Mediators of Inflammation

Dr.Djumadi Achmad, SpPA(K)

 The two events of acute inflammation

1. Vascular changes
– Vasodilatation
– Increased vascular permeability
– Stasis
2. Cellular events
– Emigration of cells from microvessels
– Accumulation at sites of injury

The process is orchestrated by release of chemical

mediators

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 Mediators of Inflammation
 Substances that initiate and regulate inflammatory
reactions
 Many mediators have been identified and targeted
therapeutically to limit inflammation
 The most important mediators of acute inflammation are:
• Vasoactive amines,
• Lipid products (prostaglandins and leukotrienes),
• Cytokines (including chemokines),
• Products of complement activation
 General Principles of Mediator Production
and Actions
• Locally produced by cells or from plasma proteins
• Active mediators : only in response to various stimuli
• Most of the mediators are short-lived
• One mediator can stimulate the release of other
mediators
• One mediator can stimulate > 1 target cells or molecules
Vasoactive Amines (Histamine & Serotonin)

– Released by mast cells/basophils (histamine),

and platelets (serotonin) in response to
• injury (trauma, heat), immune reactions (IgE-mast cell
FcR), anaphylatoxins (C3a, C5a), cytokines (IL-1, IL-8),
neuropeptides (e.g., substance P)
– Cause arteriolar dilatation and increases
permeability (immediate phase reaction)
– Induce endothelial cell contraction in venules
– Binds to H1 receptors
– Inactivated by histaminase
 Arachidonic Acid Metabolites

• The lipid mediators prostaglandins and leukotrienes

• Present in membrane phospholipids
• Stimulate vascular and cellular reactions in acute
inflammation
 Arachidonic acid metabolites

 Cyclooxygenase pathway; Prostaglandins and thromboxan

 Lipoxygenase pathway: Leukotrienes
 Lipoxins :suppress inflammation by inhibiting the recruitment
of leukocytes ( inhibit neutrophilchemotaxis and adhesion to
endothelium)
 Inhibitors of Prostaglandins and Leukotrienes

1. Non-selective Cyclooxygenase inhibitors

• Aspirin, NSAID (e.g. Ibuprofen)
• Inhibit both COX-1 and COX-2
• Effective in treating pain and fever
2. Selective COX-2 inhibitors
• 200-300 fold more potent in blocking COX-2 than
COX-1
• No side effects of such as gastric ulceration
• Does not inhibit platelet production of TXA2 
promote vascular thrombosis
 Inhibitors of Prostaglandins and Leukotrienes

3. Lipoxygenase inhibitors
• (e.g., Zileuton) are useful in the treatment of asthma
4. Leukotriene receptor antagonists
• Prevent the actions of the leukotrienes
• (e.g., Montelukast) effective for treatment of asthma
5. Corticosteroids
• Broad-spectrum antiinflammatory agents
• Reduce the transcription of genes encoding COX-2,
phospholipase A2, proinflammatory cytokines (e.g.,
IL-l and TNF), and iNOS
Cyclooxygenase (COX) inhibitors
 Cytokines

• Cytokines are proteins produced by many cell types

(activated lymphocytes, macrophages, and dendritic
cells, endothelial, epithelial, and connective tissue cells)
• Mediate and regulate immune and inflammatory
reactions
• Chemokines are a family of small proteins (8 to 10 kD)
that act primarily as chemoattractants for specific types
of leukocytes
 Tumor Necrosis Factor (TNF) and lnterleukin-1 (IL-l)

• Promoting adhesion and migration of leukocytes

• Produced mainly by activated macrophages and dendritic cells
• TNF is also produced by T lymphocytes and mast cells
• IL-l is also produced by some epithelial cells
• The actions of TNF and IL-l :
– Endothelial activation  increased adhesion molecules (E- and P-
selectins and ligands for leukocyte integrins)
– increased production of cytokines and chemokines, growth factors,
and eicosanoids
– Activation of leukocytes and other cells
– Systemic acute-phase response
 Chemokines  four major groups :

