Chemical mediator of inflammation from Robbins /notes form
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Robbins Basic Pathology chemical mediators of inflammation histamine eicosanoids cytokines complement
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https://pmc.ncbi.nlm.nih.gov/articles/PMC5993766
Chemical Mediators of Inflammation - Robbins Notes
Definition: Chemical mediators initiate, amplify, regulate, and terminate inflammatory reactions. They are produced locally at the site of inflammation or generated from plasma precursors.
General properties
- Cell-derived mediators
- Preformed and stored in granules: e.g., histamine
- Synthesized de novo after stimulation: e.g., prostaglandins, leukotrienes, cytokines
- Plasma-derived mediators
- Produced mainly in liver and circulate as inactive precursors.
- Activated by proteolytic cleavage at the inflammatory site: e.g., complement, kinins.
- Most mediators are short-lived and rapidly inactivated.
- One mediator may stimulate release of other mediators.
- Mediators can have harmful effects when excessive, including tissue injury.
Robbins & Kumar Basic Pathology, pp. 33-39.
1. Vasoactive amines
| Mediator | Main source | Important actions |
|---|---|---|
| Histamine | Mast cells, basophils, platelets | Arteriolar vasodilation; increased venular permeability by endothelial contraction; bronchoconstriction |
| Serotonin (5-HT) | Platelets, enterochromaffin cells | Vascular effects, less important than histamine in humans |
Histamine
- The principal mediator of the immediate transient increase in vascular permeability.
- Released by:
- Physical injury, heat, cold
- IgE-mediated mast-cell activation
- Anaphylatoxins C3a and C5a
- Neuropeptides such as substance P
- Some cytokines
- Acts mainly through H1 receptors on endothelial cells.
- Causes:
- Vasodilation
- Endothelial contraction, particularly in postcapillary venules
- Increased vascular permeability and edema
- Bronchoconstriction
2. Arachidonic acid metabolites (Eicosanoids)
Arachidonic acid is released from membrane phospholipids by phospholipase A2. It is metabolized through:
- Cyclooxygenase (COX) pathway: prostaglandins and thromboxane
- Lipoxygenase pathway: leukotrienes and lipoxins
A. Cyclooxygenase pathway
| Mediator | Major actions |
|---|---|
| PGI2 (Prostacyclin) | Vasodilation; inhibits platelet aggregation |
| PGE2 | Vasodilation; pain sensitization; fever |
| PGD2 | Vasodilation; increased vascular permeability |
| TXA2 (Thromboxane A2) | Vasoconstriction; promotes platelet aggregation |
B. Lipoxygenase pathway
| Mediator | Major actions |
|---|---|
| LTB4 | Powerful neutrophil chemotaxis; leukocyte activation; adhesion and ROS generation |
| LTC4, LTD4, LTE4 | Bronchospasm; vasoconstriction; increased vascular permeability |
| Lipoxins (LXA4, LXB4) | Inhibit neutrophil recruitment and adhesion, hence anti-inflammatory or pro-resolution action |
Pharmacologic correlation
- NSAIDs inhibit cyclooxygenase and therefore reduce prostaglandin formation.
- Glucocorticoids inhibit phospholipase A2 activity and suppress transcription of COX-2, reducing both prostaglandins and leukotrienes.
- Leukotriene inhibitors are useful in bronchial asthma.
3. Cytokines and chemokines
A. TNF and IL-1
Main source: Activated macrophages, dendritic cells, mast cells, endothelial cells, and some lymphocytes.
Local actions
- Endothelial activation:
- Increased expression of adhesion molecules
- Promotes leukocyte recruitment
- Increased production of chemokines and other cytokines
- Increased procoagulant activity of endothelium
Systemic actions
- Fever
- Acute-phase protein production by liver
- Leukocytosis
- In severe infection: hypotension, disseminated intravascular coagulation, metabolic derangements, septic shock
B. Chemokines
- Small cytokines that direct leukocyte migration.
- Major functions:
- Chemotaxis
- Activation of leukocytes
- Increased affinity of leukocyte integrins
- Examples:
- CXCL8 / IL-8: recruits neutrophils
- CCL2 / MCP-1: recruits monocytes
- Eotaxin: recruits eosinophils
C. Other cytokines
- IL-6: acute-phase response and fever.
