Immunometabolism, Active Resolution of Inflammation, and Specialized Pro-resolving Mediators (SPMs) from EPA/DHA

ARTICLE FORMAT RATIONALE

Given the nature of this subject — an emerging mechanistic and translational field lacking sufficient homogeneous interventional clinical trials for formal meta-analysis — the most scientifically appropriate format is a Narrative Clinical Review Article. This choice aligns with the predominant output of the SPM literature itself, which comprises mechanistic reviews, preclinical investigations, and early-phase translational studies rather than large-scale randomized controlled trials amenable to pooled quantitative synthesis.

ABSTRACT

Background: The prevailing paradigm in clinical medicine frames acute inflammation as a process requiring pharmacological suppression, predominantly through cyclooxygenase (COX) inhibition via non-steroidal anti-inflammatory drugs (NSAIDs). Emerging evidence from immunometabolism and resolution biology challenges this framework fundamentally. Inflammation resolution is not a passive deterioration of the inflammatory signal but an actively orchestrated biochemical programme governed by a superfamily of endogenous lipid autacoids — the Specialized Pro-resolving Mediators (SPMs).

Objective: This review synthesizes current evidence on the biosynthesis, receptor-mediated mechanisms, and clinical implications of SPMs derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with particular attention to the paradox created by conventional NSAID therapy, which may simultaneously attenuate pro-inflammatory signalling and impair the active resolution phase.

Methods: A narrative review of peer-reviewed literature was conducted, drawing from seminal works by Serhan et al. and subsequent translational investigations published between 2002 and 2025, encompassing mechanistic studies, preclinical animal models, and available human data.

Conclusions: SPMs — including E-series and D-series resolvins, protectins, maresins, and lipoxins — constitute a biologically active resolution programme essential for tissue homeostasis. Deficiency in SPM biosynthesis, including that induced by COX-inhibiting NSAIDs, may perpetuate rather than resolve inflammatory chronicity. Resolution pharmacology represents a paradigm shift from anti-inflammatory antagonism to pro-resolving agonism.

Keywords: Specialized pro-resolving mediators, SPM, resolvins, protectins, lipoxins, maresins, EPA, DHA, inflammation resolution, immunometabolism, NSAIDs, efferocytosis

1. INTRODUCTION

Inflammation occupies a central position in the pathophysiology of the most prevalent non-communicable diseases of the modern era: cardiovascular disease, type 2 diabetes mellitus, neurodegenerative disorders, rheumatoid arthritis, inflammatory bowel disease, and metabolic syndrome. For over a century, therapeutic strategy has been oriented toward suppressing the inflammatory cascade — most notably through inhibition of COX enzymes by NSAIDs and, more recently, by targeted biological agents neutralizing pro-inflammatory cytokines such as TNF-α and IL-6.

This suppression-oriented paradigm rests on an implicit assumption: that once pro-inflammatory mediators are blocked, inflammation will subside passively. Contemporary research in resolution biology has demonstrated this assumption to be profoundly incomplete. Inflammation, like its induction, possesses a discrete, biochemically active termination programme. Failure of this programme — rather than excessive induction — may constitute the central mechanism through which acute inflammation transitions to pathological chronicity.

Charles Serhan and colleagues at Harvard Medical School identified and structurally elucidated the first generation of endogenous resolution mediators in the early 2000s, coining the term "specialized pro-resolving mediators" (SPMs) to encompass lipoxins, resolvins, protectins, and, subsequently, maresins. [^1] These molecules are stereoselectively biosynthesized from polyunsaturated fatty acid (PUFA) precursors — most critically EPA (eicosapentaenoic acid, 20:5n-3) and DHA (docosahexaenoic acid, 22:6n-3) — via coordinated lipoxygenase (LOX) and COX-2 pathways, often requiring transcellular biosynthesis between neutrophils, platelets, endothelial cells, and macrophages. [^2]

The clinical implications of this discovery are far-reaching. If resolution is active, then its failure carries diagnostic and therapeutic weight. If COX-2 participates in generating pro-resolving signals, then its indiscriminate inhibition carries consequences beyond the intended suppression of prostaglandin synthesis. This review examines both the mechanistic architecture of SPM biology and the clinical considerations that follow.

