Merged from 2 sources — review for redundancy.
Oxylipins are a family of bioactive lipid mediators derived from enzymatic or non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs), including Omega-3 and omega-6 fatty acids. This family encompasses Prostaglandins, leukotrienes, thromboxanes, Resolvins, Protectins, and Maresins, functioning as paracrine and autocrine signaling molecules that regulate inflammation, resolution, pain perception, vascular tone, and immune responses. The balance between pro-inflammatory and pro-resolving oxylipins determines tissue inflammatory status and healing outcomes.
Imagine your neighborhood has two competing factories on the same street, both making signaling flares that tell emergency services what to do. The omega-6 factory (fed by linoleic acid and arachidonic acid) cranks out red flares—PGE2, leukotrienes, thromboxanes—that call in fire trucks, ambulances, and police (pro-inflammatory). When red flares dominate, the neighborhood stays on high alert: sirens blaring, streets blocked, chronic inflammation. The Omega-3 factory (fed by EPA and DHA) produces green flares—Resolvins, Protectins, Maresins—that signal "stand down, clean up the debris, restore normal traffic" (pro-resolving). Both factories use the same enzymatic machinery (Cyclooxygenase, lipoxygenase, Cytochrome P450) to convert their raw materials into flares. The problem: in modern diets, the omega-6 factory runs at 20× capacity compared to the omega-3 factory (omega-6:Omega-3 ratio of 20:1 instead of 1:1). This creates a city perpetually flooded with red flares—chronic pain, peripheral neuropathy, tissue damage—because the green "resolution" flares never arrive. Change the raw material supply (normalize omega-6 to omega-3 ratio), and the factories produce balanced signals: inflammation when needed, resolution when the job is done.
Oxylipins are synthesized through three major enzymatic pathways acting on 20-carbon (eicosanoid) and 22-carbon (docosanoid) PUFAs:
Omega-6 Pathway (Pro-Inflammatory Cascade):
Omega-3 Pathway (Pro-Resolving Cascade):
Non-Enzymatic Pathway:
- Free radical oxidation of PUFAs → F₂-isoprostanes (oxidative stress markers), 12,13-diHOME (linoleic acid-derived) → mitochondrial dysfunction, nociceptor activation
Key Enzyme Competition:
The same enzymes (COX, LOX, CYP450) compete for omega-6 vs Omega-3 substrates. High dietary omega-6 saturates enzymes with AA, preventing EPA/DHA metabolism → oxylipin profile skews pro-inflammatory. omega-6 to omega-3 ratio of 1:1 to 4:1 (ancestral) vs modern 15:1 to 20:1 determines inflammatory tone.
graph TD
A[Dietary PUFAs] --> B["Omega-6: Linoleic Acid"]
A --> C["Omega-3: EPA/DHA"]
B --> D[Arachidonic Acid AA]
D --> E[COX-1/COX-2]
D --> F[5-LOX]
D --> G[CYP450]
E --> H["PGE2, TXA2<br/>Pro-inflammatory"]
F --> I["LTB4, LTC4<br/>Chemotaxis, Pain"]
G --> J["EETs<br/>Vascular effects"]
C --> K[EPA]
C --> L[DHA]
K --> M["5-LOX → RvE1-3"]
L --> N["15-LOX → RvD1-6"]
L --> O[Protectins, Maresins]
M --> P["Resolution:<br/>↓Neutrophils<br/>↑Efferocytosis"]
N --> P
O --> P
H --> Q["EP Receptors → TRPV1 sensitization"]
I --> R["BLT1 → Peripheral sensitization"]
Q --> S[Chronic Pain]
R --> S
P --> T[Tissue Homeostasis]
Measurement:
Lipidomics via LC-MS/MS quantifies oxylipin panels: PGE2, LTB4, RvD1, RvE1, Maresins. Pro-inflammatory:pro-resolving ratio predicts pain chronicity and metabolic dysfunction.
Diagnostic Value:
The oxylipin profile is a functional biomarker of inflammatory resolution capacity—not just whether inflammation is present, but whether tissues can turn it off. High PGE2:RvD1 ratios (>10:1) predict chronic pain, peripheral neuropathy, cardiovascular disease, and Type 2 Diabetes. Unlike CRP or IL-6 (static inflammation markers), oxylipins reveal the dynamic balance between fire-starting and fire-fighting.
