Pathology chapters
Chemical mediators and arachidonic acid metabolites
The main chemical mediators of inflammation (histamine, prostaglandins, leukotrienes, cytokines, complement, kinins and others), where they come from and what they do, with the arachidonic acid pathways and the drugs that block them.
- Histamine (from mast cells) is the first mediator, causing vasodilation and increased venular permeability.
- Arachidonic acid (released by phospholipase A2) is turned by cyclo-oxygenase into prostaglandins and thromboxane and by 5-lipoxygenase into leukotrienes: PGE2 causes pain and fever, TXA2 aggregates platelets, PGI2 inhibits them, LTB4 attracts neutrophils, and LTC4/D4/E4 constrict bronchi.
- TNF and IL-1 drive fever and the acute-phase response; complement C3a/C5a release histamine (anaphylatoxins), C5a attracts cells, C3b opsonises; bradykinin causes pain.
On this page
Overview
The events of inflammation (vasodilation, leakage, cell recruitment, pain and fever) are driven by chemical mediators. They come from cells (preformed or newly made) or from plasma proteins (activated in the blood). Most act briefly and are quickly broken down, which keeps inflammation under control.
Cell-derived mediators
Vasoactive amines
| Mediator | Source | Actions |
|---|---|---|
| Histamine | Mast cells (main), basophils, platelets; preformed | Arteriolar dilation, increased venular permeability; bronchoconstriction; the first mediator released |
| Serotonin (5-HT) | Platelets, enterochromaffin cells | Similar to histamine; vasoconstriction in some vessels |
Mast cells release histamine in response to injury (heat, trauma), IgE cross-linking (allergy), anaphylatoxins (C3a, C5a) and some drugs.
Arachidonic acid metabolites (eicosanoids)
Arachidonic acid is a fatty acid in cell membrane phospholipids. It is released by phospholipase A2, then follows two main pathways:
1. Cyclo-oxygenase (COX) pathway (COX-1 and COX-2):
| Product | Main source | Actions |
|---|---|---|
| PGE2 | Many cells | Vasodilation, pain (sensitises nerve endings), fever |
| PGD2 | Mast cells | Vasodilation, permeability; bronchoconstriction |
| PGI2 (prostacyclin) | Endothelium | Vasodilation, inhibits platelet aggregation |
| TXA2 (thromboxane A2) | Platelets | Vasoconstriction, platelet aggregation |
| PGF2α | Many | Uterine and bronchial contraction |
TXA2 (platelets) promotes clotting; PGI2 (endothelium) prevents it. Their balance keeps blood flowing.
2. Lipoxygenase pathway (5-lipoxygenase, in leucocytes):
| Product | Actions |
|---|---|
| LTB4 | Powerful chemotaxis and activation of neutrophils |
| LTC4, LTD4, LTE4 (cysteinyl leukotrienes) | Bronchospasm (much stronger than histamine), vasoconstriction, increased permeability; formerly called the slow-reacting substance of anaphylaxis |
| Lipoxins | Anti-inflammatory: inhibit neutrophil recruitment; help end inflammation |
LTB4 = chemotaxis. LTC4, D4, E4 = bronchospasm (asthma).
Drugs that act on the pathway
| Drug | Action |
|---|---|
| Corticosteroids | Reduce phospholipase A2 activity (via lipocortin/annexin) and COX-2 expression → less prostaglandin and leukotriene; broad anti-inflammatory effect |
| NSAIDs (aspirin, ibuprofen) | Block COX → less prostaglandin and thromboxane; reduce pain, fever and inflammation |
| Aspirin (low dose) | Irreversibly blocks platelet COX → less TXA2 → antiplatelet effect |
| COX-2 inhibitors (celecoxib) | Less stomach injury, but higher cardiovascular risk (less PGI2 while TXA2 continues) |
| Montelukast | Blocks the cysteinyl leukotriene receptor (asthma) |
| Zileuton | Blocks 5-lipoxygenase |
NSAIDs block COX, so more arachidonic acid may go down the lipoxygenase path, producing more leukotrienes; this is one explanation for aspirin-exacerbated asthma.