1. C-X-C chemokines : IL-8

– Secreted by activated macrophages, endothelial cells, and other cell
under stimulation by microbial products, IL-l and TNF
– Action : chemotaxis and activation of neutrophils

2. C-C chemokines : chemotaxis for monocytes, eosinophils, basophils

and lymphocytes
– MCP-1 (monocyte chemoattractant protein-1)
– MIP-1α (macrophage inflammatory protein-1α)
– RANTES (regulated and normal T-cell expressed and secreted)
– Eotaxin : selectively recruits eosinophils
 Chemokines  four major groups :

3. C chemokines :
– e.g., lymphotactin are relatively specific for lymphocytes

4. CX3C chemokines : fractalkine  2 forms

– Cell surface-bound protein on endothelial cells : adhesion of
monocytes and T cells
– Soluble form, derived by proteolysis of the membrane-bound protein :
chemotasis for monocytes & T cells
Figure 3-11 Major roles of cytokines in acute inflammation. PDGF, Platelet-derived
growth factor; PGE, prostaglandin E; PGl, prostaglandin I.
 Nitric Oxide

• Soluble gas produced from arginine by the

action of nitric oxide synthase (NOS)
• Three types of NOS :
1. endothelial (eNOS)  NO to maintain
vascular tone
2. neuronal (nNOS)  NO as neurotransmitter
3. inducible (iNOS)  NO for microbial killing
 Nitric Oxide

• In inflammation, NO produced by
endothelial cells and macrophages,
causes:
 vascular smooth muscle relaxation 
vasodilation
 kills microbes in activated macrophages
 counteracts platelet adhesion, aggregation,
and degranulation
 Plasma proteases

– Kinins
– Clotting system
– Fibrinolitic system
– Complement
 Kinin System

• Leads to formation of bradykinin from HMWK

• Effects of bradykinin
– Increased vascular permeability
– Arteriolar dilatation
– Bronchial smooth muscle contraction
– Pain
• Sort half-life (inactivated by kininases)
 Clotting / fibrinolytic system

• Fibrin clot at site of injury helps in trapping the cause

• Fibrin clot provides a framework for inflammatory cells
• Xa causes increased vascular permeability and
leukocytes migration
• Thrombin causes leukocytes adhesion, platelets
aggregation, generation of fibrinopeptides, and is
chemotactic
• Fibrinopeptides are chemotactic & induce
vasopermeability
 Clotting / fibrinolytic system (continued)

• XIIa also activates the fibrinolytic pathway to prevent

widespread thrombosis.
• Fibrin split products increase vascular permeability
• Plasmin cleaves C3 to form C3a, leading to dilatation
and increased permeability
• Plasmin activates XIIa amplifying the entire process

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 Thrombin as an Inflammatory Mediator

• Binds to protease-activated receptors (PARs) expressed

on platelets, endothelial cells, sm.muscles leading to:
– P-selectin mobilization
– Expression of integrin ligands
– Chemokine production
– Prostaglandin production by activating cyclooxygenase-2
– Production of PAF
– Production of NO

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 Complement system

• Role in immunity
– Membrane Attack Complex (MAC C5-9)
– Punches a hole in bacterial membrane

If you have deficiencies in the MAC

you are predisposed to infections that are
encapsulated : Neisseria, Strept, Hemoph,
Listeria
Complement system
 Roles of complement in inflammation

1. Vascular effects (c3a & c5a)

o ↑vascular permeability and vasodilation
o Similar to histamine

2. Activates lipoxygenase pathway of arachidonic

acid metabolism (c5a)

3. Leukocyte activation, adhesion and chemotaxis (c5a)

4. Phagocytosis
o c3b acts as opsonin
Figure 2-15 Interrelationships between the four plasma mediator systems triggered
by activation of factor XII (Hageman factor)..