Mismatch Paradigm:
The modern oxylipin disaster reflects evolutionary mismatch: hunter-gatherer diets provided omega-6:Omega-3 ratios of 1:1 to 2:1 (equal red and green flares). Industrial seed oils (linoleic acid from soy, corn, sunflower) shifted ratios to 20:1—20 fire trucks for every 1 cleanup crew. The Cytochrome P450 and LOX enzymes evolved expecting balanced substrate competition; flooding them with omega-6 creates a pro-nociceptive, pro-thrombotic, anti-resolution metabolic environment.
Connection to Metamodel 5 (Resolution):
Oxylipins are the molecular currency of resolution capacity. Specialized pro-resolving mediators (SPMs)—Resolvins, Protectins, Maresins—actively terminate inflammation, unlike passive glucocorticoid suppression. SPM deficiency (from low Omega-3 intake or 5-LOX/15-LOX polymorphisms) causes "resolution failure"—injuries never fully heal, pain persists, chronic low-grade inflammation becomes tissue baseline.
Pain Mechanisms:
Pronociceptive oxylipins (PGE2, LTB4, 12,13-diHOME) directly sensitize TRPV1 and voltage-gated sodium channels on dorsal root ganglia neurons. In peripheral neuropathy, high omega-6 oxylipins reduce intraepidermal nerve fibre density (IENF) and upregulate ATF3 (neuronal stress marker). This is diet-induced neuropathy—small-fiber neuropathy caused by lysophospholipids and oxylipin-mediated nerve terminal damage.
Intervention Strategies:
- Dietary correction: Reduce omega-6 (eliminate seed oils) + increase omega-3 (EPA/DHA 2-4g/day) → normalizes oxylipin synthesis within 8-12 weeks
- Enzyme modulation:
- PLA2G7 inhibition: darapladib blocks Lp-PLA2 → ↓lysophospholipids and oxidized oxylipins (experimental for peripheral neuropathy)
- Direct SPM supplementation: RvE1, RvD1 (experimental, not widely available)
Clinical Thresholds:
- PGE2 >150 pg/mL → systemic inflammatory drive
- LTB4 >50 pg/mL → neutrophilic inflammation
- RvD1 <2 ng/mL → resolution deficiency
- Omega-6:Omega-3 ratio >10:1 → high chronic pain risk
Selfish Immune System:
From the selfish immune system perspective, oxylipins represent resource allocation: pro-inflammatory oxylipins mobilize energy (fever, anorexia, muscle catabolism) for defense; pro-resolving oxylipins signal "threat cleared, restore energy to growth/reproduction." Chronic oxylipin imbalance creates a Selfish Brain trapped in defense mode—constant Hypothalamic Inflammation, insulin resistance, reproductive suppression.
- Oxylipins are derivatives of 20- and 22-carbon polyunsaturated fatty acids (arachidonic acid, EPA, DHA)
- Pro-inflammatory oxylipins: PGE2 (EP receptor activation), LTB4 (neutrophil chemotaxis), TXA₂ (platelet aggregation)
- Pro-resolving oxylipins: Resolvins (RvD1-6, RvE1-3), Protectins, Maresins (MaR1-2)
- Same enzymes process both pathways: Cyclooxygenase (COX), lipoxygenase (LOX), Cytochrome P450 (CYP)
- Modern omega-6:Omega-3 ratios (15:1 to 20:1) vs ancestral (1:1) create pro-inflammatory oxylipin dominance
- PGE2 at nociceptors → sensitizes TRPV1 channels → peripheral sensitization and chronic pain
- 12,13-diHOME (omega-6 oxylipin) → mitochondrial dysfunction, exercise intolerance
- RvD1 binds ALX-FPR2 receptor → ↓NF-kB activation, ↑macrophage efferocytosis
- Aspirin acetylates COX-2 → switches from PGE2 production to aspirin-triggered Resolvins
- High PGE2:RvD1 ratio predicts peripheral neuropathy risk independent of glycemic control
- Oxylipin profile measurable via LC-MS/MS lipidomics (research/advanced clinical labs)
- EPA/DHA supplementation 2-4g/day shifts oxylipin profile toward resolution in 8-12 weeks
- Darapladib (Lp-PLA2 inhibitor) reduces lysophospholipids and oxidized oxylipins in peripheral neuropathy models
- omega-6 to omega-3 ratio — the dietary ratio determines competitive substrate availability for oxylipin synthesis; modern ratios (>15:1) saturate enzymes with omega-6
- arachidonic acid — the primary omega-6 substrate for pro-inflammatory oxylipins (PGE2, LTB4, thromboxanes)
- linoleic acid — dietary omega-6 precursor converted to arachidonic acid; also produces 12,13-diHOME (mitochondrial toxin)
