Lipoxins are specialized pro-resolving mediators (SPMs) derived from arachidonic acid (omega-6) that actively terminate inflammation and promote tissue repair. They represent the body's endogenous 'class switch' from pro-inflammatory eicosanoids to resolution mediators, with aspirin-triggered lipoxins (ATL) being even more potent resolution signals.
graph TD
subgraph "Substrate"
AA["Arachidonic acid<br/>(omega-6)"]
end
subgraph "Native Lipoxin Pathway"
AA -->|"15-lipoxygenase<br/>(15-LO)"| HPETE["15-HPETE"]
HPETE -->|"5-lipoxygenase<br/>(5-LO)"| LXA4["Lipoxin A4"]
HPETE -->|"5-LO"| LXB4["Lipoxin B4"]
end
subgraph "Aspirin-Triggered Pathway"
AA -->|"aspirin acetylates<br/>COX-2"| EPI["15-epi-lipoxins<br/>(aspirin-triggered lipoxins)<br/>more potent"]
end
subgraph "ALX/FPR2 Receptor Effects"
LXA4 -->|"binds ALX/FPR2"| STOP["Stop neutrophil<br/>recruitment &<br/>infiltration"]
LXA4 --> EFFC["Enhance macrophage<br/>efferocytosis"]
LXA4 --> M2["M1 → M2 macrophage<br/>polarisation"]
LXA4 --> REPAIR["Epithelial barrier<br/>repair"]
EPI -->|"binds ALX/FPR2"| STOP
EPI --> EFFC
LXB4 -->|"binds ALX/FPR2"| STOP
end
STOP --> RESOLVE["Inflammation<br/>resolution"]
EFFC --> RESOLVE
M2 --> RESOLVE
REPAIR --> RESOLVE
style AA fill:#f8d7da,stroke:#dc3545
style HPETE fill:#fff3cd,stroke:#ffc107
style LXA4 fill:#d4edda,stroke:#28a745
style LXB4 fill:#d4edda,stroke:#28a745
style EPI fill:#d4edda,stroke:#28a745
style STOP fill:#cce5ff,stroke:#004085
style EFFC fill:#cce5ff,stroke:#004085
style M2 fill:#cce5ff,stroke:#004085
style REPAIR fill:#cce5ff,stroke:#004085
style RESOLVE fill:#d4edda,stroke:#28a745
graph LR
AA2["Arachidonic acid"] --> PRO["Early inflammation<br/>COX-1/2 → prostaglandins<br/>5-LO → leukotrienes"]
PRO -->|"eicosanoid<br/>class switch"| SWITCH["Enzymatic shift<br/>15-LO activation"]
SWITCH --> RES["Resolution phase<br/>15-LO + 5-LO → lipoxins"]
RES --> HEAL["Tissue homeostasis<br/>restored"]
ASA["Low-dose aspirin"] -->|"acetylates COX-2"| ATL["Aspirin-triggered<br/>lipoxins"]
ATL --> HEAL
style AA2 fill:#f8d7da,stroke:#dc3545
style PRO fill:#f8d7da,stroke:#dc3545
style SWITCH fill:#fff3cd,stroke:#ffc107
style RES fill:#d4edda,stroke:#28a745
style HEAL fill:#d4edda,stroke:#28a745
style ASA fill:#cce5ff,stroke:#004085
style ATL fill:#d4edda,stroke:#28a745
Lipoxins are produced through sequential enzymatic reactions: 15-lipoxygenase (15-LO) converts arachidonic acid to 15-HPETE, then 5-LO produces lipoxin A4 and B4. Aspirin acetylates COX-2, creating 15-epi-lipoxins (aspirin-triggered lipoxins). Lipoxins bind to ALX/FPR2 receptors on neutrophils, macrophages, and epithelial cells, blocking neutrophil recruitment, enhancing macrophage efferocytosis, stimulating M1-to-M2 macrophage polarization, and promoting epithelial repair.
Lipoxins demonstrate that the same fatty acid (arachidonic acid) that produces pro-inflammatory prostaglandins and leukotrienes also generates resolution signals—the key is enzymatic pathway switching. This eicosanoid class switch is central to inflammation resolution. Low-dose aspirin's benefits partly derive from promoting aspirin-triggered lipoxins. Supporting this pathway is fundamental to cPNI resolution protocols.
- Derived from arachidonic acid (omega-6) through 15-LO and 5-LO pathways
- First SPM family discovered (before resolvins, protectins, maresins)
- Aspirin-triggered lipoxins (15-epi-lipoxins) are more potent than native lipoxins
- Bind to ALX/FPR2 receptors
- Stop neutrophil recruitment and infiltration
- Enhance macrophage efferocytosis (cleanup of apoptotic cells)
- Promote M1-to-M2 macrophage polarization
- Stimulate epithelial barrier repair
- Produced by endothelial cells, neutrophils, and TH2 cells
- Low-dose aspirin promotes lipoxin production
- Represent endogenous inflammation resolution mechanism
- specialized pro-resolving mediators — lipoxins are the first discovered class of SPMs
- arachidonic acid — substrate for lipoxin synthesis via 15-LO and 5-LO
- 15-lox — enzyme converting arachidonic acid to precursor for lipoxin synthesis
- 5-LO — enzyme completing lipoxin synthesis from 15-HPETE
- eicosanoid class switch — lipoxins represent the switch from pro-inflammatory to pro-resolving eicosanoids
- aspirin — acetylates COX-2 to produce aspirin-triggered lipoxins
- aspirin-triggered lipoxins — more potent lipoxin form produced by aspirin-acetylated COX-2
- ALX-FPR2 receptor — G-protein coupled receptor binding lipoxins
- neutrophils — lipoxins stop neutrophil recruitment and tissue infiltration
- macrophages — lipoxins enhance macrophage efferocytosis and M2 polarization
- M1-M2-macrophage-polarization — lipoxins drive shift from M1 to M2 phenotype
- efferocytosis — lipoxins enhance macrophage clearance of apoptotic cells
- prostaglandins — same substrate produces pro-inflammatory prostaglandins early, lipoxins later
- leukotrienes — same enzyme pathways produce leukotrienes then lipoxins
- resolvins — omega-3-derived SPMs with complementary resolution functions
- inflammation resolution — lipoxins actively terminate inflammation and promote healing
- COX-2 — aspirin acetylation of COX-2 produces aspirin-triggered lipoxins
- epithelial cells — lipoxins promote epithelial barrier repair
- omega-6 — lipoxins are omega-6-derived resolution mediators
- resolvomics — lipoxins are central mediators in resolution pharmacology
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