2. IMMUNOMETABOLISM AND THE LIPID MEDIATOR SWITCH: CONCEPTUAL FRAMEWORK

The inflammatory response is now understood to proceed through at least three sequential phases governed by distinct lipid mediator classes. During the initiation phase, arachidonic acid (AA, 20:4n-6) is liberated from membrane phospholipids by phospholipase A₂ and converted by COX-1/2 to prostaglandins (PGE₂, PGI₂) and by 5-lipoxygenase (5-LOX) to leukotrienes (LTB₄, LTC₄), which collectively orchestrate vasodilation, increased vascular permeability, and neutrophil recruitment.

A critical but underappreciated phenomenon occurs at the resolution phase: the same enzymatic machinery — most notably COX-2, which is induced during early inflammation — undergoes a functional switch. Rather than continuing to generate pro-inflammatory prostaglandins, COX-2 begins to produce 15-hydroxyeicosatetraenoic acid (15-HETE), a precursor substrate for 5-LOX-mediated synthesis of lipoxins. [^3] Simultaneously, EPA and DHA become substrates for 15-LOX and 5-LOX pathways in activated leukocytes, generating the E-series and D-series resolvins, protectins, and maresins.

This "lipid mediator class switch" — from prostaglandins/leukotrienes to SPMs — represents a fundamental immunometabolic reprogramming. It requires substrate availability (adequate EPA and DHA), enzymatic competence (functional LOX enzymes), and transcellular cooperation between multiple cell types. Failure at any of these levels precludes effective resolution. [^4]

The concept of immunometabolism as applied to resolution biology further posits that cellular metabolic state directly regulates SPM biosynthetic capacity. Macrophage polarization toward pro-inflammatory M1 phenotypes — favoured in states of obesity, insulin resistance, and metabolic syndrome — is associated with suppressed efferocytotic capacity and reduced SPM production, creating a biochemical environment permissive to non-resolving chronic inflammation. [^5]

3. BIOSYNTHESIS OF SPMs: STRUCTURAL FAMILIES AND ENZYMATIC PATHWAYS

3.1 Lipoxins

Lipoxins (LXA₄ and LXB₄) are the archetypal and historically first-identified SPMs, generated from arachidonic acid via sequential lipoxygenase interactions. Three principal biosynthetic routes have been described: (1) 15-LOX/5-LOX cooperation in leukocyte-epithelial or leukocyte-platelet transcellular interactions; (2) 12-LOX/5-LOX cooperation; and (3) aspirin-acetylated COX-2, which converts AA to the 15(R)-HETE intermediate subsequently processed by 5-LOX to yield the 15-epi-lipoxins (also termed aspirin-triggered lipoxins, ATL). [^6]

This third route is particularly instructive: low-dose aspirin, uniquely among NSAIDs, retains the capacity to acetylate COX-2 rather than simply blocking it, thereby redirecting its catalytic output toward pro-resolving ATL biosynthesis. Conventional non-selective NSAIDs and selective COX-2 inhibitors (coxibs), by contrast, suppress COX-2 activity globally, ablating both prostaglandin production and this aspirin-triggered resolution pathway simultaneously.

3.2 E-Series Resolvins (RvE1–RvE3)

E-series resolvins are biosynthesized from EPA (20:5n-3) via two routes. The first involves aspirin-acetylated COX-2 converting EPA to 18(R)-HEPE, which is then processed by 5-LOX in neutrophils to RvE1 or RvE2. The second, COX-2-independent route proceeds via cytochrome P450 enzymes to generate 18(S)-HEPE intermediates. RvE1, the best characterised member, signals through the ChemR23 receptor on neutrophils and macrophages, potently inhibiting NF-κB activation and reducing pro-inflammatory cytokine expression.