- Specialized pro-resolving mediators (SPMs) — the subset of oxylipins derived from Omega-3 fatty acids that actively terminate inflammation
- Resolvins — Omega-3-derived oxylipins (RvD1-6, RvE1-3) that bind ALX-FPR2, GPR32, ChemR23 to promote resolution
- Protectins — DHA-derived oxylipins (PD1/neuroprotectin D1) with neuroprotective and anti-inflammatory effects
- Maresins — DHA-derived oxylipins (MaR1-2) that enhance macrophage efferocytosis and tissue regeneration
- prostaglandin E2 — dominant pro-inflammatory oxylipin from arachidonic acid via COX-2; sensitizes TRPV1 and EP receptors
- Cyclooxygenase — enzyme converting arachidonic acid to Prostaglandins and thromboxanes; COX-2 inducible by IL-1β, TNF-α
- COX-2 — inducible cyclooxygenase; aspirin acetylation switches output from PGE2 to aspirin-triggered Resolvins
- 5-LOX — enzyme converting arachidonic acid to leukotrienes (LTB4) and EPA to Resolvin E-series
- 15-LOX — enzyme converting DHA to Resolvin D-series, Protectins, Maresins
- Cytochrome P450 — enzyme family producing EETs from arachidonic acid and epoxy-docosanoids from DHA
- peripheral neuropathy — high omega-6 oxylipins (PGE2, 12,13-diHOME) reduce intraepidermal nerve fibre density and sensitize nociceptors
- TRPV1 — transient receptor potential vanilloid 1 channel on nociceptors; sensitized by PGE2 via EP receptor-PKA signaling
- chronic pain — sustained pro-inflammatory oxylipin dominance creates peripheral and central sensitization
- PLA2G7 — lipoprotein-associated phospholipase A2; produces lysophospholipids and oxidized oxylipins; inhibited by darapladib
- lysophospholipids — lipid mediators produced alongside oxylipins; contribute to neuropathic pain
- darapladib — Lp-PLA2 inhibitor reducing oxidized oxylipins and lysophospholipids; experimental for peripheral neuropathy
- resolution — active termination of inflammation mediated by Omega-3-derived oxylipins; failure causes chronic inflammation
- Omega-3 fatty acids — EPA and DHA substrates for pro-resolving oxylipin synthesis
- EPA — eicosapentaenoic acid (20:5 n-3); substrate for Resolvin E-series
- DHA — docosahexaenoic acid (22:6 n-3); substrate for Resolvin D-series, Protectins, Maresins
- leukotrienes — pro-inflammatory oxylipins from arachidonic acid via 5-LOX; LTB4 drives neutrophil chemotaxis
- inflammation — oxylipins are primary lipid mediators initiating and resolving inflammatory responses
- immune responses — oxylipins regulate leukocyte trafficking, cytokine production, and phagocytosis
- NF-kB — transcription factor driving pro-inflammatory gene expression; inhibited by Resolvins
- ALX-FPR2 — G-protein coupled receptor for RvD1, lipoxin A4; triggers anti-inflammatory signaling
- diet-induced neuropathy — peripheral neuropathy caused by high omega-6 intake and resultant pronociceptive oxylipin profile
- small-fiber neuropathy — oxylipin-mediated damage to unmyelinated C-fibers; seen with high PGE2:RvD1 ratios
- Aspirin — acetylates COX-2, creating aspirin-triggered Resolvins (AT-RvD1, AT-LXA₄)
- Hypothalamic Inflammation — oxylipins contribute to hypothalamic NF-kB activation in obesity; Resolvins reverse this
- chronic low-grade inflammation — sustained elevation of pro-inflammatory oxylipins without resolution signals
- insulin resistance — pro-inflammatory oxylipins (especially PGE2) impair insulin signaling via JNK and IKK activation
Oxylipins are bioactive lipid signaling molecules generated through enzymatic or non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs), primarily arachidonic acid (AA, omega-6) and EPA/DHA (omega-3). They function as dual-action mediators: AA-derived oxylipins (e.g., prostaglandin E2, Leukotriene B4) amplify inflammation and pain, while EPA/DHA-derived oxylipins (resolvins, protectins, maresins) actively terminate inflammatory cascades and promote tissue resolution. The ratio of pro-inflammatory to pro-resolving oxylipins determines inflammatory tone, pain sensitivity, and healing capacity across all physiological systems.
