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. Author manuscript; available in PMC: 2014 Aug 1.
Published in final edited form as: Curr Opin Pharmacol. 2013 Jun 6;13(4):632–640. doi: 10.1016/j.coph.2013.05.012

Resolution Phase Lipid Mediators of Inflammation: Agonists of Resolution

Charles N Serhan 1, Nan Chiang 1
PMCID: PMC3732499  NIHMSID: NIHMS482424  PMID: 23747022

Abstract

Lipid mediators are appreciated for their roles in leukocyte traffic required in host defense. With identification of novel resolution phase mediators, resolvins, protectins and maresins, these 3 families and their aspirin-triggered forms, given their potent stereoselective actions with human cells and animal disease models, are coined specialized pro-resolving mediators (SPM). Stereochemistries of key SPM are established and several groups reported organic synthesis. Given availability, this 2 year-review period expands their potent pro-resolving and nonredundant actions. Collectively, they support the concept that return of acute inflammation involves active biosynthesis and SPM signaling towards homeostasis.

Introducing Specialized Pro-Resolving Mediators

All cells in multi-cellular organisms require chemical gradients of signals that instruct each to move or to stop and clear tissues as needed. In acute inflammatory responses many chemical signals are produced, some from exogenous microbial origins while others are biosynthesized by the host response to tissue injury and invasion [1]. This laboratory focused on mechanisms and mediators in endogenous anti-inflammation and its resolution [2,3]. Using a systems approach with LC-MS-MS-based lipidomics, in vivo animal models, exudate cell trafficking and functional assessment with human cells, we identified novel bioactive products generated within the resolution phase of acute sterile inflammation that activate pro-resolving mechanisms [3,4**,5].

Focusing on self-limited resolving exudates also permitted a direct assessment of the host’s responses that actively return to homeostasis. An informative bioassay that proved critical in the initial structural elucidation studies focused on human polymorphonuclear neutrophil (PMN) transmigration across endothelial cells and epithelial cells since PMN excessive infiltration is central to many pathologies [3]. Attention was focused here because PMN are among the first responders to injury and microbial invasion in all organs. Our hypothesis that endogenous mediators are produced via cell-cell interactions within the inflammatory exudates to control the magnitude and duration of local inflammation proved to be the case and is relevant to human translation, since anti-PMN therapy [6] to limit tissue damage and uncontrolled inflammation has increasing appeal. From these, the resolvins, protectins and maresins (Figure 1) were uncovered and these fundamental cellular processes proved predictive of SPM actions in complex disease models, because cessation of PMN entry into tissue and their removal of apoptotic PMN as well as anti-PMN regulators are central to many organs and diseases.

Figure 1. Specialized pro-resolving mediators (SPM): chemical structures.

Figure 1

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Among chemical signals at the site of an acute inflammatory response, those that originate from host essential fatty acids are of particular interest because of their nutritional regulation of the response via essential fatty acids EPA and DHA and the potential to design small molecule mimetics of these molecules. Those produced from arachidonic acid, including prostaglandins and leukotriene B4, are involved in the initiating steps that permit leukocytes to leave post-capillary venules, i.e. diapedesis. Mediators produced from EPA and DHA, i.e. SPM, possess potent pro-resolving actions that include cessation of PMN tissue infiltration, counter-regulation of chemokines and cytokines, reduction in pain [40] and stimulation of macrophage-mediated actions, i.e. efferocytosis, phagocytosis of microbes [10**,60].

In these, we also learned that omega-3 essential eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are substrates for biosynthesis in self-resolving exudates of potent anti-inflammatory pro-resolving mediators [4**,5]. Identification of omega-3 as nutrients that fuel pro-resolving mechanisms opened new areas of investigation since uncontrolled inflammation is now widely appreciated to underlie many widely occurring diseases, and omega-3-derived SPM are documented in humans in health and disease (Table 1). For further detail on SPM (resolvins, protectins and maresins), readers are directed to recent reviews on biosynthesis [7], stereoselective actions and total organic synthesis [8]. Herein we review key initial observations that permitted a relatively rapid expansion and confirmation from many laboratories reported during 2010–2012.

Table 1.

