Chemical Mediators of Inflammation

Where mediators come from

Cell-derived mediators. Some are preformed and stored in granules, ready for release within seconds (histamine in mast cells, serotonin in platelets). Others are synthesized on demand after a stimulus: prostaglandins, leukotrienes, platelet-activating factor (PAF), nitric oxide (NO), and cytokines.

Plasma-derived mediators. Kinins, complement proteins, and clotting factors are made by the liver and circulate as inactive precursors; proteolytic cascades switch them on at the site of injury. Most mediators, of either origin, are short-lived: they decay, are degraded by enzymes, or are neutralized by inhibitors, which keeps inflammation local and limited.

Vasoactive amines

Histamine. Stored in mast cells (the richest source), basophils, and platelets. Release is triggered by IgE cross-linking on mast cells, the anaphylatoxins C3a and C5a, physical injury (trauma, cold, heat), neuropeptides such as substance P, and cytokines. Acting on H1 receptors, histamine dilates arterioles and makes endothelial cells of postcapillary venules contract, opening interendothelial gaps. This is the classic immediate, transient phase of increased permeability: it begins within minutes and fades in about 15–30 minutes.

Serotonin. The second vasoactive amine is stored in platelet dense granules and in enterochromaffin cells of the gut; platelets release it when they aggregate.

Arachidonic acid metabolites

Release. Phospholipase A2 (PLA2), activated by rising cytosolic Ca²⁺ and kinase signaling, cleaves arachidonic acid, a 20-carbon polyunsaturated fatty acid, from membrane phospholipids. Cyclooxygenase (COX) then produces prostaglandins and thromboxane, while 5-lipoxygenase (5-LOX) produces leukotrienes. COX-1 is constitutive (gastric mucosa, platelets, kidney); COX-2 is induced at sites of inflammation.

Glucocorticoids work upstream of both pathways: they induce annexin A1 (lipocortin), which inhibits PLA2, and they suppress COX-2 transcription. NSAIDs block only COX, zileuton only 5-LOX, and montelukast and zafirlukast only the CysLT1 receptor.

PGI2 vs TXA2. Endothelial prostacyclin (PGI2) raises cAMP in smooth muscle, dilating vessels, and inhibits platelet aggregation. Platelet thromboxane A2, made via COX-1, signals through Gq and Ca²⁺ to constrict vessels and promote aggregation. Low-dose aspirin irreversibly acetylates COX-1; anucleate platelets cannot make new enzyme, so TXA2 stays off for their 7–10-day lifespan, whereas endothelial cells resynthesize COX and restore PGI2.

PGE2. Dilates arterioles and potentiates edema, sensitizes nociceptors (hyperalgesia), and raises the hypothalamic set point in fever. It also protects the gastric mucosa and dilates renal afferent arterioles, which is why NSAIDs cause ulcers and can reduce GFR. Together with PGI2 it keeps the fetal ductus arteriosus open: indomethacin or ibuprofen closes a patent ductus, whereas alprostadil (PGE1) keeps it open. Misoprostol and epoprostenol are other prostanoid agonists, not closers.

PGD2 and PGF2α. PGD2 is the main COX product of mast cells; it dilates vessels, increases venular permeability, constricts bronchi, and recruits eosinophils and Th2 cells. Niacin flushing is largely PGD2-mediated, so aspirin taken beforehand blunts it. PGF2α contracts uterine and bronchial smooth muscle and small arterioles, contributing to dysmenorrhea and labor.

Leukotrienes. 5-LOX converts arachidonic acid to LTA4, which neutrophils turn into LTB4. LTB4 is a potent neutrophil chemoattractant that also activates neutrophils and increases their adhesion to venular endothelium; the other major neutrophil chemotaxins are C5a, IL-8 (CXCL8), and bacterial N-formyl peptides. The cysteinyl leukotrienes LTC4, LTD4, and LTE4, the historic slow-reacting substance of anaphylaxis, cause intense bronchoconstriction, vasoconstriction, and venular leak, far more potently than histamine, and are central to asthma.

Aspirin-exacerbated respiratory disease: in patients with asthma and nasal polyps, COX inhibitors divert arachidonic acid into the 5-LOX pathway, and the surge of cysteinyl leukotrienes triggers bronchospasm.

Lipoxins and pro-resolving lipids. Lipoxins (LXA4, LXB4) are made transcellularly: platelet 12-lipoxygenase converts neutrophil-derived LTA4. They inhibit neutrophil chemotaxis and adhesion and promote macrophage clearance of apoptotic cells. With omega-3-derived resolvins and protectins, they actively end inflammation. Aspirin-acetylated COX-2 makes 15-epi-lipoxins (aspirin-triggered lipoxins).

Kinins, nitric oxide, and PAF

Bradykinin. Increases vascular permeability, dilates arterioles, contracts nonvascular smooth muscle, and causes pain. Activated factor XII also launches intrinsic clotting, fibrinolysis, and complement activation: one trigger, four systems.

Bradykinin excess causes angioedema without hives or itch. ACE inhibitors block its degradation (dry cough, swelling of lips, tongue, and airway). Hereditary angioedema, a deficiency of C1-esterase inhibitor, removes the brake on kallikrein and factor XIIa and also allows C4 consumption (low C4). Because histamine is not the driver, antihistamines work poorly.

Nitric oxide. Made from L-arginine by endothelial NOS (eNOS) and by inducible NOS (iNOS) in cytokine-activated macrophages. NO relaxes vascular smooth muscle through cGMP, reduces platelet and leukocyte adhesion, and helps kill microbes. Massive iNOS-derived NO contributes to the refractory vasodilation of septic shock.

Platelet-activating factor. A phospholipid mediator from platelets, mast cells, neutrophils, and endothelium. It aggregates platelets and constricts bronchi, and at tiny concentrations it dilates vessels and increases venular permeability far more potently than histamine.

Mediators behind the cardinal signs and fever

Fever. Exogenous pyrogens such as LPS stimulate macrophages to release IL-1, TNF, and IL-6. These cytokines induce COX-2 in hypothalamic vascular endothelium, and the resulting PGE2 raises cAMP and resets the thermoregulatory set point upward. NSAIDs and acetaminophen lower fever by blocking this PGE2 synthesis; acetaminophen is a good antipyretic and analgesic but has little anti-inflammatory effect in peripheral tissues.