Imagine your body's inflammatory response as a firefighting operation. When tissue damage occurs, you need both firefighters (pro-inflammatory oxylipins) to show up quickly and extinguish the fire, AND a cleanup crew (pro-resolving oxylipins) to assess damage, remove debris, and rebuild.
AA-derived oxylipins are the first responders—they arrive fast, recruit more help (neutrophils, macrophages), increase blood flow (vasodilation), and make nerve endings hyper-alert to prevent further injury (pain). PGE2 is like the fire captain shouting through a megaphone, amplifying the alarm signal. But if these firefighters never leave—if they keep hosing down a house that's already safe—you get chronic inflammation and waterlogged tissue that can't heal.
EPA/DHA-derived oxylipins are the specialized cleanup crew. They actively tell the firefighters to stand down, help surviving cells repair membranes, clear away dead neutrophils (efferocytosis), and signal "all clear" to the nervous system. RvD1, for example, literally flips macrophages from "attack mode" (M1) to "repair mode" (M2). But here's the catch: the Western diet—loaded with omega-6 oils—floods your body with firefighters while starving it of cleanup crews. The fire alarm never stops, debris piles up, and the neighborhood (your tissues) becomes chronically inflamed.
graph TD
A[Membrane Phospholipids] -->|PLA2G7/cPLA2| B[Free PUFAs]
B --> C["Linoleic Acid 18:2n6"]
B --> D["Arachidonic Acid 20:4n6"]
B --> E["EPA 20:5n3"]
B --> F["DHA 22:6n3"]
C -->|Oxidation| G[9-HODE, 13-HODE]
C -->|12/15-LOX| H[9,10-EpOME, 12,13-diHOME]
D -->|COX-1/COX-2| I[PGE2, PGI2, TXA2]
D -->|5-LOX| J[LTB4, LTC4, LTD4, LTE4]
D -->|12/15-LOX| K[12-HETE, 15-HETE]
D -->|CYP450| L[EETs, HETEs]
E -->|15-LOX| M[18-HEPE]
E -->|Aspirin-COX-2| N[AT-RvE1, AT-RvE2]
E -->|5-LOX| O[RvE1, RvE2, RvE3]
F -->|15-LOX| P[17-HDHA]
F -->|Aspirin-COX-2| Q[AT-RvD1-6]
F -->|5-LOX| R[RvD1-6, PD1, MaR1]
G --> S["TRPV1 activation → Pain"]
H --> T["Pronociceptive signaling → Neuropathy"]
I --> U["EP1-4 receptors → Inflammation/Pain"]
J --> V["BLT1/2 receptors → Leukocyte recruitment"]
M --> W["ChemR23 → Anti-inflammatory"]
O --> X["ERV1/ChemR23 → Resolution"]
P --> Y[RvD/PD/MaR biosynthesis]
R --> Z["ALX-FPR2/GPR32 → Resolution/Tissue repair"]
Enzymatic Pathway Details:
-
Liberation Phase: phospholipase A2 (particularly PLA2G7 and cPLA2) cleaves PUFAs from membrane phospholipids at the sn-2 position. PLA2G7 specifically releases linoleic acid (LA, 18:2n-6), generating lysophosphatidylcholine + free LA.
-
Pro-inflammatory Arm (Omega-6 dominant):
- COX pathway: COX-1 (constitutive) and COX-2 (inducible) convert AA → PGG2 → PGH2 → tissue-specific prostaglandins (PGE2, PGD2, PGF2α, PGI2) and thromboxane A2 (TXA2). PGE2 binds EP1-4 receptors → cAMP/PKA or IP3/Ca²⁺ signaling → enhanced pain sensitivity, fever, vasodilation.
