1. Chemical Mediators
Dr Shoaib Raza

2. Chemical Mediators
Mediators are generated either from cells or plasma proteins
Platelets, neutrophil, monocytes/macrophages, mast cells, mesenchymal and epithelial cells
Proteins are mainly produced in the liver
Active mediators are produced in response to various stimuli
One mediator can stimulate the release of other mediators
Mediators vary in their range of cellular targets
Most mediators are short lived, once they are activated or released from the cells

3. Vasoactive Amines Histamine & Serotonin Stimuli are
Stored as preformed molecules in cells
Mast cell are the richest source of histamine
Also present in basophils, and platelets
Richest source of serotonin is platelet
Stimuli are
Physical injury, trauma, heat, cold etc
Binding of antibodies to mast cells
C3a and C5a (anaphylatoxins)
Histamine releasing protein derived from leukocytes
Neuropeptides (substance P)
Cytokines (IL-1, IL-8)

4. Functions of Histamine & Serotonin
Vasodilation of arterioles
Increases permeability of venules
Immediate transient phase of increased vascular permeability
Producing inter-endothelial gaps
Release of serotonin from platelets is stimulated after their aggregation
Platelet release reaction
Also results in increased vascular permeability

5. Arachidonic Acid Metabolites
AA is a 20-carbon polyunsaturated fatty acid (eicosatetraenoic acid) formed from essential fatty acids
Usually esterified in the membrane phospholipids
Mechanical, physical and chemical stimuli (mediators) release AA from membrane phospholipid through phospholipase A2.
AA derived mediators also called as eicosanoids
Two major classes/pathways
Lipoxygenase pathway
Cyclooxygenase pathway
They can mediate virtually every step of inflammation

8. Prostaglandins and Leukotrienes
Produced by mast cells, Mac, endothelial cells, and many other cell types
Divided into series based on structural features as coded by a letter (e.g. PGD, PGE, PGF, PGG, PGH) and a subscript numeral (e.g. 1,2), which indicates the number of double bond .
The most important PGs are
PGE2, PGD2, PGF2α, PGI2 (prostacyclin), and TxA2 (Thromboxane)
Vasodilation: PGI2, PGE1, PGE2, PGD2
Vasoconstriction: TxA2, LTC4, LTD4, LTE4
Increased vascular permeability: Leukotrienes C4, D4, E4,
Chemotaxis, leukocyte adhesion: LTB4, HETE
Bronchoconstriction: LTC4, LTD4, LTE4
Inhibition of platelet aggregation: PGI2
Platelet aggregation: TxA2

9. Platelet Activating Factor (PAF)
Phospholipid derived mediator
Released from mast cells, platelets, basophil, neutrophil, Mac, endothelium, etc
Causes
Platelet aggregation
Vasoconstriction
Bronchoconstriction
Increased leukocyte adhesion to endothelial cells
Chemotaxis
Degranulation
Oxidative burst
Boos the synthesis of other mediators, particularly eicosanoids

10. Reactive Oxygen Species
Released extracellularly from activated leukocytes
May cause
Endothelial cell damage
Injury to other cell types
Inactivation of antiproteases, e.g. α-1 antitrypsin, increases destruction of extracellular matrix
Antioxidants:
Superoxide dismutase
Catalase
Glutathione peroxidase
Ceruloplasmin
Transferrin

11. Nitric Oxide Has dual action in inflammation Promotes vasodilation
Inhibitor of cellular components of inflammation
Reduces platelet aggregation
Inhibits mast cell induced inflammation
Inhibits leukocyte recruitment
Thought to be an endogenous mechanism for controlling inflammatory response

12. Cytokines and Chemokines
Proteins produced by many cell types that modulate the function of other cell types
Activated lymphocytes, Mac, endothelial cells, epithelial and CT cells
TNF (Mac, mast cells, T cells)
↑ expression of adhesion molecules on endothelial cells
↑ secretion of other cytokines
Systemic effects
IL-1 (Mac, Endothelial cells)
Similar to TNF, greater role in fever
IL-6 (Mac)
Systemic effects (acute phase reaction)
Chemokines (Mac, EC, MC, T-cells)
Recruitment of leukocytes at site of inflammation
Migration of cells to normal tissues

14. Complement System Plasma protein derived mediators
More than 20 proteins are included, synthesized in the liver
Numbered from C1 to C9
Present in the inactive form
Activated by:
Classical pathway
Alternate pathway
Lectin pathway

16. Functions of Complement System
Inflammation
C3a, C5a, C4a: (Anaphylatoxins)
Stimulate histamine release from mast cells
Vasodilation and increased vascular permeability
C5a:
Chemotactic agent for neutrophil, eosinophil, monocyte, basophil
Activates lipoxygenase pathway
Phagocytosis
C3b:
Opsonization
Cell Lysis:
C3b-C9 (Membrane Attack Complex)
Deposition of MAC to cell surface makes it more permeable to water and ion, result in lysis of membrane and cell death

17. Coagulation and Kinin Systems
Inflammation and blood clotting are often intertwined
Thrombin:
Promotes inflammation by engaging with receptors
Mobilization of P-selectins
Cytokine production from endothelial cells
Expression of ELAM-1
Prostaglandin synthesis by cyclooxygenase pathway
Production of PAF & NO
Kinins
Vasoactive peptides
Bradykinin increases vascular permeability, bronchoconstriction, pain
kallikrein causes chemotaxis, converts C5 to C5a

18. Role of mediators in different reactions of inflammation
Role in inflammation
Mediators
Vasodilation
PGD2, E2, F2α, I2, NO, Histamine
Increased vascular permeability
Histamine, Serotonin, C3a & C5a, Bradykinin, LT C4, D4, E4, PAF
Chemotaxis, leukocyte recruitment & activation
TNF, IL-1, IL-8, C3a & C5a, LTB4, Bacterial products,
Fever
IL-1, IL-6, TNF, PGE2
Pain
PGE2, Bradykinin
Tissue Damage
Lysosomal enzymes of leukocytes, ROS, NO