Cytokines
| Cytokine | Main actions |
|---|---|
| TNF and IL-1 | Activate endothelium (adhesion molecules), fever, acute-phase response, cachexia (TNF), leucocyte activation |
| IL-6 | Acute-phase proteins (CRP, fibrinogen) from the liver |
| Chemokines (IL-8 = CXCL8) | Chemotaxis (IL-8 attracts neutrophils) |
| IL-17 | Recruits neutrophils |
| Interferon-γ | Activates macrophages (chronic inflammation) |
Other cell-derived mediators
- Nitric oxide (NO): made by endothelium and macrophages; vasodilation, reduces platelet adhesion, kills microbes (in macrophages).
- Platelet-activating factor (PAF): platelet aggregation, vasoconstriction or dilation, bronchoconstriction, permeability.
- Reactive oxygen species and lysosomal enzymes from leucocytes: kill microbes but damage tissue.
- Neuropeptides (substance P): pain, permeability.
Plasma protein-derived mediators
Complement system
Activated by the classical (antibody), alternative (microbial surfaces) and lectin pathways, all meeting at C3.
| Component | Action |
|---|---|
| C3a, C5a | Anaphylatoxins: trigger histamine release from mast cells → vasodilation, permeability |
| C5a | Powerful chemotaxis of neutrophils; activates lipoxygenase |
| C3b | Opsonin: aids phagocytosis |
| C5b–C9 | Membrane attack complex (MAC): punches holes in microbes (especially Neisseria) |
Complement: C3a, C5a anaphylatoxins; C5a chemotaxis; C3b opsonin; C5–9 MAC. Deficiency of C5–C9 predisposes to recurrent Neisseria infections.
Kinin system
Bradykinin is formed from kininogen by kallikrein (activated by factor XII).
- Increases vascular permeability, causes vasodilation, contracts smooth muscle.
- Causes pain.
- Broken down by ACE (kininase II); this is why ACE inhibitors can cause cough and angioedema.
Clotting and fibrinolytic systems
- Thrombin activates endothelium and leucocytes (protease-activated receptors).
- Fibrin degradation products increase permeability.
- Factor XII (Hageman factor) links clotting, kinin, fibrinolysis and complement.
Summary by effect
| Effect | Main mediators |
|---|---|
| Vasodilation | Histamine, prostaglandins (PGE2, PGI2), nitric oxide |
| Increased permeability | Histamine, serotonin, C3a, C5a, bradykinin, LTC4/D4/E4, PAF |
| Chemotaxis | C5a, LTB4, IL-8, bacterial products |
| Fever | IL-1, TNF, IL-6, PGE2 |
| Pain | PGE2, bradykinin, substance P |
| Tissue damage | Lysosomal enzymes, reactive oxygen species, NO |
Expect: the first mediator (histamine) and its source, the COX and lipoxygenase products and their actions (TXA2 vs PGI2, LTB4 chemotaxis, LTC4/D4/E4 bronchospasm), the site of action of steroids vs NSAIDs, cytokines in fever, complement components and their roles, bradykinin and ACE inhibitors, and the summary table by effect.
Quick revision
- Histamine: first, from mast cells; vasodilation and venular permeability.
- Phospholipase A2 (blocked by steroids) → arachidonic acid.
- COX (blocked by NSAIDs): PGE2 (pain, fever), PGI2 (anti-aggregation), TXA2 (aggregation).
- Lipoxygenase: LTB4 (chemotaxis), LTC4/D4/E4 (bronchospasm); lipoxins anti-inflammatory.
- TNF, IL-1: fever, endothelial activation; IL-6: acute-phase proteins; IL-8: chemotaxis.
- Complement: C3a/C5a anaphylatoxins, C5a chemotaxis, C3b opsonin, C5–9 MAC.
- Bradykinin: pain, permeability; broken down by ACE.
Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
Which mediator is released first in acute inflammation?
Histamine, from mast cells.
What is the role of thromboxane A2?
It causes vasoconstriction and platelet aggregation.
Which mediators cause fever?
Cytokines IL-1 and TNF (and IL-6), which raise prostaglandin E2 in the hypothalamus.
How do corticosteroids reduce inflammation?
They reduce phospholipase A2 activity and COX-2 expression, lowering production of both prostaglandins and leukotrienes, among many other effects.