- 5-LOX pathway: 5-lipoxygenase + FLAP converts AA → 5-HPETE → LTA4 → LTB4 (neutrophil chemoattractant via BLT1) or cysteinyl leukotrienes (LTC4, LTD4, LTE4 via CysLT receptors → bronchoconstriction, vascular permeability).
- 12/15-LOX pathway: 12-LOX → 12-HETE; 15-LOX → 15-HETE (moderate inflammatory activity, context-dependent).
- CYP450 pathway: Cytochrome P450 epoxygenases → epoxyeicosatrienoic acids (EETs) → vasodilation, cardioprotection; ω-hydroxylases → 20-HETE → vasoconstriction.
-
Pronociceptive LA-derived oxylipins: LA oxidation via 12/15-LOX → 9-HODE, 13-HODE, and epoxy metabolites 9,10-EpOME and 12,13-diHOME. These bind TRPV1 channels on dorsal root ganglia neurons → Ca²⁺ influx → nociceptive signaling. High LA diets (>15% total energy) → accumulation in nerve membranes → peripheral neuropathy with reduced intraepidermal nerve fibre density.
-
Pro-resolving Arm (Omega-3 dominant):
- E-series resolvins: EPA + 5-LOX → 18-HEPE → RvE1, RvE2, RvE3 (bind ERV1/ChemR23 → inhibit NF-κB, promote M2 macrophage polarization, stimulate efferocytosis).
- D-series resolvins: DHA + 15-LOX → 17-HDHA → RvD1-6 (bind ALX-FPR2, GPR32 → reduce neutrophil infiltration, enhance phagocytosis, inhibit NLRP3 inflammasome).
- Protectins: DHA + 15-LOX → PD1/NPD1 (neuroprotectin D1 in CNS → anti-apoptotic, promotes neural repair).
- Maresins: DHA + 12-LOX → MaR1, MaR2 (macrophage mediators → tissue regeneration, wound closure).
- Aspirin-triggered forms: Aspirin acetylates COX-2 (Ser530) → switches activity to produce 15R-HEPE/17R-HDHA → AT-RvE1, AT-RvD1-6 (same receptors, enhanced stability).
-
Metabolic Inactivation: Oxylipins undergo rapid deactivation via dehydrogenases (15-PGDH for prostaglandins), β-oxidation, and ω-oxidation → urinary/fecal excretion (t½ typically 30 seconds to 5 minutes).
-
Threshold Effects: omega-6 to omega-3 ratio >10:1 shifts oxylipin balance toward chronic inflammation. Ratio <4:1 permits SPM production sufficient for timely resolution. Modern Western diets average 15-20:1.
cPNI Relevance Across Conditions:
-
Chronic Pain Syndromes (fibromyalgia, chronic low-grade inflammation, peripheral neuropathy): High dietary LA → pronociceptive oxylipins (12,13-diHOME) accumulate in peripheral nerves → TRPV1 sensitization → allodynia and mechanical hypersensitivity even in absence of ongoing tissue damage. Patients often present with bilateral burning pain, reduced IENF density on skin biopsy, and elevated AA/EPA ratios on RBC fatty acid testing. Oxylipin profiling (lipidomics) predicts pain severity better than traditional inflammatory markers.
-
Autoimmune Diseases (rheumatoid arthritis, Crohn's disease, multiple sclerosis): Deficient SPM production → failed resolution → chronic inflammatory feedback loops. RA synovial fluid shows elevated LTB4:RvD1 ratios (>50:1). Therapeutic intervention: reduce omega-6 intake (<5% calories), supplement EPA/DHA (2-4g/day targeting omega-3 index >8%), consider aspirin (75-325mg/day) to generate aspirin-triggered resolvins if no contraindications.
-
Metabolic Syndrome & CVD: PGE2 and LTB4 drive insulin resistance via inflammatory signaling in adipocytes and hepatocytes. Oxylipins mediate the transition from metabolic flexibility to metabolic dysfunction. RvD1 and MaR1 improve insulin sensitivity, reduce hepatic steatosis, and promote M2 macrophage phenotype in adipose tissue. Target: omega-6 to omega-3 ratio <5:1 for metabolic recovery.