3.3 D-Series Resolvins (RvD1–RvD6) and Aspirin-Triggered Forms

DHA (22:6n-3) is the substrate for D-series resolvin biosynthesis via 15-LOX and 5-LOX in a transcellular reaction involving endothelial cells and leukocytes. Aspirin-triggered D-series resolvins (AT-RvD1 through AT-RvD6) are generated when aspirin-acetylated COX-2 produces 17(R)-HDHA, which undergoes further LOX-mediated processing. D-series resolvins signal through the GPR32 and ALX/FPR2 receptors and are among the most potent endogenous neutrophil stop-signals identified to date.

3.4 Protectins and Neuroprotectin D1 (NPD1)

Protectins (also termed neuroprotectins when describing their CNS activity) are generated from DHA via 15-LOX, producing 17-HDHA intermediates that cyclise to form the characteristic trihydroxy-containing structure. Protectin D1 (PD1/NPD1) is particularly abundant in neural tissue and displays potent neuroprotective and retinal-protective actions in addition to pro-resolving effects in systemic inflammation. [^4]

3.5 Maresins (MaR1, MaR2)

Maresins were identified more recently by Serhan and colleagues, generated from DHA by macrophage 12-LOX. They are particularly notable for their capacity to stimulate tissue regeneration and their role in pain resolution. MaR1 reduces neutrophil infiltration, enhances efferocytosis, and promotes mucosal healing. [^7] More recently, n-3 docosapentaenoic acid (n-3 DPA)-derived SPMs including MaR1ₙ₋₃ DPA have been described, which appear to be generated preferentially during DHA supplementation via retroconversion pathways. [^8]

4. MECHANISMS OF PRO-RESOLVING ACTION

4.1 Counter-Regulation of Neutrophil Recruitment

One of the first and most critical functions of SPMs is the temporal limitation of polymorphonuclear neutrophil (PMN) extravasation. Once neutrophils have performed their antimicrobial functions, their continued presence at inflamed sites leads to collateral tissue destruction through degranulation, reactive oxygen species (ROS) release, and myeloperoxidase (MPO) activity. SPMs act as active "stop signals" for neutrophil trafficking, downregulating selectin and integrin expression and inhibiting the CXCL8 (IL-8) chemotaxis axis. [^9]

RvD1 and LXA₄ both signal through the ALX/FPR2 receptor, a G protein-coupled receptor expressed on neutrophils, to reduce Mac-1 (CD11b/CD18) expression and inhibit MPO-mediated anti-apoptotic signalling, thereby permitting neutrophil caspase-3-dependent apoptosis and subsequent clearance. [^10]

4.2 Macrophage Phenotypic Reprogramming and Efferocytosis

Efferocytosis — the phagocytic clearance of apoptotic cells by macrophages — is arguably the most mechanistically critical step in the resolution programme. Failure of efferocytosis results in secondary necrosis of apoptotic neutrophils, release of damage-associated molecular patterns (DAMPs), and perpetuation of the NF-κB-driven inflammatory cycle. SPMs, particularly RvD2, MaR1, and LXA₄, upregulate macrophage phagocytic capacity and stimulate the M2-like phenotype shift associated with anti-inflammatory IL-10 production and tissue repair. [^2]

Crucially, once efferocytosis is complete, macrophages expressing the SPM biosynthetic apparatus — including 15-LOX — migrate via efflux to regional lymph nodes, physically removing pro-inflammatory cellular debris from the resolution site. This macrophage egress is actively stimulated by D-series resolvins and represents a distinct resolution mechanism not addressed by any NSAID class. [^5]

4.3 Counter-Regulation of Pro-inflammatory Cytokine Cascades

SPMs exert multiple points of control over the pro-inflammatory cytokine network. RvE1 inhibits NF-κB nuclear translocation and reduces TNF-α, IL-1β, and IL-6 transcription. RvD1 reduces NLRP3 inflammasome activation in macrophages. LXA₄ inhibits the neutrophil oxidative burst and leukotriene synthesis via transcellular metabolic interference. Importantly, these effects are achieved without immunosuppression: host antimicrobial defence, including macrophage killing capacity and mucosal IgA responses, is preserved or enhanced, since SPMs also stimulate phagocytosis of viable pathogens.

