Chemical Mediators of Inflammation
Sources • receptors • vascular effects • leukocyte recruitment • fever and pain • complement • resolution • therapeutic targets
Chemical mediators are short-lived signals that initiate, amplify, coordinate and terminate inflammation. They arise from plasma proteins or activated cells and act locally or systemically. Some are preformed and act within seconds; others are synthesised after stimulation and persist longer. The final response depends on the balance between pro-inflammatory and pro-resolution mediators.
Learning outcomes
- Classify mediators as cell-derived or plasma-derived and preformed or newly synthesised.
- Explain the actions of histamine, serotonin, eicosanoids, platelet-activating factor, cytokines, chemokines, complement, kinins, nitric oxide, ROS and lysosomal enzymes.
- Link mediators to redness, swelling, pain, fever, bronchospasm, leukocyte recruitment and shock.
- Describe inactivation and checks that prevent uncontrolled inflammation.
- Map common emergency treatments to mediator pathways without confusing mechanism with diagnosis.
1. Classification
| Category | Examples | Typical timing |
|---|---|---|
| Cell-derived, preformed | Histamine, serotonin, lysosomal enzymes. | Seconds to minutes. |
| Cell-derived, newly synthesised | Prostaglandins, leukotrienes, PAF, cytokines, chemokines, NO. | Minutes to hours. |
| Plasma-derived | Complement, kinins, coagulation/fibrinolytic products. | Rapidly activated by cascades. |
| Pro-resolution | Lipoxins, resolvins, protectins, maresins, IL-10, TGF-β. | Later termination and repair. |
2. Histamine
Histamine is stored mainly in mast-cell granules and also in basophils and platelets. It is released by IgE cross-linking, complement C3a/C5a, neuropeptides, physical injury and some drugs.
| Receptor/effect | Inflammatory result |
|---|---|
| H1 on endothelium | Venular contraction, permeability, itching and bronchoconstriction. |
| H1 on smooth muscle/nerves | Urticaria, pain and bronchospasm. |
| H2 | Vasodilation and gastric acid secretion; modulates immune cells. |
Histamine is rapidly degraded by methyltransferase and diamine oxidase. Antihistamines block H1 effects but do not reverse the hypotension or airway compromise of anaphylaxis; adrenaline remains first-line.
3. Serotonin
Serotonin is stored in platelets and enterochromaffin cells. Platelet activation, tissue injury and some neuroendocrine tumours release it. It can increase vascular tone or permeability and contribute to pain, nausea and bronchial effects. Its role is generally less dominant than histamine in acute inflammation.
4. Eicosanoids
Membrane phospholipids are converted by phospholipase A2 to arachidonic acid. Cyclo-oxygenase (COX-1/COX-2) produces prostaglandins and thromboxane; 5-lipoxygenase produces leukotrienes. Aspirin and NSAIDs inhibit COX; glucocorticoids reduce phospholipase A2 activity and COX-2 expression.
| Mediator | Main source/action | Clinical relevance |
|---|---|---|
| PGE2 | Vasodilation, pain sensitisation and fever through hypothalamic set-point change. | Fever, pain, dysmenorrhoea; reduced by NSAIDs. |
| PGI2 (prostacyclin) | Endothelial vasodilation and inhibition of platelet aggregation. | Balances thromboxane; vascular protection. |
| TXA2 | Platelet aggregation and vasoconstriction. | Thrombosis and platelet haemostasis. |
| LTB4 | Potent neutrophil chemotaxis and activation. | Airway inflammation and leukocyte recruitment. |
| LTC4, LTD4, LTE4 | Bronchoconstriction, increased permeability and mucus secretion. | Asthma and anaphylaxis. |
| Lipoxins | Inhibit neutrophil recruitment and promote resolution. | Endogenous anti-inflammatory pathway. |
5. Platelet-activating factor (PAF)
PAF is produced by platelets, leukocytes, endothelium and mast cells. It increases platelet aggregation, leukocyte adhesion, chemotaxis, degranulation, bronchoconstriction and vascular permeability. At high concentrations it causes vasodilation, hypotension and shock. It amplifies histamine, eicosanoid and cytokine responses.
