Inflammation is controlled by a wide range of chemicals released either from cells at the site of injury or from plasma. These chemical mediators start, control, amplify and eventually stop the inflammatory process. They can be harmful if released in excess.
Mediators come from two major sources:
- Plasma-derived mediators: Complement, kinins and clotting factors. They circulate as inactive precursors and require activation.
- Cell-derived mediators: Stored in granules (e.g., histamine) or synthesized freshly (e.g., prostaglandins).
1. Vasoactive Amines
a) Histamine
Stored in mast cells, basophils and platelets. It is one of the earliest mediators released.
Main actions:
- Vasodilation
- Increased vascular permeability
- Itching and pain
Stimuli for release:
- Physical injury (heat, trauma)
- IgE-mediated allergic reactions
- Complement fragments C3a and C5a
- Leukocyte-derived proteins
- Neuropeptides (substance P)
- Cytokines like IL-1 and IL-8
b) Serotonin
Found mainly in platelet granules. Its actions resemble histamine but are less potent. Released during platelet aggregation.
2. Neuropeptides
Small protein mediators (e.g., substance P) that regulate pain transmission, blood vessel tone and permeability. Prominent in nerves of lungs and gastrointestinal tract.
3. Platelet Activating Factor (PAF)
Released by basophils, mast cells, leukocytes, platelets and endothelial cells.
Roles in inflammation:
- Increases vascular permeability
- Causes vasodilation at low doses and vasoconstriction at high doses
- Bronchoconstriction
- Enhances leukocyte adhesion
- Acts as a chemotactic factor
4. Cytokines
Produced mainly by macrophages and lymphocytes (IL-1 to IL-10, TNF-α, IFN-γ). They coordinate and regulate inflammation.
Key functions:
- IL-1 and TNF-α: Activate leukocytes, stimulate B and T cell proliferation, increase natural killer cell activity.
- IL-1, IL-6, TNF-α: Cause fever and acute-phase response.
- Stimulate liver to produce acute-phase proteins (complement, coagulation factors).
- Increase intracellular calcium → activation of phospholipase A2.
- During chronic inflammation, promote fibroblast activation and release of enzymes causing cartilage and bone destruction.
5. Nitric Oxide (NO)
A free radical gas produced by endothelial cells, macrophages and some neurons. It acts as a signalling molecule.
Functions:
- Maintains normal vascular tone
- Causes vasodilation
- Prevents platelet aggregation
- High levels induced by cytokines enhance macrophage killing
- May contribute to joint damage in arthritis
6. Plasma-Derived Mediator Systems
Three major protein cascades—kinin system, clotting system and complement system—play major roles in inflammation.
a) Kinin, Clotting and Fibrinolytic System
Initiated by activation of the Hageman factor (Factor XII).
- Factor XII activates prekallikrein → kallikrein.
- Kallikrein converts kininogen → bradykinin.
Actions of Bradykinin:
- Increases vascular permeability
- Causes pain
- Contracts smooth muscle
Kallikrein also activates plasminogen, increasing permeability and vasodilation. Thrombin from the clotting pathway forms fibrin; split products from fibrin cause chemotaxis.
b) Complement System
Contains about 20 proteins synthesized in the liver. Activated by classical or alternative pathways, both forming the Membrane Attack Complex (MAC).
Major inflammatory actions:
- C3a, C5a: Cause histamine release and vasodilation
- C5a: Strong chemotactic factor
- C3b: Acts as a major opsonin—coats bacteria and enhances phagocytosis
- MAC: Causes lysis of microbes
c) Kinin System (Detailed)
Kinins like bradykinin cause:
- Intense vasodilation
- Increased permeability
- Pain
d) Clotting System
Activated during endothelial injury. Helps stop bleeding and generates peptides that contribute to permeability and chemotaxis.
Chemical Mediators Classified by Effect
Vasodilation:
- Histamine
- Nitric oxide
- Prostaglandins (PGI2, PGE2, PGD2)
Increased Vascular Permeability:
- Histamine
- C3a, C5a
- Bradykinin
- Reactive oxygen species
- Leukotrienes (LTC4, LTD4, LTE4)
- Platelet-activating factor
Chemotaxis:
- C5a
- Leukotrienes (LTB4, LTC4)
- TNF, IL-1, IL-8
- Bacterial products
Fever:
- IL-1, TNF, IL-6
- Prostaglandins
Pain:
- Bradykinin
- Substance P
- Prostaglandins
Tissue Damage:
- Reactive oxygen species
- Nitric oxide
- Lysosomal enzymes
Detailed Notes:
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