-
Gut Barrier Dysfunction: COX-2-derived PGE2 increases intestinal permeability via EP4 receptor → tight junction disruption. Conversely, RvE1 restores barrier integrity by upregulating occludin and ZO-1. Patients with leaky gut, IBS, or IBD benefit from dietary omega-6 reduction + targeted EPA supplementation.
-
Neuroinflammation & Depression: Brain microglia produce oxylipins locally. Chronic stress + high AA diet → microglial PGE2 production → hippocampal neuroinflammation → impaired neurogenesis → anhedonia. DHA-derived neuroprotectin D1 (NPD1) reverses this by promoting BDNF expression and synaptic plasticity. Clinical biomarker: RBC DHA <4% predicts poor antidepressant response.
Metamodel Integration:
-
Metamodel 1 (Evolutionary Mismatch): The omega-6 flood from seed oils (corn, soybean, sunflower) represents a 100-fold increase in LA intake vs. Paleolithic diets (2-3% vs. 15-20% of calories). Our enzymatic machinery evolved for 1:1 omega-6:omega-3 ratios; the current 20:1 average overwhelms resolution capacity.
-
Selfish Immune System: In chronic inflammation, immune cells preferentially consume AA → oxylipin production → self-perpetuating inflammatory cycle that diverts resources from tissue repair (resolution takes energy; perpetual alarm is metabolically cheaper short-term but catastrophic long-term).
Intervention Hierarchy:
-
Dietary: Eliminate seed oils (corn, soybean, safflower), reduce LA to <5% calories (≈10g/day). Increase EPA/DHA via fatty fish (3-4x/week) or algal/fish oil (2-4g/day). Target omega-3 index 8-12%.
-
Pharmacological:
- darapladib (experimental PLA2G7 inhibitor) reduces LA-derived oxylipins → reverses diet-induced neuropathy in animal models (not yet approved for human use).
- Low-dose aspirin (75-100mg/day) → aspirin-triggered SPMs via COX-2 acetylation.
- NSAIDs (ibuprofen, naproxen) block COX non-selectively → reduce PGE2 but also block SPM precursors (double-edged sword).
-
Lifestyle: cold exposure and heat therapy modulate oxylipin production (cold → reduced COX-2 activity; heat → HSP-mediated resolution pathway activation). exercise transiently increases SPM production post-workout (resolution of exercise-induced inflammation).
Clinical Thresholds:
- Omega-6:omega-3 ratio >10:1 → chronic inflammatory risk
- RBC AA/EPA ratio >15:1 → high cardiovascular/inflammatory disease risk
- PGE2 >150 pg/mL (serum) → active inflammation
- RvD1 <50 pg/mL (plasma) → deficient resolution capacity
- omega-3 index <4% → critical deficiency; 8-12% → optimal
- PLA2G7 releases linoleic acid from oxidized LDL and cellular membranes, generating the pronociceptive oxylipins 9,10-EpOME and 12,13-diHOME
- darapladib (selective PLA2G7 inhibitor) reverses LA-induced peripheral neuropathy in rodent models by reducing toxic oxylipin accumulation
- High omega-6 diets (>12% calories) increase inflammatory oxylipin production 3-5 fold within 4-8 weeks
- Western diets contain omega-6:omega-3 ratios of 15-20:1 vs. evolutionary baseline of 1-4:1
- PGE2 (via EP1/EP3 receptors) sensitizes TRPV1 channels → thermal hyperalgesia at ≥37°C (normal threshold 43°C)
- Leukotriene B4 recruits neutrophils at concentrations as low as 1 nM (half-maximal chemotaxis)
- RvD1 inhibits NLRP3 inflammasome activation at 10-100 nM, preventing IL-1β release
- Aspirin at 75-325 mg/day acetylates COX-2 → shifts from PG synthesis to aspirin-triggered resolvins (AT-RvD1, AT-RvE1) with t½ >24 hours
- SPM production requires adequate 15-LOX and 5-LOX enzymatic activity—genetic polymorphisms can impair resolution capacity
- Oxylipin half-lives range from 30 seconds (PGI2) to 5 minutes (most prostaglandins) to >1 hour (some resolvins), necessitating continuous biosynthesis
- 12,13-diHOME plasma levels >500 nM correlate with reduced intraepidermal nerve fibre density and neuropathic pain scores >6/10
- RvE1 at 100 ng dosing reduces postoperative pain scores by 40% and accelerates wound healing 30% faster in animal models