4.4 Tissue Regeneration and Vascular Endothelial Homeostasis

The resolution phase terminates not merely with the cessation of inflammation but with active tissue repair. MaR1 and protectin D1 have been shown to stimulate intestinal mucosal epithelial regeneration in animal models. Resolvins promote angiogenesis and fibroblast activation in an orderly, pro-healing pattern. Of particular clinical relevance is the role of SPMs in endothelial barrier restoration: RvD1 and RvD2 reduce vascular permeability and enhance tight junction protein expression in inflamed endothelium, thereby restoring vascular integrity. [^11]

5. THE NSAID PARADOX: WHEN ANTI-INFLAMMATION IMPAIRS RESOLUTION

5.1 COX-2: A Dual Role in Induction and Resolution

The cardinal point of intervention for most NSAIDs — COX-2 inhibition — is itself a participant in the resolution programme, not merely the inflammatory cascade. COX-2, induced during acute inflammation by NF-κB and IL-1β, generates not only the PGE₂ and PGI₂ that mediate vasodilation and pain but also, during the resolution phase, PGD₂ and its metabolite 15-deoxy-Δ¹²·¹⁴-PGJ₂ (15d-PGJ₂), which are endogenous PPARγ agonists with direct anti-inflammatory activity. Most significantly, it is COX-2 — when acetylated by aspirin — that generates the 18(R)-HEPE and 17(R)-HDHA precursors for aspirin-triggered resolvins.

A landmark study by Chan and Moore (2010) published in the Journal of Immunology demonstrated this paradox experimentally in murine collagen-induced arthritis. COX-2 and PGE₂ were present in joints during the resolution phase, and blocking COX-2 activity in this window perpetuated, rather than attenuated, inflammation. Repletion with PGE₂ analogs restored homeostasis through a mechanism dependent on lipoxin A₄ production — demonstrating an endogenous COX-2→PGE₂→LXA₄ feedback loop that conventional NSAID therapy disrupts. [^12]

5.2 Selective COX-2 Inhibitors and Resolution Failure

The introduction of selective COX-2 inhibitors (celecoxib, rofecoxib) was clinically motivated by their superior gastrointestinal tolerability over non-selective NSAIDs. However, the observed increased cardiovascular risk — particularly the thrombotic events that led to rofecoxib withdrawal — may be interpretable not only through the prostacyclin/thromboxane imbalance hypothesis but also through resolution biology. Selective COX-2 inhibition eliminates both PGI₂ (vasodilatory) and the COX-2-dependent resolution pathway (aspirin-triggered lipoxins/resolvins), a dual suppression with implications extending beyond the haemostatic axis.

5.3 Clinical Implications for Long-term NSAID Use

The foregoing mechanistic data suggest a clinically important hypothesis: long-term, regular-dose NSAID therapy — particularly with non-selective agents and selective COX-2 inhibitors — may, in specific patient populations and disease contexts, paradoxically contribute to the perpetuation of chronic inflammatory states by impairing the active resolution programme. This is most relevant in:

• Osteoarthritis and rheumatoid arthritis, where chronic NSAID use is standard practice and where defects in SPM biosynthesis have been documented. [^13]
• Atherosclerosis, in which impaired resolution — not merely inflammatory induction — is now recognized as a primary pathophysiological driver of plaque progression and instability. [^11]
• Chronic heart failure, where RvD1 plasma levels are significantly reduced relative to healthy controls, GPR32 receptor expression on T lymphocytes is downregulated, and the SPM signalling axis is functionally compromised. [^14]
• Post-surgical inflammation, where the use of perioperative NSAIDs may blunt the resolution programme that is physiologically required for wound healing and anastomotic integrity.

