cell and tissue site biosynthesis and actions, as outlined in Figure 3.
Although some aspects of these responses appear redundant, the overall return from the battle of acute inflammation or catabasis is a critical event in homeostasis of an organ and organism. Therefore, it is not surprising if some of the biological responses and roles of SPM appear to overlap at this stage. Along these lines, the specific receptors identified that are expressed on target cell types may also answer the degree of selectivity and specificity of this proresolving system. In experimental inflammation and resolution model systems in vivo, it has been established that proresolving lipid mediators, such as RvE1 and NPD1, can shorten resolution time.23x23Navarro-Xavier, RA, Newson, J, Silveira, VLF, Farrow, SN, Gilroy, DW, and Bystrom, J. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J Immunol. 2010;
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Crossref | PubMed | Scopus (387) | Google ScholarSee all References These findings are encouraging, and results along these lines open the possibility for resolution-based pharmacology and new approaches to therapeutics.
Whether the encouraging results observed in animal disease models translate to human disease and their treatment remain to be determined. Along these lines, recent human trials in ocular iritis (dry eye) have yielded reduced signs and symptoms (http://eyedocnews.com/002059-resolvyx-announces-positive-data-from-trial-of-resolvin-rx-10045-for-dry-eye/, last accessed August 18, 2010). Hence, using endogenous proresolving mechanisms, and specifically SPM, as a means for resolution-based therapeutics may have wide applications in treatment and prevention of human diseases.
The results reviewed herein also provide a potential mechanism of action for ω-3 fatty acids in regulating the amplitude and duration of acute inflammatory responses via the formation of SPM (Table 1;8x8Serhan, CN, Clish, CB, Brannon, J, Colgan, SP, Chiang, N, and Gronert, K. 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. 2000;
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Crossref | PubMed | Scopus (352) | Google ScholarSee all References). Whether a direct correlation exists in humans between dose or ingestion of ω-3 fatty acids with local production of SPM at sites of inflammation remains of interest. In this context, the fat-1 transgenic mouse, which endogenously produces and stores increased levels of ω-3 EPA and DHA in tissues, on challenge, was found to biosynthesize increased levels of resolvins and protectins as well as 3-series prostaglandins from endogenous substrates.119x119Hudert, CA, Weylandt, KH, Wang, J, Lu, Y, Hong, S, Dignass, A, Serhan, CN, and Kang, JX. Transgenic mice rich in endogenous n-3 fatty acids are protected from colitis. Proc Natl Acad Sci USA. 2006;
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Conclusion
In summary, given the fundamental role of the acute inflammatory response and its natural resolution to homeostasis, it is not surprising that the SPM have proven to possess actions relevant to many disease models (Table 1;8x8Serhan, CN, Clish, CB, Brannon, J, Colgan, SP, Chiang, N, and Gronert, K. 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. 2000;
192: 1197–1204
Crossref | PubMed | Scopus (422) | Google ScholarSee all References, 9x9Serhan, CN, Hong, S, Gronert, K, Colgan, SP, Devchand, PR, Mirick, G, and Moussignac, R-L. 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. 2002;
196: 1025–1037
Crossref | PubMed | Scopus (601) | Google ScholarSee all References, 20x20Hong, S, Gronert, K, Devchand, P, Moussignac, R-L, and Serhan, CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autacoids in anti-inflammation. J Biol Chem. 2003;
278: 14677–14687
Crossref | PubMed | Scopus (435) | Google ScholarSee all References, 21x21Serhan, CN, Yang, R, Martinod, K, Kasuga, K, Pillai, PS, Porter, TF, Oh, SF, and Spite, M. Maresins: novel macrophage mediators with potent anti-inflammatory and pro-resolving actions. J Exp Med. 2009;
206: 15–23
Crossref | PubMed | Scopus (199) | Google ScholarSee all References, 40x40Bannenberg, GL, Chiang, N, Ariel, A, Arita, M, Tjonahen, E, Gotlinger, KH, Hong, S, and Serhan, CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;
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PubMed | Google ScholarSee all References, 42x42Spite, M, Norling, LV, Summers, L, Yang, R, Cooper, D, Petasis, NA, Flower, RJ, Perretti, M, and Serhan, CN. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;