6. Cytokines
| Cytokine | Main source | Major effects |
|---|---|---|
| TNF | Macrophages, T cells, mast cells. | Endothelial activation, fever, leukocyte recruitment, cachexia and shock. |
| IL-1 | Macrophages, endothelium. | Fever, endothelial adhesion molecules and acute-phase response. |
| IL-6 | Macrophages, T cells, endothelium. | CRP/fibrinogen production, fever and B-cell support. |
| IL-8/CXCL8 | Macrophages, endothelium. | Neutrophil chemotaxis and activation. |
| IL-12 | Dendritic cells, macrophages. | NK/T-cell IFN-γ response against intracellular organisms. |
| IFN-γ | Th1 cells, NK cells. | Macrophage activation and granulomatous immunity. |
| IL-17 | Th17 cells. | Neutrophil recruitment and mucosal defence. |
| IL-10 | Macrophages, T regulatory cells. | Suppresses inflammatory cytokines and supports resolution. |
7. Chemokines
Chemokines are small chemotactic cytokines. Endothelial and stromal chemokines create gradients that direct leukocytes to tissue. Different chemokines select different cells.
- CXCL8/IL-8: neutrophils.
- CCL2/MCP-1: monocytes.
- CCL11/eotaxin: eosinophils.
- CXCL13: B-cell and follicular organisation.
- CCL19/CCL21: lymphocyte and dendritic-cell trafficking.
8. Complement mediators
| Component | Function |
|---|---|
| C3a, C5a | Anaphylatoxins; mast-cell degranulation and vascular permeability. |
| C5a | Powerful leukocyte chemoattractant and activator; increases adhesion and ROS. |
| C3b/iC3b | Opsonisation for phagocytosis. |
| C5b–9 | Membrane attack complex; lysis of susceptible microbes and cells. |
Complement is regulated by soluble and membrane inhibitors. Deficiency predisposes to infection or immune disease; excessive activation contributes to sepsis, vasculitis and reperfusion injury.
9. Kinins and coagulation-linked mediators
Bradykinin
Bradykinin is generated from high-molecular-weight kininogen by kallikrein. It causes pain, vasodilation, increased permeability and bronchial smooth-muscle contraction. ACE degrades bradykinin; ACE inhibitors can produce cough and, rarely, life-threatening angioedema.
Coagulation and fibrinolysis
Thrombin activates platelets, endothelium and protease-activated receptors. Fibrin contains infection but can organise into scar. Plasmin degrades fibrin and can activate complement and inflammatory mediators. In sepsis, dysregulated coagulation creates microthrombi and bleeding simultaneously.
10. Nitric oxide
Endothelial NOS produces NO for physiologic vasodilation; inducible NOS in macrophages and other cells produces larger amounts during inflammation. NO kills microbes and relaxes smooth muscle, but excess NO contributes to vasoplegia and septic shock. Reactive nitrogen species can combine with superoxide to form peroxynitrite.
11. Reactive oxygen species and lysosomal enzymes
Neutrophils and macrophages use ROS and lysosomal enzymes to kill organisms. Extracellular release damages host tissue.
- ROS: superoxide, hydrogen peroxide, hydroxyl radical and hypochlorous acid.
- Enzymes: elastase, collagenase, cathepsins, phospholipases and matrix metalloproteinases.
- Protection: catalase, superoxide dismutase, glutathione, alpha-1-antitrypsin and tissue inhibitors of metalloproteinases.
12. Neuropeptides and alarmins
Substance P, CGRP and other neuropeptides increase vasodilation, permeability and pain. ATP, HMGB1, mitochondrial DNA and heat-shock proteins act as alarmins/DAMPs. Their release links nerve activation, tissue damage and innate immunity.
13. Pro-resolution mediators
| Mediator | Resolution function |
|---|---|
| Lipoxins | Stop neutrophil recruitment and promote efferocytosis. |
| Resolvins/protectins/maresins | Reduce leukocyte infiltration, enhance debris clearance and restore barrier function. |
| IL-10 | Suppresses macrophage and dendritic-cell inflammatory cytokines. |
| TGF-β | Limits inflammation and stimulates repair/fibrosis. |
| Adenosine | Dampens leukocyte activation and promotes vascular regulation. |
14. Mediator inactivation and checks
- Short half-lives and rapid enzymatic degradation.
