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Mediators of Inflammation: DR - Djumadi Achmad, Sppa (K)

The document summarizes several key mediators of acute inflammation: 1. Vasoactive amines like histamine and serotonin cause vasodilation and increased vascular permeability. 2. Lipid mediators like prostaglandins and leukotrienes are produced from arachidonic acid and promote vascular and cellular reactions. 3. Cytokines such as TNF, IL-1, and chemokines mediate and regulate immune and inflammatory reactions by recruiting and activating leukocytes.

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56 views33 pages

Mediators of Inflammation: DR - Djumadi Achmad, Sppa (K)

The document summarizes several key mediators of acute inflammation: 1. Vasoactive amines like histamine and serotonin cause vasodilation and increased vascular permeability. 2. Lipid mediators like prostaglandins and leukotrienes are produced from arachidonic acid and promote vascular and cellular reactions. 3. Cytokines such as TNF, IL-1, and chemokines mediate and regulate immune and inflammatory reactions by recruiting and activating leukocytes.

Uploaded by

Elearning FK Unhas
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© © All Rights Reserved
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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

2
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

26
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

27
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)..

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