Specialized pro-resolving mediators (LX, Rv, PD and MaR1) in humans

SPM Disease/tissues Formation
Lipoxins & Aspirin-triggered lipoxins (ATL) Colitis Elevated mucosal LXA4 in ulcerative colitis individuals in remission [72]
Type 2 Diabetes Increased plasma ATL with intake of pioglitazone [73]
Rheumatoid Arthritis LXA4 present in synovial fluid from rheumatoid arthritis patients [74]
Localized Aggressive Periodontitis (LAP) Less LXA4 in LAP whole blood compared to healthy donors [32]
Asthma Higher urinary ATL levels in aspirin-tolerant asthma than in aspirin-intolerant asthma [75]
Peripheral artery disease Lower plasma levels of ATL in patients with symptomatic peripheral artery disease than in healthy volunteers [76]
Adipose tissues LXA4 identified in human adipocytes from obese patients [77]
Resolvins Synovial fluid RvD5 present in synovial fluid from rheumatoid arthritis patients [74]
Blood (healthy volunteers) Plasma RvD1, RvD2 and 17-HDHA identified with oral omega-3 supplementation [78]
Adipose tissues RvD1 and RvD2 identified in human adipocytes from obese patients [77]
Human plasma RvE1 and RvD1 identified in human plasma (~1nM) [79]
Protectin Asthma Decreased PD1 in eosinophils from patients with severe asthma compared to healthy individuals [39]
Embryonic stem cells PD1 produced in embryonic stem cells [80]
Maresins Synovial fluid MaR1 is identified in synovial fluid from rheumatoid arthritis patients [74]
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What is pro-resolving vs. anti-inflammation?

Introducing Immunoresolvents

SPM are agonists acting on PMN and macrophages to stimulate resolution. Given this novel mechanism of pro-resolving actions, SPM demonstrate potent actions in animal disease models [9*]. Given their ability to stimulate resolution of inflammation without immune suppression [see below and ref. 10**], we recognize that SPM are immunoresolvents; by definition, they stimulate resolution [9*].

Confirming SPM Structures

It was essential to confirm SPM structure and actions for each family member (Figure 2). To this end, we devised a systematic approach matching endogenous SPM to those prepared by organic synthesis. This approach was deemed necessary because SPMs are produced in small quantities in vivo (i.e. picogram-nanogram range), act locally and are inactivated [reviewed in ref. 8]. These transient small quantities precluded direct NMR analysis. The original identification of D-series resolvins (Rv) reported structural elucidation of several distinct bioactive structures RvD1 through RvD6 in resolving murine exudates, their biosynthesis by human endothelial cell leukocytes and potent actions in murine as well as human acute inflammation [4**]. Recently, we established complete stereochemistry for the third member of D-series RvD3 and its aspirin-triggered form [11]. We confirmed their potent actions regulating PMN infiltration as well as enhancing macrophage phagocytosis and efferocytosis, thus establishing their specific and potent anti-inflammatory and pro-resolving actions.

Figure 2. Structures of SPM.

Figure 2

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Classic eicosanoids each carry established stereoselectivity in their actions [61]. Establishing the complete stereochemical assignment for each of the separate resolvin, protectin and maresin (SPM) structures shown herein was key to affirming novel actions on leukocytes. In this period 2010–2012, the structures of RvD1, its aspirin-triggered 17R-epimer, RvD2 [62], aspirin-triggered (AT)-protectin D1 [12] and MaR1 [9*] were assigned and several were made commercially available. Recently, using LC-MS/MS-based metabololipidomics we matched RvD3 with 4S,11R,17S-trihydroxydocosa-5Z,7E,9E,13Z,15E,19Z-hexaenoic acid, and AT-RvD3 matched 4S,11R,17R-trihydroxydocosa-5Z,7E,9E,1ZE,15E,19Z-hexaenoic acid. In this period, we also established the stereochemical assignments for AT-PD1 [12] and that of maresin 1 (MaR1; 7R,14S-dihydroxydocosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) [9*]. The total organic syntheses of MaR1 and additional SPM were also achieved by Rodriguez and Spur using Sonogashira coupling [63]; these investigators also reported resolvin D6 [64] and synthesis of resolvin E2 [65]. Kobayashi et al. reported stereoselective total synthesis of protectin D1 [66], resolvin E2 [67] and resolvin E1 [68]. See reference [8] for further details.