- IL-17: recruits neutrophils and monocytes.
- IFN-gamma: activates macrophages.
- IL-10 and TGF-beta: anti-inflammatory effects.
4. Complement system
Activated by:
- Classical pathway: antigen-antibody complexes
- Alternative pathway: microbial surfaces
- Lectin pathway: microbial carbohydrates
| Complement product | Main action |
|---|---|
| C3a, C5a | Anaphylatoxins: histamine release from mast cells, vasodilation, increased vascular permeability |
| C5a | Strong chemotactic factor for neutrophils, monocytes, eosinophils; leukocyte activation |
| C3b | Opsonization and enhanced phagocytosis |
| C5b-C9 | Membrane attack complex: lysis of microbes/cells |
High-yield:
- C3a and C5a = anaphylatoxins
- C5a = chemotaxis
- C3b = opsonization
- C5b-9 = cell lysis
5. Kinin system
Bradykinin
Formed from high-molecular-weight kininogen by kallikrein.
Actions
- Vasodilation
- Increased vascular permeability
- Bronchoconstriction
- Pain
Inactivated by: kininases, including angiotensin-converting enzyme (ACE).
This accounts for bradykinin accumulation and cough/angioedema in some patients receiving ACE inhibitors.
This accounts for bradykinin accumulation and cough/angioedema in some patients receiving ACE inhibitors.
6. Platelet-activating factor (PAF)
Sources: Platelets, mast cells, basophils, neutrophils, macrophages, and endothelial cells.
Actions
- Platelet aggregation
- Vasoconstriction and bronchoconstriction
- At low concentration: vasodilation and increased vascular permeability
- Leukocyte adhesion, chemotaxis, degranulation, and oxidative burst
7. Nitric oxide (NO)
Sources
- Endothelial cells: endothelial nitric oxide synthase, eNOS
- Activated macrophages: inducible nitric oxide synthase, iNOS
Actions
- Vasodilation
- Inhibits platelet aggregation and adhesion
- Reduces leukocyte recruitment
- Macrophage-derived NO contributes to microbial killing
8. Reactive oxygen species and lysosomal enzymes
| Mediator | Source | Action |
|---|---|---|
| Reactive oxygen species | Neutrophils, macrophages | Kill microbes; can damage host tissue |
| Lysosomal proteases | Neutrophils, macrophages | Degrade microbes and extracellular matrix; may cause tissue injury if released extracellularly |
- Antioxidants and antiproteases limit host injury.
- Examples: superoxide dismutase, catalase, ceruloplasmin, alpha-1 antitrypsin.
9. Neuropeptides
Example: Substance P
Actions
- Pain transmission
- Vasodilation
- Increased vascular permeability
- May promote histamine release
Rapid revision table
| Mediator | Key action |
|---|---|
| Histamine | Vasodilation, increased permeability |
| PGE2 | Pain, fever, vasodilation |
| PGI2 | Vasodilation, inhibits platelet aggregation |
| TXA2 | Vasoconstriction, platelet aggregation |
| LTB4 | Neutrophil chemotaxis and activation |
| LTC4/LTD4/LTE4 | Bronchospasm, permeability |
| Lipoxins | Inhibit neutrophil recruitment |
| TNF, IL-1 | Endothelial activation, fever, acute-phase response |
| IL-8 | Neutrophil chemotaxis |
| C3a, C5a | Anaphylatoxins |
| C5a | Chemotaxis |
| C3b | Opsonization |
| C5b-9 | Cell lysis |
| Bradykinin | Pain, permeability, vasodilation |
| NO | Vasodilation, microbicidal activity |
| PAF | Platelet activation, leukocyte activation |
Mnemonic:
“HISTamine makes vessels LEAK; PGE2 gives Pain and Pyrexia; LTB4 Leads leukocytes; C3b Coats bacteria; C5a Calls leukocytes.”
“HISTamine makes vessels LEAK; PGE2 gives Pain and Pyrexia; LTB4 Leads leukocytes; C3b Coats bacteria; C5a Calls leukocytes.”
Source: Robbins & Kumar Basic Pathology, “Mediators of Inflammation,” pp. 33-39.
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