Overview
Prostaglandins (PGs) are 20-carbon lipid autacoids derived from membrane phospholipids via a conserved biosynthetic cascade. They act in a paracrine or autocrine manner with very short plasma half-lives (~1–2 minutes) due to rapid enzymatic inactivation (15-PGDH). Together with thromboxanes, prostacyclin, and leukotrienes they constitute the eicosanoids — lipid mediators critical to inflammation, immunity, pain, fever, parturition, platelet activation, renal function, and gastric mucosal protection.
The pathway is triggered when cell membranes are perturbed (mechanical stress, cytokines, growth factors) — cytosolic phospholipase A₂α (cPLA₂α) is activated, releasing arachidonic acid (AA) from the sn-2 position of membrane phosphatidylcholine and phosphatidylethanolamine. AA then serves as substrate for cyclooxygenases (COX-1 and COX-2), which catalyse the committed, rate-limiting step of the prostanoid pathway.
Aspirin's irreversible acetylation of COX Ser530 is the cornerstone of antiplatelet therapy and anti-inflammatory medicine — one of the most important pharmacological mechanisms in clinical practice. The distinction between COX-1 (constitutive) and COX-2 (inducible) provides a therapeutic window for selective anti-inflammatory drugs, though selective COX-2 inhibition carries prothrombotic risk due to loss of PGI₂ without impairing TXA₂.
Structure & Prostanoid Family
All prostaglandins share a cyclopentane ring attached to two aliphatic chains (C1–C7 carboxylic acid chain and C13–C20 ω-chain), forming a 20-carbon "prostanoic acid" skeleton. The letter (E, F, D, I) indicates the substituents on the ring; the number subscript indicates the number of double bonds in the side chains.
| Prostanoid | Synthase | Primary source | Main receptors | Key effects |
|---|---|---|---|---|
| PGE₂ (prostaglandin E₂) | mPGES-1 (inducible), mPGES-2, cPGES | Macrophages, mast cells, DCs, endothelium, gastric mucosa, kidney | EP1–EP4 (4 GPCR subtypes) | Fever, pain sensitisation, inflammation, gastric mucus/HCO₃⁻ secretion, renal vasodilation, immunomodulation |
| PGI₂ (prostacyclin) | PGI₂ synthase (PGIS/CYP8A1) | Vascular endothelium | IP receptor (Gαs → cAMP) | Vasodilation, platelet aggregation inhibition, anti-thrombotic, cytoprotection |
| TXA₂ (thromboxane A₂) | TXA₂ synthase (TBXAS1/CYP5A1) | Platelets (COX-1) | TP receptor (Gαq → Ca²⁺) | Platelet aggregation, vasoconstriction, bronchoconstriction |
| PGD₂ | H-PGDS (haematopoietic), L-PGDS | Mast cells, brain, testes | DP1, DP2 (CRTH2) | Sleep regulation, allergic inflammation, inhibits platelet aggregation; OAB treatment (DP2 antagonists) |
| PGF₂α | AKR1B1 (PGF synthase) | Uterus, lung, kidney | FP receptor (Gαq) | Uterine contraction, luteolysis, bronchoconstriction, raised IOP (prostaglandin analogue glaucoma drops) |
Mechanism — COX Pathway & Aspirin
┌──────────────────────────────────────────────────────────────────────┐ │ ARACHIDONIC ACID CASCADE → PROSTANOIDS │ │ │ │ Membrane phospholipids (PC, PE) │ │ │ (stimulus: mechanical stress, IL-1β, TNF, LPS, Ca²⁺ ↑) │ │ cPLA₂α (cytosolic phospholipase A₂α) │ │ │ [Ca²⁺-dependent; ERK/p38 MAP-kinase phosphorylation] │ │ ▼ │ │ Arachidonic acid (AA; C20:4 n-6) — released to cytoplasm │ │ │ │ │ ┌────┴──────────────────────────────────────────────┐ │ │ │ │ │ │ │ COX-1 (PTGS1) COX-2 (PTGS2) 5-LOX pathway │ │ constitutive inducible (NFκB, HIF-1α) → leukotrienes │ │ platelets, macrophages, epithelia, (separate) │ │ GI mucosa fibroblasts, synovium │ │ │ │ │ │ Both: cyclooxygenase step (AA + 2O₂ → PGG₂) │ │ peroxidase step (PGG₂ → PGH₂) │ │ │ │ │ ┌──────────────┼──────────────┬────────────┐ │ │ mPGES PGIS TXA₂S PGDS │ │ │ │ │ │ │ │ PGE₂ PGI₂ TXA₂ PGD₂ │ │ (EP1-EP4) (IP-R) (TP-R) (DP1/2) │ │ │ │ PGE₂ → EP3 (Gαi): suppress cAMP in parietal cells (↓HCl) │ │ PGE₂ → EP4 (Gαs): immunosuppressive on DCs, NK cells │ │ PGI₂ → IP (Gαs): cAMP↑ → PKA → MLC dephosphorylation │ │ → vasodilation + platelet cAMP → ↓TXA₂ response │ │ TXA₂ → TP (Gαq): IP₃→Ca²⁺ → platelet activation │ │ → shape change → GPIIb/IIIa → fibrinogen binding │ │ │ ├──────────────────────────────────────────────────────────────────────┤ │ ASPIRIN (ACETYLSALICYLIC ACID) MECHANISM │ │ │ │ Aspirin → deacetylated to salicylate + acetyl group │ │ Acetyl group → covalent bond → COX-1/COX-2 Ser530 (COX-1) │ │ Ser516 (COX-2) │ │ │ │ │ Ser530 in COX channel → blocks AA access → NO PGH₂ │ │ │ │ │ COX-1 in platelets (anucleate → cannot synthesise new COX) │ │ → Irreversible inhibition → NO TXA₂ for platelet LIFETIME │ │ → Anti-platelet effect lasts 7–10 days (platelet lifespan) │ │ │ │ COX-2 in endothelium (nucleated → resynthesises COX-2 in hours) │ │ → Transient inhibition → PGI₂ resumes │ │ │ │ Low-dose aspirin (75–100 mg): preferentially inhibits platelet │ │ TXA₂ (high-sensitivity COX-1) over endothelial PGI₂ │ │ → Net anti-thrombotic effect │ │ │ │ NSAIDs (ibuprofen, naproxen): reversible, non-selective │ │ COX-1 + COX-2 inhibition (competitive) → anti-inflammatory │ │ but compete with aspirin for COX-1 Ser530 binding │ │ │ │ Selective COX-2 inhibitors (celecoxib, rofecoxib): │ │ ↓PGE₂/PGI₂ inflammation → less GI toxicity │ │ BUT ↓PGI₂ without ↓TXA₂ → ↑thrombotic risk (Vioxx withdrawal) │ └──────────────────────────────────────────────────────────────────────┘
- Cell membrane disruption → cPLA₂α activation (Ca²⁺ + ERK phosphorylation) → AA liberated from phospholipid sn-2 position by cleavage of the ester bond.
- COX cyclooxygenase domain: AA enters hydrophobic channel; two sequential oxygenations → PGG₂ (C9-C11 endoperoxide, C15-hydroperoxide).
- COX peroxidase domain: heme-mediated reduction → PGG₂ → PGH₂ (unstable; half-life 5 min at 37°C).
- PGH₂ is isomerised by cell-specific terminal synthases: mPGES-1 (GSH-dependent, inducible) → PGE₂; PGIS (CYP8A1, vascular endothelium) → PGI₂ (prostacyclin); TBXAS1 (platelet) → TXA₂.
- Prostanoids exit the cell (MRP4/ABCC4 transporter or simple diffusion) → bind cognate GPCRs on same/neighbouring cells → intracellular signalling (cAMP or Ca²⁺ depending on receptor subtype).
- Aspirin: acetyl-CoA-like acetyl group is transferred to COX-1 Ser530 OH → ester bond → permanent steric blockade of AA access. Anucleate platelets cannot replenish COX-1 → anti-platelet effect throughout 10-day platelet lifespan.
Physiological Roles
| System | Prostanoid | Role |
|---|---|---|
| Fever (pyrexia) | PGE₂ (EP3 in OVLT/POMC) | IL-1β/IL-6 → COX-2 in circumventricular organs → PGE₂ → EP3R in preoptic area → raises thermoregulatory set-point; aspirin/paracetamol block this |
| Pain sensitisation | PGE₂ (EP1, EP4 on DRG) | Reduces threshold of TRPV1 and Nav1.8 on nociceptors → peripheral sensitisation; spinal COX-2 → central sensitisation |
| Gastric cytoprotection | PGE₂, PGI₂ (EP3, IP) | COX-1 in gastric mucosa → PGE₂ → ↑mucus/HCO₃⁻ secretion, ↑mucosal blood flow, ↓parietal cell HCl; NSAID inhibition → ulcers |
| Platelet haemostasis | TXA₂ (TP) / PGI₂ (IP) | TXA₂: platelet activation + aggregation + vasoconstriction; PGI₂: antagonises TXA₂, vasodilates; balance governs thrombosis vs haemorrhage |
| Renal function | PGE₂ (EP4), PGI₂ (IP) | Afferent arteriole vasodilation; maintain GFR when RAAS activated; NSAIDs → acute kidney injury in volume-depleted/CKD patients |
| Parturition | PGE₂, PGF₂α (FP) | Uterine contractions; cervical ripening; misoprostol (PGE₁ analogue) / dinoprostone (PGE₂) for labour induction; indomethacin closes PDA |
| Sleep | PGD₂ (DP1 in basal forebrain) | PGD₂ accumulates during waking → VLPO activation → NREM sleep; SCI/PGD₂-linked narcolepsy models |
Pharmacology & Clinical Use
Aspirin — 75–300 mg daily for secondary CVD prevention (anti-TXA₂); 1–4 g for fever/inflammation (paediatric Reye syndrome risk with viral illness — contraindicated under 16 years). Irreversible anti-platelet; preoperative hold 7–10 days for elective surgery (not CABG).
