Inflammation is a tightly regulated process driven by a variety of chemical mediators. These mediators act locally and systemically to produce vasodilation, increased vascular permeability, pain, and leukocyte recruitment.
Vasoactive Amines
- Histamine: Basophils, Mast cells, Platelets
- Action:
- Vasodilation (arterioles)
- ↑ Vascular permeability (venules)
- Triggers for Release –
- IgE-mediated mast cell reaction (allergy, anaphylaxis)
- Physical injury (trauma, cold, heat)
- Anaphylatoxins: C3a, C5a
- Cytokines: IL-1, IL-8
- 🩸 Key Point: Histamine acts mainly on H1 receptors on endothelial cells → causes endothelial contraction and leakage.
- Action:
- Serotonin: Platelets and some neuroendocrine cells
- Action
- Vasodilation
- ↑ Vascular permeability
- Action
⚡ Note: Serotonin functions similarly to histamine but is less potent in inflammation.
Kinin System
The Kinin system generates bradykinin, a powerful mediator of inflammation.
- Reaction
- Factor XII (Hageman factor) → activated form
- Converts prekallikrein → kallikrein
- Kallikrein cleaves high molecular weight kininogen (HMWK) → bradykinin
- Effects of Bradykinin
- ↑ Vascular permeability
- Vasodilation
- Pain (stimulates sensory nerve endings)
- Bronchoconstriction
Arachidonic Acid Metabolites (Eicosanoids)
Arachidonic acid (AA) is released from cell membranes by phospholipase A₂ and metabolized via two main pathways:
- Cyclooxygenase (COX) Pathway → Prostaglandins & Thromboxanes
- Thromboxane A₂ (TXA₂)
- Source: Platelets Vasoconstriction,
- Action: Platelet aggregation
- Prostacyclin (PGI₂)
- Source: Endothelium
- Action: Vasodilation, ↓ Platelet aggregation
- Prostaglandin E₂ (PGE₂)
- Various cells
- Action: Pain, Fever
- PGD₂, PGF₂α
- Source: Mast cells
- Action: Vasodilation, ↑ Vascular permeability
- Thromboxane A₂ (TXA₂)
- Lipoxygenase (LOX) Pathway → Leukotrienes & Lipoxins
- LTB₄
- Neutrophil chemotaxis (attracts and activates)
- LTC₄, LTD₄, LTE₄
- Vasoconstriction, Bronchospasm, ↑ Permeability
- Lipoxins (LXA₄, LXB₄)
- Anti-inflammatory; inhibits neutrophil recruitment
- LTB₄
⚖️ Balance: Leukotrienes promote inflammation, while lipoxins resolve it.
Complement System
Remember: Complement amplifies the inflammatory cascade. Activated complement fragments enhance vascular and cellular phases of inflammation.
| Component | Function |
|---|---|
| C3a, C5a | Anaphylatoxins → trigger histamine release → ↑ permeability |
| C5a | Chemotactic for neutrophils and monocytes |
| C3b | Opsonization → enhances phagocytosis |
| C5b–C9 | Membrane Attack Complex (MAC) → cell lysis |
Activity:
Cytokines
| Cytokine | Produced By | Function |
|---|---|---|
| IL-1, TNF-α | Macrophages | Fever, Acute phase protein production, Endothelial activation |
| IL-6 | Macrophages, T cells | Fever, Acute-phase response |
| IL-8 (CXCL8) | Macrophages | Neutrophil chemotaxis |
| IL-12, IFN-γ | Macrophages, NK cells | Activate macrophages and promote a Th1 response |
Activity:
Mediators of Fever
| Mediator | Mechanism |
|---|---|
| Cytokines: IL-1, IL-6, TNF-α | Stimulate prostaglandin synthesis in the hypothalamus |
| Prostaglandin E₂ (PGE₂) | Raises hypothalamic temperature set point |
Key Points to Remember
- Histamine and serotonin → early vascular changes
- Bradykinin → pain and permeability
- Prostaglandins → pain and fever
- Leukotrienes → bronchoconstriction and chemotaxis
- Complement → opsonization and lysis
- Cytokines → systemic inflammatory effects
Learning Objective
By the end of this topic, the student should be able to:
Identify the major chemical mediators of inflammation, their sources, and their primary actions on blood vessels, leukocytes, and tissues.