In this period, we also established stereochemical assignments for AT-PD1 [12] and maresin 1 (MaR1) [9*] (Figure 2). MaR1’s defining actions were confirmed with synthetic MaR1, i.e. limiting PMN infiltration in peritonitis (ng/mouse range) as well as enhancing human macrophage uptake of apoptotic PMNs. Importantly, MaR1 also accelerates regeneration in planaria. In neurons, MaR1 dose-dependently inhibits TRPV1 currents, blocks capsaicin-induced inward currents (IC50 ≈ 0.5 nM) and reduces inflammatory and neuropathic pain in mice. These findings also suggest that signals are shared in resolutive cellular-trafficking key in tissue regeneration across phyla. Of note, the stereoselective actions of each SPM also proved to be highly effective in regulating human PMN and monocytes in microfluidic chambers [13], establishing the human translational potential of novel SPM. Using similar strategies, RvE3 was recently identified as 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, and the two stereoisomers were assigned 17R,18R- and 17R,18S-dihydroxy groups. Both 18R- and 18S-RvE3 reduce PMN infiltration [14,15], as does RvE2 [13].

Targeted LM Metabololipidomics for Resolution Lipid Mediators: Microparticles and leukocyte subpopulations

With many of the main SPM stereochemistry established, it was next possible to carry out LM-metabololipidomics profiling via LC-MS-MS-based analyses with distinct human phagocyte populations, namely PMN, apoptotic PMN, and macrophages [16]. Efferocytosis increases SPM biosynthesis, including RvD1, RvD2, and RvE2, which was further elevated in PMN-microparticle co-incubations [17]. Using deuterium-labeled precursors showed that apoptotic PMN and microparticles each contribute to SPM biosynthesis during efferocytosis. Hence, microparticles regulate specific endogenous LM during defined stages of acute inflammatory process. Also, classic M2 macrophage phenotypes produce SPM, MaR1 and lipoxin (LX) A4 with lower leukotriene (LT) B4 and prostaglandin than M1 cells, establishing LM signature profiles of human PMN, apoptotic PMN and macrophage subpopulations.

Infections

We recently examined underlying mechanisms for how bacterial infections impact active resolution of inflammation. In self-resolving E. coli infections, dominant SPM are RvD5 and PD1, levels of which are significantly greater than in exudates from higher titer E. coli challenged mice. Germ-free mice produce endogenous RvD1 and PD1 levels higher than conventional mice. RvD1 and RvD5 (ng/mouse) each reduce bacterial titers and increased survival. RvD5 activates the RvD1 receptor (Figure 3) enhancing E. coli phagocytosis. In E. coli infections, SPM (RvD1, RvD5, PD1) together with ciprofloxacin heighten host antimicrobial responses. SPM in skin infections enhance clearance of Staphylococcus aureus and lower vancomycin dose. These demonstrate that specific SPM are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for host bacterial clearance. These endogenous resolution mechanisms are of interest in host defense because initiation of the host response is controlled by prostaglandins and leukotrienes, which when uncontrolled can lead to reduced survival during infection [10**].

Figure 3. SPM and their receptors.

Figure 3

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ALX and GPR32, 2 GPCRs for RvD1 on human phagocytes. ALX is a lipoxin A4 receptor and GPR32. RvD1 displays specific binding, reduces actin polymerization and CD11b on PMN, as well as stimulates macrophage phagocytosis in an ALX and GPR32-dependent manner [21]. The aspirin-triggered epimer 17R-RvD1 and stable analog 17-R/S-methyl-RvD1 each dose-dependently activate ALX/FPR2 and GPR32 in GPCR-overexpressing β-arrestin systems and electric cell-substrate impedance sensing [23]. RvD5 also activates human GPR32-β-arrestin systems and stimulates macrophage phagocytosis of E.coli enhanced by GPR32 [10**]. RvD3 and AT-RvD3 each activate this GPCR, contributing to their pro-resolving actions in stimulating macrophage phagocytosis [11].