It bears emphasis that the evidence for NSAID-induced resolution impairment is currently strongest in preclinical models; while mechanistic plausibility is substantial, direct human RCT evidence demonstrating that NSAID discontinuation improves resolution outcomes in chronic inflammatory disease is not yet available. This represents a critical gap in translational research.

6. DEFICIENT SPM BIOSYNTHESIS IN CHRONIC DISEASE

A growing body of evidence documents quantifiable SPM deficiencies across multiple chronic inflammatory conditions, consistent with the resolution-failure hypothesis.

In cardiovascular disease, DHA and EPA phospholipid content are inversely associated with circulating IL-6, TNF-α, and MCP-1 in subjects with low-grade chronic inflammation, and plasma SPM precursor concentrations (14-HDHA, 4-HDHA, 18-HEPE) are inversely correlated with these inflammatory markers. [^15] In atherosclerotic plaques, SPM concentrations are reduced at sites of active inflammation compared to stable fibrous regions, and impaired efferocytosis — a direct consequence of SPM deficiency — correlates with plaque necrotic core expansion. [^11]

In rheumatoid arthritis, synovial fluid SPM concentrations are reduced during flare relative to clinical remission, and joint tissue 15-LOX expression is downregulated in active disease. In animal models of collagen-induced arthritis, exogenous resolvin and protectin administration reduces histopathological arthritis scores, attenuates cartilage erosion, and promotes bone preservation — effects not replicated by equivalent anti-inflammatory doses of conventional NSAIDs. [^13]

In metabolic syndrome and non-alcoholic steatohepatitis (NASH), adipose tissue macrophages in obese individuals exhibit profoundly impaired efferocytosis and reduced expression of SPM biosynthetic enzymes. Resolvin D1 administration in murine obesity models reduces adipose tissue inflammation, improves insulin signalling, and attenuates hepatic steatosis through mechanisms distinct from those of anti-inflammatory blockade. [^5]

In neurological disease, DHA-derived neuroprotectin D1 (NPD1) is reduced in hippocampal tissue from Alzheimer's disease patients relative to age-matched controls, and its administration in animal models attenuates Aβ peptide-induced neuronal apoptosis — an observation with implications for understanding the chronic neuroinflammatory component of neurodegenerative disease. [^4]

7. HUMAN EVIDENCE: EPA AND DHA SUPPLEMENTATION AND SPM PRODUCTION

Despite the mechanistic richness of the SPM field, direct human evidence linking omega-3 PUFA supplementation to quantifiable SPM increases remains an area of active investigation, with findings that are robust for precursor accumulation but more mixed for fully formed SPMs.

Calder (2020), in a comprehensive review of human SPM measurement studies, documented SPM detection in plasma, serum, cerebrospinal fluid, synovial fluid, sputum, breast milk, and multiple tissue compartments across healthy subjects, paediatric populations, and individuals with diverse diseases. Both EPA and DHA supplementation increased circulating precursor concentrations (18-HEPE for EPA, 17-HDHA and 14-HDHA for DHA), but conversion to fully formed resolvins was variable and frequently incomplete in human subjects — suggesting that substrate availability alone is insufficient and that enzymatic competence may be rate-limiting in inflammatory contexts. [^16]

In a randomized crossover trial, So et al. compared EPA (3 g/day) versus DHA (3 g/day) supplementation in 21 subjects with elevated hsCRP, finding that DHA generated a broader range of SPMs than EPA, including DPA-derived resolvins (RvD5ₙ₋₃ DPA and MaR1ₙ₋₃ DPA). Notably, plasma MaR1ₙ₋₃ DPA concentrations were inversely correlated with LPS-induced TNF-α expression in blood monocytes — providing the most direct available human evidence linking SPM concentrations to attenuated inflammatory response. [^8]

A recent expert consensus panel (Martindale et al., 2025), applying a Delphi methodology, concluded that SPM biosynthesis is frequently impaired in critical illness, obesity, and chronic inflammatory states, and that SPM-enriched enteral nutrition may represent a clinically relevant strategy — but emphasized that rigorously designed clinical trials are needed to define effective dosing and clinical endpoints. [^17]