- Antioxidants and protease inhibitors neutralise damaging products.
- Complement regulators prevent runaway cascade activation.
- Endothelial barrier repair limits ongoing leak.
- Neutrophil apoptosis and macrophage efferocytosis terminate cellular injury.
- Lymphatic drainage removes fluid, proteins and cells.
15. Drug–mediator connections
| Drug/class | Mediator pathway affected | Important clinical point |
|---|---|---|
| H1 antihistamines | Block histamine H1 effects. | Relieve itch/urticaria; not a substitute for adrenaline in anaphylaxis. |
| NSAIDs | Inhibit COX and prostaglandin synthesis. | Analgesia/antipyresis; GI, renal and cardiovascular risks. |
| Corticosteroids | Suppress cytokines, phospholipase A2 and COX-2 induction. | Useful in selected immune/allergic disease; infection and metabolic risks. |
| Leukotriene modifiers | Block CysLT receptors or 5-lipoxygenase. | Asthma/allergic airway disease; not for immediate anaphylaxis. |
| ACE inhibitors | Reduce bradykinin breakdown. | Cough/angioedema; airway emergency requires urgent support. |
| Anti-TNF/IL therapies | Neutralise specific cytokines. | Chronic inflammatory diseases; screen for infection and monitor risk. |
| Adrenaline | Alpha/beta effects counter histamine, PAF and leukotriene physiology. | First-line for anaphylaxis. |
16. Applied cases
Anaphylaxis
Histamine, leukotrienes, PAF and bradykinin-like vascular effects produce oedema, bronchospasm and shock. Give IM adrenaline promptly and support airway/breathing/circulation.
Septic shock
TNF, IL-1, IL-6, NO, complement, coagulation and DAMPs combine to cause vasodilation, leak, microthrombi and organ dysfunction. Treat infection/source and support perfusion.
NSAID-sensitive asthma
COX inhibition can shunt arachidonic acid toward leukotrienes in susceptible patients, causing bronchospasm. Ask about asthma and previous reactions; treat acute bronchospasm urgently.
17. Quick self-test
- Which mediator causes rapid venular permeability?
Answer: Histamine. - Which eicosanoid causes neutrophil chemotaxis?
Answer: LTB4. - Which complement fragment is a potent chemoattractant?
Answer: C5a. - What causes fever and acute-phase responses?
Answer: Cytokines, especially IL-1, TNF and IL-6, acting through prostaglandins and the liver. - Why can excess NO cause shock?
Answer: It produces profound vasodilation and vascular hyporesponsiveness. - Which mediator is linked to ACE-inhibitor angioedema?
Answer: Bradykinin. - Name two pro-resolution mediators.
Answer: Lipoxins, resolvins, protectins, maresins, IL-10 or TGF-β. - Why are antihistamines not enough in anaphylaxis?
Answer: They do not rapidly reverse bronchospasm, vasodilation and shock; adrenaline is required.
18. Take-home summary
- Mediators may be cell-derived or plasma-derived, preformed or newly synthesised, pro-inflammatory or pro-resolution.
- Histamine, eicosanoids, cytokines, chemokines, complement, kinins, PAF, NO, ROS and enzymes coordinate vascular and cellular events.
- Excess mediator activity causes pain, oedema, bronchospasm, thrombosis, tissue injury and shock.
- Resolution requires mediator decay, efferocytosis, lymphatic drainage and pro-resolution signals.
- Drugs should be matched to the clinical syndrome: adrenaline for anaphylaxis, antimicrobials/source control for infection, and selective anti-inflammatory therapy when indicated.
Selected references
- NCBI Bookshelf: Acute Inflammation
- NCBI Bookshelf: Inflammation and Repair
- NCBI Bookshelf: Anaphylaxis
- NCBI Bookshelf: Sepsis and Septic Shock
Educational note: This resource supports learning and clinical reasoning. Current local protocols, senior supervision and national guidelines take precedence in patient care.