ChemR23, a specific receptor for RvE1, is related to lipoxin and leukotriene receptors in deduced amino acid sequences. ChemR23 specifically binds tritiated RvE1 and signals to activate monocytes, reduce dendritic cell migration and IL-12 production [18]. RvE1-ChemR23 interactions also stimulate macrophage phagocytosis via phosphorylation signaling pathways including ribosomal protein S6, a downstream target of PI3K/Akt signaling and the Raf/ERK pathways [69]. 18S-RvE1 also binds to ChemR23 with increased affinity and potency compared with the R-epimer, but is rapidly inactivated [70]. RvE2 is a partial agonist for ChemR23 [71].

BLT1, a leukotriene B4 receptor, also directly interacts with RvE1, which inhibits calcium mobilization, NF-kB activation and PMN infiltration in vivo [19]. Both 18S-RvE1 and RvE2 also bind to BLT1 [70,71] demonstrating ligand specificity and related structural features of resolvins.

TG mice. We constructed mice overexpressing human ALX. The pro-resolving actions of RvD1 were further enhanced in ALX-TG mice. Transgenic mice were also prepared overexpressing human ChemR23, the RvE1 receptor, on myeloid cells. In these TG mice, RvE1 is 10-fold more potent in limiting PMN infiltration in zymosan-initiated peritonitis, and ligature-induced alveolar bone loss was diminished in ChemR23tg mice. Hence, RvE1 modulates osteoclast differentiation and bone remodeling by direct actions on bone, in addition to anti-inflammation and pro-resolution [23].

KO mice. In fpr2/ALX-deficient mice (mouse orthologue of human ALX), anti-inflammatory actions of RvD1 are lost [24]. RvD1 regulates acute inflammation in part via human ALX and GPR-32 receptors. In BLT1 knockout mice, anti-inflammatory actions of RvE1 were sharply reduced when given at low doses (100 ng i.v.) in peritonitis. In contrast, higher doses of RvE1 (1.0 µg i.v.) reduce PMN infiltration in a BLT1-independent manner. Taken together, RvE1 binds to BLT1 as a partial agonist and serves as a local damper of BLT1 signals on leukocytes along with ChemR23-mediated counter-regulatory actions to mediate the resolution of inflammation [19].

SPM Receptors

Receptor identification

RvE1: We identified an orphan G-protein coupled receptor (GPCR) ChemR23 for RvE1 (Figure 3). ChemR23 binds 3H-RvE1 and stereoselectively transduces signals to monocytes and dendritic cells [18]. Of note, RvE1 also directly interacts with BLT1, a LTB4 receptor, inhibiting calcium mobilization, NF-kB activation and PMN infiltration [19]. Therefore RvE1 gives cell-type specific actions, serving as an agonist for ChemR23 on mononuclear and dendritic cells as well as an antagonist for BLT1 signals on PMN. ChemR23-dependent actions of RvE1 were recently confirmed in mouse fibrosis [20]. RvD1: RvD1’s pro-resolving actions are mediated via both ALX and human GPR32 [21]. D-series Rv ligands for GPR32 identified include RvD5, RvD3 and AT-RvD3 [10**,11; see figure legend for details]. PD1: PD1 displays specific binding with human retinal pigment epithelial cells and PMN. Neither RvE1 nor LXA4 competes for [3H]-NPD1/PD1 specific binding with human PMN, suggesting specific receptors for PD1 [22].

Receptor overexpression and knockdown in vivo

Earlier we constructed TG mice overexpressing human ALX. RvD1 showed enhanced actions in limiting PMN infiltration in zymosan-initiated peritonitis [23]. These actions of RvD1 were abolished in fpr2/ALX null mice [24], indicating that RvD1 dampens acute inflammation in part via activating ALX. We also prepared transgenic mice overexpressing human ChemR23/ERV, on myeloid cells. In these TG mice, RvE1 is more potent at limiting PMN infiltration in peritonitis and protecting alveolar bone loss [25].