RESOLUTION PHARMACOLOGY: THERAPEUTIC HORIZONS

Immunoresolvent Agonist Strategy

Buckley, Gilroy, and Serhan (2014), in a pivotal conceptual paper in Immunity, articulated the therapeutic shift required by SPM biology: from antagonism of inflammatory induction to agonism of the resolution phase. This distinction is not semantic. Antagonists (NSAIDs, biologics) reduce inflammatory load but may leave the resolution programme unactivated. Agonists of resolution (exogenous SPMs, stable synthetic analogs) actively engage the clearance and repair machinery. [^18]

Stable synthetic SPM analogs have been developed to overcome the short in vivo half-life of native SPMs (typically seconds to minutes). Benzo-lipoxin analogs, AT-RvD1 methyl esters, and protectin analogs have demonstrated therapeutic efficacy in multiple preclinical models including peritonitis, arthritis, colitis, acute lung injury, and ischaemia-reperfusion injury. Clinical trial data are currently limited but emerging.

Omega-3 PUFA as Resolution Nutrition

From a clinical and nutritional standpoint, adequate EPA and DHA intake may be understood as providing the substrate required for the resolution programme. Population-level deficiency in omega-3 PUFAs — characteristic of Western dietary patterns — would, within this framework, constitute a structural impediment to effective inflammation resolution across the lifetime. However, as noted above, the human data linking higher EPA/DHA intake to higher circulating SPMs is present but incomplete in its translation to clinical outcomes; the field awaits larger, resolution-endpoint-focused trials. [^16]

Aspirin Repositioning

Low-dose aspirin (75–325 mg/day) occupies a unique and instructive position in this framework. While it irreversibly inhibits COX-1 and acetylates COX-2 (rather than blocking it), the acetylated COX-2 retains catalytic activity directed toward generating 15(R)-HEPE and 17(R)-HDHA — the precursors of aspirin-triggered resolvins. This mechanistic distinction explains why aspirin, unlike other NSAIDs, produces ATL and aspirin-triggered D-series resolvins, providing a resolution-promoting action that conventional NSAIDs and coxibs lack. The therapeutic implications for aspirin's proven role in cardiovascular secondary prevention may extend beyond its antiplatelet mechanism to include resolution pharmacology. [^19]

CRITICAL APPRAISAL AND LIMITATIONS OF CURRENT EVIDENCE

This review acknowledges several important limitations of the SPM field that the clinician-scientist should weigh:

1. Predominance of preclinical data. The most mechanistically detailed evidence — biosynthetic pathway elucidation, receptor pharmacology, disease model efficacy — derives from murine and ex vivo systems. Preclinical SPM concentrations used in experiments frequently exceed physiologically achievable levels following dietary intervention, raising questions of translational dosing.
2. Analytical challenges in SPM quantification. The measurement of circulating SPMs presents significant technical obstacles: these molecules exist at picomolar concentrations, are rapidly metabolised, and require liquid chromatography-tandem mass spectrometry (LC-MS/MS) for reliable quantification. Methodological variability across laboratories has contributed to discordant findings. [^20]
3. Receptor validation debates. A recent comprehensive review (Park, 2025) in Biochemical Pharmacology raised substantive methodological concerns regarding SPM receptor pharmacology, specifically questioning the reproducibility of receptor binding studies and the endogenous concentration-response relationships for some SPM-receptor interactions. This perspective, while representing a minority scientific position relative to the broader literature, merits acknowledgment by clinicians evaluating translational claims. [^20]
4. Limited RCT evidence in humans. As of this review, no large, randomised, adequately powered clinical trial has prospectively tested an SPM-based therapeutic intervention against a defined clinical inflammatory endpoint. The field remains at the translational interface, with the most rigorous human data coming from biomarker and ex vivo mechanistic studies rather than outcome trials.