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Crossref | PubMed | Scopus (153) | Google ScholarSee all References, 47x47Arita, M, Yoshida, M, Hong, S, Tjonahen, E, Glickman, JN, Petasis, NA, Blumberg, RS, and Serhan, CN. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci USA. 2005;
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82: 27–34
Abstract | Full Text | Full Text PDF | PubMed | Scopus (36) | Google ScholarSee all References, 64x64Ariel, A, Li, P-L, Wang, W, Tang, W-X, Fredman, G, Hong, S, Gotlinger, KH, and Serhan, CN. The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering. J Biol Chem. 2005;
280: 43079–43086
Crossref | PubMed | Scopus (99) | Google ScholarSee all References, 65x65Levy, BD, Kohli, P, Gotlinger, K, Haworth, O, Hong, S, Kazani, S, Israel, E, Haley, KJ, and Serhan, CN. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J Immunol. 2007;
178: 496–502
PubMed | Google ScholarSee all References, 66x66Hassan, IR and Gronert, K. Acute changes in dietary omega-3 and omega-6 polyunsaturated fatty acids have a pronounced impact on survival following ischemic renal injury and formation of renoprotective docosahexaenoic acid-derived protectin D1. J Immunol. 2009;
182: 3223–3232
Crossref | PubMed | Scopus (51) | Google ScholarSee all References, 67x67Sheets, KG, Zhou, Y, Ertel, MK, Knott, EJ, Regan, CE Jr, Elison, JR, Gordon, WC, Gjorstrup, P, and Bazan, NG. Neuroprotectin D1 attenuates laser-induced choroidal neovascularization in mouse. Mol Vis. 2010;
16: 320–329
PubMed | Google ScholarSee all References, 68x68He, J and Bazan, HE. Omega-3 fatty acids in dry eye and corneal nerve regeneration after refractive surgery. Prostaglandins Leukot Essent Fatty Acids. 2010;
82: 319–325
Abstract | Full Text | Full Text PDF | PubMed | Scopus (13) | Google ScholarSee all References, 69x69Lukiw, WJ, Cui, JG, Marcheselli, VL, Bodker, M, Botkjaer, A, Gotlinger, K, Serhan, CN, and Bazan, NG. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005;
115: 2774–2783
Crossref | PubMed | Scopus (352) | Google ScholarSee all References). Because SPM limit neutrophilic infiltration as well as enhance macrophage resolution responses (Figures 3 and 4), the new pathways uncovered are likely to be relevant in maintaining tissue homeostasis as well as playing a role in diseases characterized by excessive uncontrolled inflammation. The link between ω-3 fatty acids and their roles in resolution was unexpected and implies that the timing and duration of acute inflammation and its local resolution are linked to nutritional genomics and nutrition. Hence, it is intriguing that a process as fundamental as active resolution could be regulated by micronutrients and that edema plays a functional role in regulating the extent and duration of a resolving exudate. Because SPM are not immunosuppressive but rather enhance host defenses, stimulate resolution, and, hence, are proresolving, they may serve as agonists for new therapeutic approaches. In addition, it is clear from these early studies on SPM and endogenous termination programs that programmed resolution involves many mediators, pathways, and mechanisms yet to be uncovered and that anti-inflammation and its control are distinctly separate and not equivalent to the actions of local proresolving mediators that can also encompass and regulate the magnitude of endogenous anti-inflammation. Thus, it is fortuitous that the SPM limit neutrophil entry and tissue damage as well as possess anti-inflammatory pharmacological actions in addition to stimulating proresolving pathways and enhancing host microbial defense mechanisms.
Acknowledgements
I thank Mary H. Small for expert assistance with manuscript preparation, the members of my laboratory and collaborators for their expertise and efforts in the reports referenced herein, and those not directly cited due to space limitations.
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Supported by National Institutes of Health grants DE019938, GM038765, and DK074448 . The content is solely the responsibility of the author and does not necessarily reflect the official views of NIDCR, NIGMS, NIDDK, or the National Institutes of Health.
The author is inventor on patents assigned to Brigham and Women's Hospital and Partners HealthCare on the composition of matter, uses, and clinical development of anti-inflammatory and proresolving lipid mediators. These are licensed for clinical development. C.N.S. retains founder stock in Resolvyx Pharmaceuticals.