- linoleic acid — is the omega-6 precursor for pronociceptive oxylipins including 12,13-diHOME; dietary excess drives neuropathic pain
- arachidonic acid — serves as substrate for both inflammatory oxylipins (PGE2, LTB4 via COX/LOX) and some resolving mediators (via 15-LOX)
- PLA2G7 — enzyme liberating linoleic acid from oxidized phospholipids, generating neurotoxic oxylipin precursors
- prostaglandin E2 — major pro-inflammatory oxylipin binding EP receptors to amplify pain, fever, vasodilation, and immune activation
- Leukotriene B4 — potent neutrophil chemoattractant produced via 5-LOX; drives acute inflammatory cell recruitment
- peripheral neuropathy — caused by accumulation of pronociceptive LA-derived oxylipins (12,13-diHOME) sensitizing TRPV1 on DRG neurons
- darapladib — selective PLA2G7 inhibitor reducing LA-derived oxylipin production; reverses diet-induced neuropathy in preclinical models
- omega-6 to omega-3 ratio — determines oxylipin balance; ratios >10:1 favor inflammation while <4:1 enable resolution
- COX-2 — inducible cyclooxygenase converting AA to PGE2; acetylated by aspirin to produce aspirin-triggered resolvins
- resolvins — D-series (DHA-derived) and E-series (EPA-derived) SPMs binding ALX-FPR2/ChemR23 to terminate inflammation and promote repair
- protectins — DHA-derived SPMs (including NPD1) providing neuroprotection, reducing apoptosis, and enhancing tissue regeneration
- maresins — macrophage-derived SPMs (MaR1, MaR2) accelerating wound healing, efferocytosis, and M1→M2 phenotype switching
- specialized pro-resolving mediators — superfamily including resolvins, protectins, maresins, and lipoxins that actively resolve inflammation
- inflammation — amplified by AA-derived oxylipins and terminated by EPA/DHA-derived SPMs in dual-phase process
- pain — sensitized by PGE2, LTB4, and LA-derived oxylipins via TRPV1/TRPA1 activation; reduced by RvD1, RvE1 via neuronal resolution signaling
- TRPV1 — capsaicin/heat receptor sensitized by pronociceptive oxylipins (12,13-diHOME, PGE2) causing thermal hyperalgesia
- dorsal root ganglia — peripheral sensory neurons expressing oxylipin receptors; accumulate LA-derived metabolites in neuropathy
- diet-induced neuropathy — small fiber neuropathy resulting from high omega-6 intake → pronociceptive oxylipin accumulation in nerves
- aspirin — acetylates COX-2 Ser530, converting enzyme function from PG synthesis to aspirin-triggered resolvin production
- Omega-3 fatty acids — EPA/DHA precursors for resolvins, protectins, maresins; dietary insufficiency impairs resolution capacity
- chronic pain — sustained by oxylipin imbalance favoring pro-inflammatory mediators with deficient SPM production
- macrophages — produce maresins and respond to resolvins; shift from M1 (inflammatory) to M2 (repair) phenotype under SPM signaling
- efferocytosis — clearance of apoptotic cells enhanced by RvD1, MaR1 signaling via ALX-FPR2 on macrophages
- neutrophils — recruited by LTB4 (BLT1 receptor); apoptosis and clearance accelerated by RvE1, RvD1 to prevent secondary necrosis
- resolution — active process requiring SPM biosynthesis; failure results in chronic inflammation despite removal of initial trigger
- omega-3 index — RBC EPA+DHA percentage; <4% indicates deficiency impairing SPM production, >8% optimal for resolution capacity
- insulin resistance — exacerbated by PGE2/LTB4 inflammatory signaling in adipocytes; improved by RvD1/MaR1 metabolic actions
- depression — associated with high AA/EPA ratios and deficient DHA-derived neuroprotectin D1 in hippocampus
- wound healing — accelerated by maresins and protectins promoting angiogenesis, matrix remodeling, and re-epithelialization
- microbiome — gut bacteria produce short-chain fatty acids that modulate host oxylipin production via GPR41/43 signaling
- endothelial dysfunction — driven by TXA2/PGI2 imbalance; improved by EPA-derived resolvins restoring vascular homeostasis