CONCLUSION

The biology of inflammation resolution represents one of the most significant conceptual revisions in immunology and clinical medicine of the past two decades. The characterisation of SPMs — lipoxins, E-series and D-series resolvins, protectins, and maresins — as endogenous agonists of an active resolution programme challenges the sufficiency of the suppression paradigm that has governed anti-inflammatory pharmacology since the introduction of aspirin and corticosteroids.

For the practising clinician, the most immediately relevant implication is interpretive: the beneficial effects of omega-3 PUFAs are not explicable solely by competitive displacement of arachidonic acid from membrane phospholipids or by modest prostaglandin suppression. They are, in substantial part, attributable to the generation of a structurally and functionally distinct class of mediators that actively programme inflammatory termination, cellular clearance, and tissue repair. Conversely, the long-term prescription of COX-inhibiting NSAIDs — however effective in controlling symptomatic inflammation — must be reconsidered in light of evidence that the COX-2 axis participates in generating resolution signals, and that its chronic inhibition may attenuate the endogenous repair programme.

Resolution pharmacology — the therapeutic stimulation rather than suppression of the resolution programme — is the logical translational destination of this field. The development of stable SPM analogs, SPM-enriched nutritional formulations, and resolution-agonist receptor therapies is underway. What the field now requires is adequately powered, resolution-endpoint-focused clinical trials to translate a compelling mechanistic narrative into evidence-based clinical guidance.

As Buckley, Gilroy, and Serhan articulated in 2014: "treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation." [^18]

A decade on, that broadening has yet to reach standard clinical practice.

CONFLICTS OF INTEREST

The author declares no conflicts of interest relevant to this article.

FUNDING

No external funding was received for this review.

1. Serhan CN. Novel Pro-Resolving Lipid Mediators in Inflammation Are Leads for Resolution Physiology. Annu Rev Pharmacol Toxicol. 2014. [^1] 2. Spite M, Serhan CN. Roles of Specialized Proresolving Lipid Mediators in Inflammation Resolution and Tissue Repair. 2017. [^2] 3. Nan C, Serhan CN. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Aspects Med. 2017;57:1–29. 4. Bannenberg G, Serhan CN. Specialized pro-resolving lipid mediators in the inflammatory response: An update. Biochim Biophys Acta. 2010. [^4] 5. López-Vicario C et al. Pro-resolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome. Eur J Pharmacol. 2016. [^5] 6. Romano M et al. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. Eur J Pharmacol. 2015. [^6] 7. Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis. Prostaglandins Other Lipid Mediat. 2002. 8. Rajakariar R, Yaqoob M, Gilroy DW. COX-2 in inflammation and resolution. Mol Interv. 2006. [^3] 9. Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014. [^18] 10. Chan MM, Moore AR. Resolution of inflammation in murine autoimmune arthritis is disrupted by COX-2 inhibition and restored by PGE2-mediated LXA4 production. J Immunol. 2010. [^12] 11. Schett G, Neurath M. Resolution of chronic inflammatory disease: universal and tissue-specific concepts. Nat Commun. 2018. [^13] 12. Doran AC. Inflammation Resolution: Implications for Atherosclerosis. Circ Res. 2022. [^11] 13. So J et al. Effects of EPA and DHA supplementation on plasma specialized pro-resolving lipid mediators. Curr Dev Nutr. 2019. [^8] 14. Calder PC. Eicosapentaenoic and docosahexaenoic acid derived specialised pro-resolving mediators: concentrations in humans. Biochimie. 2020. [^16] 15. Martindale R et al. Integrating downstream mediators of Omega-3 fatty acids into enteral nutrition: Expert panel consensus. Clin Nutr. 2025. [^17] 16. Lamon-Fava S. Associations between omega-3 fatty acid-derived lipid mediators and markers of inflammation. Prostaglandins Other Lipid Mediat. 2025. [^15] 17. Park W. Eicosanoids and Inflammation: A delicate balance of Pro-Inflammatory and Pro-Resolving mediators. Biochem Pharmacol. 2025. [^20] 18. Nan C, Serhan CN. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem. 2020. 19. Serhan CN, Chiang N, Dalli J. Specialized Proresolving Mediators (SPM): Anti-Phlogistic Pro-Resolving Actions. 2015. [^21] 20. Lee HN, Surh YJ. Therapeutic potential of resolvins in prevention and treatment of inflammatory disorders. Biochem Pharmacol. 2012. [^22] 21. Abdolmaleki F et al. Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases. Clin Rev Allergy Immunol. 2019. [^23] 22. Panezai J, Van Dyke TV. Resolution of Inflammation: Intervention Strategies and Future Applications. Toxicol Appl Pharmacol. 2022.