Organs of Actions

Ocular inflammation – Clinical development

Mouse: In human and rat conjunctiva goblet cells, RvD1 and RvE1 reduce LTD4-stimulated goblet cell secretion [26]. In a murine model of dry eye, RvE1 improves the outcome measures of corneal staining and goblet cell density, indicating the potential of resolvins in treatment of dry eye [27]. In HSV-induced ocular inflammation, RvE1 significantly reduces cornea lesions and angiogenesis as well as T cells and PMN. These results indicate that RvE1 represents a novel approach to control virus-induced diseases [28*]. In human corneal epithelial cells, estradiol reduced 15-lipoxygenase (LOX) type-I and LXA4. LXA4 addition rescues the estradiol-abrogated wound healing, demonstrating gender-specific differences in the corneal repair mediated by the 15-LOX-LXA4 circuit [29]. Human. In a Phase 2 clinical trial in patients with dry eye syndrome, a RvE1 analog significantly improved signs and symptoms. This is the first demonstration of clinical efficacy for the novel class of resolvin therapeutics [30]. The Phase III clinical trial is in progress (Safety and Efficacy Study of RX-10045 on the Signs and Symptoms of Dry Eye, identifier NCT00799552; URL: http://www.clinicaltrials.gov).

Salivary – Sjögren's syndrome

With salivary epithelium, RvD1 (100 ng/ml) rescues TNF-α-induced tight junction and cytoskeletal disruption, and enhances cell migration and polarity in an ALX-dependent manner. These findings suggest RvD1 promotes repair in salivary epithelium and restores salivary gland dysfunction [31].

Oral inflammation

In localized aggressive periodontitis (LAP) patients, macrophages exhibit reduced phagocytosis. RvE1 rescues impaired phagocytic activity of LAP macrophages [32]. Humanized nanoparticles containing 17R-RvD1 or LXA4 analog protect in a model of temporomandibular joint disease [17].

Airway inflammation

In allergic airways, RvE1 promotes resolution in part via suppressing IL-23 and IL-6 as well as increasing IFN-γ [33]. Also, RvE1 regulates NK cell migration and cytotoxicity [34]. AT-RvD1 and RvD1 each markedly shortens resolution intervals for lung eosinophilia [35]. In acute lung injury, AT-RvD1 improves epithelial and endothelial barrier integrity, decreases airway resistance and increases epinephrine levels in bronchoalveolar lavages [36]. Of interest, Fat-1 transgenic mice with increased endogenous lung n-3 [37] show higher PD1 and RvE1 after bronchoprovocation. These animals suggest a protective role for endogenous SPM in allergic airway responses, decreasing airway inflammation [38]. Human eosinophils generate PD1, which is impaired in severe asthmatics, and PD1 reduces eosinophil chemotaxis [39].

Pain and Neuroinflammation

Resolvins are potent pain regulators [40]. Intrathecal RvD1 (40ng) strongly reduces postoperative surgical pain in rats [41]. RvE1 (intrathecal) prevents nerve injury-induced mechanical allodynia [42]. Along these lines, RvD1 (100 ng/kg) significantly decreases TNBS-induced mechanical allodynia and blocked cytokine production in spinal dorsal horn [43]. RvD2 (0.01–1 ng) prevents formalin-induced pain. As part of the molecular mechanisms, RvD2, RvE1, and RvD1 each differentially regulates transient receptor potential (TRP) channels [44]. AT-RvD1 significantly reverses thermal hypersensitivity, and knockdown of epidermal TRPV3 blunts these anti-nociceptive actions [45]. In arthritis, AT-RvD1 exhibits marked anti-hyperalgesia and decreases production of TNF-α and IL-1β in rat hind paw [46**]. RvD1 also attenuates neuroinflammation, stimulating phagocytosis of amyloid-β (Aβ) by Alzheimer disease macrophages and inhibits Aβ-induced apoptosis in a GPR32-dependent manner [47]. In addition, RvD1 strongly decreases cytokine production in amyotrophic lateral sclerosis (ALS) macrophages [48].

Skin

Mouse. PMN infiltration to skin was used for structure elucidation of resolvins [3] that proved critical for clinical development. In mouse burn models, RvD2 at 25pg/g given systemically post-burn prevents thrombosis of deep dermal vasculature, dermal necrosis and PMN-mediated damage [49*]. In 2,4-dinitrofluorobenzene-stimulated dermatitis, RvE1 reduces skin lesions by lowering IL-4 and IFN-γ in activated CD4(+) T cells as well as serum IgE [50]. Human. Topical treatment with an aspirin-triggered/LXA4 stable analog (15(R/S)-methyl-LXA4) significantly reduces the severity of eczema in a two-center, double-blind, placebo-controlled, randomized, parallel-group comparative study with sixty infants [51**].

