What are the major cell derived mediators of Inflammation? Describe their role in acute Inflammation.

Major Cell-Derived Mediators of Inflammation

Cell-derived mediators are crucial signaling molecules that orchestrate the inflammatory response. They are produced by various cells, including immune cells (mast cells, macrophages, neutrophils, lymphocytes) and tissue resident cells. These mediators can act locally or systemically, influencing vascular permeability, leukocyte recruitment, and other aspects of inflammation.

1. Vasoactive Amines

• Histamine: Primarily stored in mast cells and basophils, histamine is released upon cell activation. It causes vasodilation, increasing vascular permeability, and contributes to edema. It also induces bronchoconstriction and can cause pain.
• Serotonin: Found in platelets and enterochromaffin cells, serotonin also causes vasoconstriction (initially) followed by vasodilation, increasing vascular permeability. It plays a role in pain sensation.

2. Eicosanoids

Eicosanoids are lipid mediators derived from arachidonic acid metabolism. They are potent signaling molecules with diverse effects on inflammation.

• Prostaglandins (PGs): Synthesized by cyclooxygenase (COX) enzymes (COX-1 and COX-2), PGs mediate vasodilation, pain, and fever. Different PGs have distinct effects; for example, PGE2 is a major mediator of inflammation and pain, while PGI2 inhibits platelet aggregation.
• Leukotrienes (LTs): Produced by lipoxygenase (LOX) enzymes, LTs are potent chemoattractants for neutrophils and other leukocytes. LTB4 is particularly important in neutrophil recruitment. LTs also cause increased vascular permeability and bronchoconstriction.
• Lipoxins: Generated from arachidonic acid, lipoxins have anti-inflammatory effects, inhibiting neutrophil chemotaxis and adhesion.

3. Cytokines

Cytokines are small proteins secreted by immune cells that regulate immune responses. They play a central role in both initiating and amplifying inflammation.

• Tumor Necrosis Factor-alpha (TNF-α): Produced by macrophages and T cells, TNF-α induces endothelial cell activation, increasing expression of adhesion molecules. It also promotes leukocyte recruitment and systemic effects like fever and cachexia.
• Interleukin-1 (IL-1): Similar to TNF-α, IL-1 is a potent pro-inflammatory cytokine that induces endothelial activation, fever, and acute phase protein synthesis by the liver.
• Interleukin-6 (IL-6): IL-6 stimulates acute phase protein production and B cell differentiation.
• Chemokines: A family of chemoattractant cytokines that guide leukocyte migration to sites of inflammation. Examples include CXCL8 (IL-8) which attracts neutrophils.

4. Platelet-Activating Factor (PAF)

PAF is a phospholipid mediator produced by various cells, including leukocytes and endothelial cells. It causes platelet aggregation, vasodilation, increased vascular permeability, and leukocyte activation. It is a potent mediator of anaphylaxis and acute inflammation.

Role in Acute Inflammation

These mediators work in concert to orchestrate the events of acute inflammation:

• Vascular Changes: Vasoactive amines (histamine, serotonin) and eicosanoids (prostaglandins) induce vasodilation and increased vascular permeability, leading to redness, heat, and swelling.
• Cellular Events: Cytokines (TNF-α, IL-1) and chemokines promote leukocyte recruitment from the bloodstream to the site of inflammation. Leukotrienes enhance neutrophil chemotaxis.
• Systemic Effects: Cytokines (TNF-α, IL-1, IL-6) induce systemic effects like fever, acute phase protein synthesis, and leukocytosis.

Mediator	Source	Primary Effects in Acute Inflammation
Histamine	Mast cells, Basophils	Vasodilation, increased vascular permeability
Prostaglandins	Macrophages, other cells	Vasodilation, pain, fever
Leukotrienes	Neutrophils, other cells	Neutrophil chemotaxis, increased vascular permeability
TNF-α	Macrophages, T cells	Endothelial activation, leukocyte recruitment, systemic effects
IL-1	Macrophages, other cells	Endothelial activation, fever, acute phase protein synthesis