[^1]: Serhan, 2014. Novel Pro-Resolving Lipid Mediators in Inflammation Are Leads for Resolution Physiology.

[^2]: Spite & Serhan, 2017. Roles of Specialized Proresolving Lipid Mediators in Inflammation Resolution and Tissue Repair.

[^3]: Rajakariar et al., 2006. COX-2 in inflammation and resolution. Molecular Interventions.

[^4]: Bannenberg & Serhan, 2010. Specialized pro-resolving lipid mediators in the inflammatory response: An update. Biochimica et Biophysica Acta.

[^5]: López‐Vicario et al., 2016. Pro-resolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases. European Journal of Pharmacology.

[^6]: Romano et al., 2015. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. European Journal of Pharmacology.

[^7]: So et al., 2019. Effects of EPA and DHA Supplementation on Plasma Specialized Pro-resolving Lipid Mediators and Blood Monocyte Inflammatory Response in Subjects with Chronic Inflammation (OR29-01-19). Current Developments in Nutrition.

[^8]: Serhan, 2005. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, Leukotrienes and Essential Fatty Acids.

[^9]: Kebir et al., 2009. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. American Journal of Respiratory and Critical Care Medicine.

[^10]: Doran, 2022. Inflammation Resolution: Implications for Atherosclerosis. Circulation Research.

[^11]: Chan & Moore, 2010. Resolution of Inflammation in Murine Autoimmune Arthritis Is Disrupted by Cyclooxygenase-2 Inhibition and Restored by Prostaglandin E2-Mediated Lipoxin A4 Production. Journal of Immunology.

[^12]: Zaninelli et al., 2021. Harnessing Inflammation Resolution in Arthritis: Current Understanding of Specialized Pro-resolving Lipid Mediators’ Contribution to Arthritis Physiopathology and Future Perspectives. Frontiers in Physiology.

[^13]: Chiurchiù et al., 2018. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes. The FASEB Journal.

[^14]: Lamon-Fava, 2025. Associations between omega-3 fatty acid-derived lipid mediators and markers of inflammation in older subjects with low-grade chronic inflammation. Prostaglandins & other lipid mediators.

[^15]: Calder, 2020. Eicosapentaenoic and docosahexaenoic acid derived specialised pro-resolving mediators: Concentrations in humans and the effects of age, sex, disease and increased omega-3 fatty acid intake. Biochimie.

[^16]: Martindale et al., 2025. Integrating downstream mediators of Omega-3 fatty acids into enteral nutrition for improved patient care: An expert panel consensus. Clinical Nutrition.

[^17]: Buckley et al., 2014. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity.

[^18]: Kolawole & Kashfi, 2022. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. International Journal of Molecular Sciences.

[^19]: Park, 2025. Eicosanoids and Inflammation: A delicate balance of Pro-Inflammatory and Pro-Resolving mediators. Biochemical Pharmacology.

[^20]: Serhan et al., 2015. Specialized Proresolving Mediators ( SPM ) : Anti-Phlogistic Pro-Resolving Actions ( see Figure 1 , Panel B ) SPM Defining.

[^21]: Lee & Surh, 2012. Therapeutic potential of resolvins in the prevention and treatment of inflammatory disorders. Biochemical Pharmacology.

[^22]: Abdolmaleki et al., 2019. Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases. Clinical reviews in allergy and immunology.

[^23]: Panezai & Dyke, 2022. Resolution of inflammation: Intervention strategies and future applications. Toxicology and Applied Pharmacology.