Gastrointestinal tract

In murine colitis, systemic RvE1, AT-RvD1, RvD2, or 17R-hydroxy-DHA each (nanogram ranges) mitigates disease severity, prevents body weight loss, colonic damage, and PMN infiltration as well as lowers select colonic cytokines. These results suggest that SPM have potential in treating inflammatory bowel diseases [52,53].

Fibrosis

In a unilateral ureteric obstruction (UUO)-driven murine fibrosis, RvE1 (300 ng/day) reduces accumulation of myofibroblasts, deposition of collagen IV and myofibroblast proliferation. RvE1 (~1–30 nM) inhibits PDGF-BB-induced proliferation in fibroblasts that proved to be ChemR23-RvE1-receptor-dependent [20].

Metabolic syndromes

RvD1 stimulates non-phlogistic phagocytosis in adipose macrophages and reduces macrophage reactive oxygen species production [54*]. Also, in leptin receptor-deficient (db/db) mice, RvD1 (2 µg/kg) increases glucose tolerance, adiponectin production and M2 macrophages [55]. Along these lines, LXA4 (1 nM) also attenuates adipose inflammation and improves insulin sensitivity in a model of age-associated adipose inflammation [56]. In diabetic wounds, local RvD1 accelerates closure and reduces accumulation of apoptotic cells in wounds [57*]. Together, SPM may give new therapeutic approaches to reduce adipose inflammation and insulin resistance, key components of type-2 diabetes.

Micro RNAs in resolution: SPM-GPCR-microRNA circuits

RvD1 accelerates resolution and controls specific miRNA expression including miR-146b, 208a, and 219. This panel of miRs is temporally regulated during self-limited inflammation and controlled by RvD1 in vivo as well as in RvD1-GPCR-dependent human macrophage responses [58**]. Macrophages overexpressing miR-219 down-regulate 5-LOX and reduce LTB4. Hence, 5-LOX is a target gene of miR-219 [58]. In addition, RvD1 at low doses (10 ng) increases miR-219 in ALX-TG mice, whereas this dose is not effective in non-TG [23]. Of note, delayed resolution initiated by high-dose zymosan challenges decreases miR-219-5p expression along with higher LTB4 and lower SPM [59]. Thus, both ALX and miR-219 are components of RvD1-initiated resolution circuits.

Conclusions

Pus bonum et laudabile -- from ancient Latin “good and laudable pus” [1,2]. Hence within pus are indeed endogenous molecules that are beneficial that we now call resolvins, protectins and maresins (the SPM), which terminate inflammation and stimulate resolution. In this review period 2010–2012, the complete stereochemistries of several additional SPM were obtained and several groups reported on their total organic synthesis. With availability of reliable commercial resolvins, in two years a body of literature emerged that confirms and expands their potent pro-resolving and anti-inflammatory actions. The SPM have also entered into human trials and are reported to be effective in skin inflammation and ocular disease. These new findings together provide further support for the novel concept that return of acute inflammatory responses to homeostasis involves active biosynthesis of pro-resolving autacoids that are receptor agonists activating resolution programs returning tissues to homeostasis and regenerating function.

Highlights.

  • The n-3 specialized pro-resolving mediators (SPM) evoke stereoselective actions

  • SPM control excessive PMN and stimulate macrophage clearance, vital for resolution

  • SPM promote resolution of inflammation, regeneration and are anti-hyperalgesia.

  • The complete stereochemistries of key SPM are now established

  • During past 2 years a body of literature confirms and expands potent actions of SPM

Acknowledgements

The authors thank Mary Halm Small for expert assistance in manuscript preparation and support from National Institutes of Health grants P01GM095467 and R01GM38765.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosure: C.N.S. is an inventor on patents [resolvins] assigned to BWH and licensed to Resolvyx Pharmaceuticals. C.N.S. was scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. C.N.S.’s interests 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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