Arachidonic acid metabolism
The biosynthesis of eicosanoids begins at the cell membrane. Under the action of phospholipases A and C, arachidonic acid is released from membrane phospholipids. Its subsequent fate depends on which enzymatic pathway is engaged:
- Cyclooxygenase pathway. The key enzyme is cyclooxygenase. Arachidonic acid is converted into intermediate metabolites (PGG2, PGH2), from which prostaglandins (PGE2, PGD2, PGFα2, prostacyclin PGI2) and thromboxane TXA2 are subsequently synthesized.
- Lipoxygenase pathway. The key enzyme is lipoxygenase. The process proceeds via the intermediate metabolite LTA4 and culminates in the formation of leukotrienes (LTB4, LTC4, LTD4, LTE4).
Prostaglandins (PG) and Thromboxanes (TX)
Prostaglandins are 20-carbon fatty acids containing a cyclopentane ring. In the focus of inflammation, they accumulate slightly later than leukotrienes and simultaneously with monokines (after 6–24 hours).
A critical regulator is prostaglandin E2 (PGE2). Interestingly, exogenous PGE2 paradoxically suppresses the immune response: it reduces macrophage cytotoxicity and cytokine production by lymphocytes by increasing intracellular cAMP. PGE2 relaxes bronchial smooth muscle, whereas PGD2 and PGF2α cause its marked spasm. Endothelial prostacyclin (PGI2) is a potent vasodilator and, paired with bradykinin, is responsible for eliciting the sensation of pain during inflammation.
Thromboxane A2 (TXA2) contains a 6-membered oxygen-containing ring. This extremely unstable compound rapidly converts into inactive TXB2. Its primary role is vasoconstriction and bronchoconstriction, as well as the stimulation of platelet aggregation.
Leukotrienes (LT) and their receptors
Leukotrienes are synthesized by macrophages, mast cells, and neutrophils. They are divided into two groups: leukotriene B4 (a potent chemoattractant and cell activator) and cysteinyl leukotrienes (C4, D4, E4), which contain glutathione in their structure.
In the liquid phase, cysteinyl forms transform into one another: LTC4 exists for 3–5 minutes, converts into LTD4 (exists for about 15 minutes), which then slowly turns into LTE4. These substances, especially LTD4, regulate local blood flow and account for the slow phase of bronchospasm in asthma. Previously, this complex was termed slow-reacting substance of anaphylaxis.
Effects are mediated through receptors spanning the membrane 7 times and coupled to G proteins:
- BLT-R1 and R2 — bind leukotriene B4.
- CysLT-R1 and R2 — receptors for Cys-LT. Specifically, CysLT-R1 has the highest affinity precisely for LTD4 and is localized on macrophages and airway epithelium, whereas CysLT-R2 (with equal affinity for LTD4 and LTC4) is expressed in brain and adrenal tissues.
Lipoxins and Platelet-activating factor (PAF)
Lipoxins (A4 and B4) are a distinct class of eicosanoids formed from arachidonic acid via the combined action of 5-lipoxygenase and 15- (or 12-) lipoxygenase. They exhibit pronounced anti-inflammatory effects: they inhibit chemotaxis and transendothelial migration of leukocytes, and reverse the effects of leukotrienes in vivo. In the presence of aspirin, aspirin-triggered lipoxin with similar properties can be formed via COX-2 activity.
PAF is synthesized de novo from lysoglyceryl ether phosphorylcholine. It causes platelet aggregation, increases vascular permeability through endothelial contraction, and induces bronchospasm. However, due to its very short half-life, its systemic impact on allergic reactions is limited.
Briefly: answers to topical questions
What is the difference between the effects of thromboxane A2 (TXA2) and prostacyclin (PGI2) on blood vessels and platelets?
- Thromboxane A2 (TXA2) — causes vasoconstriction and stimulates platelet aggregation with the release of enzymes and active factors.
- Prostacyclin (PGI2) — causes potent vasodilation, increases vascular permeability, and inhibits platelet aggregation.
| Substance | Effect on blood vessels | Effect on platelets |
|---|---|---|
| Thromboxane A2 | Constricts | Induce platelet aggregation |
| Prostacyclin | Potently dilates, increases permeability | Inhibit platelet aggregation |
To avoid confusing the receptors: BLT-R binds leukotriene B (B4), while CysLT-R binds cysteinyl leukotrienes (C4, D4, E4). The CysLT-R1 receptor has the highest affinity for the most active among them — LTD4.
Class and exam questions
What are all eicosanoids synthesized from?
Their universal precursor is arachidonic acid, which is cleaved from cell membrane phospholipids by the enzymes phospholipase A and phospholipase C.
How does prostaglandin E2 affect the immune response?
Despite its involvement in inflammation, PGE2 exerts an immunosuppressive effect: it decreases macrophage cytotoxicity, inhibits platelet aggregation, and suppresses cytokine production by lymphocytes by raising intracellular cAMP levels.
What is the "slow-reacting substance of anaphylaxis"?
This is the historical name for the complex of cysteinyl leukotrienes (LTC4, LTD4, LTE4). These very mediators are responsible for the delayed and prolonged phase of bronchospasm in bronchial asthma.
What else to study on this topic
- Features of the chemical nomenclature of prostaglandins (significance of letters and numbers in the name)
- The cascade of peptidoleukotriene transformations in the liquid phase: kinetics of enzymatic reactions
- Comparative characteristics of the biological effects of LTB4 and cysteinyl leukotrienes
- Mechanism of formation of aspirin-triggered lipoxin involving COX-2
- Structure and signal transduction mechanism via G protein-coupled rhodopsin-like receptors (CysLT-R)
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