NSAIDs — ibuprofen, naproxen, diclofenac, ketorolac: competitive reversible COX-1+2 inhibitors; GI side effects (mucus loss), renal toxicity (PGE₂-dependent afferent dilation lost), platelet dysfunction (reversible). Enteric-coated formulations; PPIs co-prescription if high GI risk.
Selective COX-2 inhibitors (coxibs) — celecoxib, etoricoxib: spares gastric COX-1 → less GI toxicity; but ↑thrombotic risk (rofecoxib withdrawn 2004 — VIGOR trial: ×5 MI vs naproxen). Celecoxib has lowest cardiovascular risk among coxibs; appropriate in GI-high-risk patients with CV monitoring.
Prostaglandin analogues (therapeutic) — misoprostol (PGE₁, EP2/3/4): gastric ulcer prophylaxis with NSAIDs, cervical ripening, medical abortion (with mifepristone); alprostadil (PGE₁): erectile dysfunction (intracavernosal), ductal-dependent CHD (IV to maintain PDA); latanoprost/bimatoprost (PGF₂α FP agonists): lower IOP in glaucoma via uveoscleral outflow; epoprostenol/iloprost (PGI₂ analogues): pulmonary arterial hypertension (vasodilation, anti-proliferative).
Pathology
| Condition | Prostanoid involvement | Mechanism |
|---|---|---|
| NSAID-induced peptic ulcer | ↓COX-1 PGE₂/PGI₂ | Loss of mucosal cytoprotection → parietal cell HCl unopposed → erosions; risk: elderly, H. pylori, prior ulcer |
| Aspirin-exacerbated respiratory disease (AERD) | COX-1 blocked → AA shunted to 5-LOX → excess LTC₄ | Samter's triad: nasal polyposis, asthma, aspirin/NSAID sensitivity; bronchoconstriction via cysteinyl leukotrienes; treat with montelukast + aspirin desensitisation |
| Bartter syndrome type I | Excess PGE₂ (COX-2 activated by NKCC2 dysfunction) | Hypokalaemia, metabolic alkalosis, elevated renin/aldosterone; indomethacin suppresses PGE₂ → corrects hypokalaemia partially |
| Colorectal cancer | COX-2 overexpression → PGE₂ → EP4 → Wnt/β-catenin, immunosuppression | Regular aspirin use associated with 20–30% reduction in CRC risk (epidemiological); COX-2 inhibitors trial ongoing (CaPP3) |
| Pulmonary arterial hypertension | ↓PGI₂ (PGIS mutations or endothelial dysfunction) | Loss of anti-proliferative, vasodilatory PGI₂ → right heart afterload ↑; prostacyclin analogues (epoprostenol, treprostinil) are first-line PAH therapy |
| Pre-eclampsia | TXA₂/PGI₂ imbalance | Placental trophoblast hypoxia → ↑TXA₂ / ↓PGI₂ → vasoconstriction, platelet aggregation, reduced placental blood flow; low-dose aspirin from 12 weeks is primary prophylaxis in high-risk women |
Connections
Prostaglandins are upstream modulators of nitric oxide (PGI₂ and eNOS cooperate to maintain endothelial vasodilation; PGE₂ can induce iNOS in macrophages), vasopressin (PGE₂ at EP3R on collecting duct antagonises V2R-cAMP → natriuresis), fibrinogen/coagulation (TXA₂ drives platelet aggregation, a key trigger for coagulation cascade), and glucocorticoids (cortisol suppresses cPLA₂α and COX-2 — the rationale for corticosteroid anti-inflammatory potency exceeding NSAIDs).
References
- Smith WL, DeWitt DL, Garavito RM (2000). Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182.
- Vane JR (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 231:232–235.
- Patrono C et al. (2017). Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th ed.). Chest 141:e89S–119S.
- Smyth EM, Grosser T, FitzGerald GA (2009). Prostanoids in health and disease. J Lipid Res 50(Suppl):S423–S428.
- Warner TD, Mitchell JA (2004). Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 18:790–804.
- Ricciotti E, FitzGerald GA (2011). Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986–1000.
- Aspirin Collaborative Group (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy. BMJ 324:71–86.