Cairo University
Faculty of Veterinary Medicine
Department of Pathology
CHEMICAL MEDIATORS OF
INFLAMMATION
‫ كوكب‬/‫د‬.‫تحت اشراف أ‬
‫ محمد محمود محمد مشالى عبد الحميد‬/‫طالب‬
07274/‫رقم‬
Introduction:
Inflammation
• provoked response to tissue injury
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chemical agents
cold, heat
trauma
invasion of microbes
• serves to destroy, dilute or wall off the injurious
agent
• induces repair
• protective response
• can be potentially harmful
CARDINAL SIGNS OF ACUTE INFLAMMATION
Heat
Redness
Swelling
Pain
Loss of function
Inflammation - Mechanism
1. Vaso dilatation
2. Exudation - Edema
3. Emigration of cells
4. Chemotaxis
5. Phagocytosis
CHEMICAL MEDIATORS OF
INFLAMMATION
Definition: Any messenger that acts on blood vessels,
inflammatory cells, or other cells to contribute to an
inflammatory response. (Pretty much anything...)
• Exogenous
– Endotoxins
• Endogenous
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Plasma
Leukocytes
Endothelial cells
Fibroblasts
Chemical Mediators of Inflammation:
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Locally produced
Histamine
Seratonin/5HT
Interleukins.
Prostaglandins
Leukotrienes
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Plasma derived
Kinins
Complements
Coagulation
system
• Plasminolysis
system
• Others: H2O2, NO
CHEMICAL MEDIATORS OF
INFLAMMATION
Facts
• Mechanism of action
– Receptor-ligand interactions (1o)
– Direct enzymatic activity
– Mediate oxidative damage
• Extensive network of interacting chemicals
• High degree of redundancy
• Guarantees amplification and maintenance of
inflammatory response
• Short t ½ and are harmful
CHEMICAL MEDIATORS
• Vasodilation
– Prostaglandins, Nitric Oxide
• Increased Vascular Permeability
– Vasoactive amines (histamine, serotonin), C3a
and C5a, Bradykinin, Leukotrienes, PAF,
• Chemotaxic Leukocyte Activation
– C5a, LTB4, Chemokines
CHEMICAL MEDIATORS OF
INFLAMMATION
• Fever
– IL-1, IL-6, TNF, Prostaglandins
• Pain
– Prostaglandins, Bradykinin
• Tissue Damage
– Neutrophil and Macrophage products
– Lysosomal enzymes
– Oxygen metabolites
– NO
Bradykinin
VASOACTIVE AMINES
• Increase Vascular Permeability and Vascular
Permeability
• Histamine and Serotonin
– Mediators in the immediate active phase of
increased permeability
– Promotes contraction of smooth muscle
– Stimulates to cells to produce eotaxins
– Serotonin found in rodent mast cells
Vasoactive Amines
Continued
• Releasing Stimulators
– Direct physical or chemical
injury
– Binding of IgE- Agcomplexes
– Fragments of C3a and
C5a
– Histamine releasing
factors (pmn’s and θ)
– Cytokines (IL-1, IL-8)
PLASMA PROTEASES
3 interrelated systems are active within this category
1. Kinin system
– Highly vasoactive
2. Complement system
• Vasoactive
• Chemotactic
3. Clotting system
• Vasoactive
• Cleaves C3
Interaction of Kinin-, Coagulation- and
Complement system during acute inflammation
Factor XII (Hageman)
Collagen, basement membrane,
platelets and microbial surfaces
XIIa
Kinin cascade
Kallikrein
Clotting cascade
Prekallikrein
Prothrombin
HMWK
Plasminogen
Thrombin
PAR*
Acute
Inflammation
Bradykinin
Fibrinolysis
Plasmin
Fibrin
Fibrinogen
Complement
C3
C3a
* Protease activated receptors
COMPLEMENT SYSTEM
• Plasma proteins - act against microbial agents
• Products of activated complement
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Vascular permeability
Chemotaxis
Opsonization
Lysis
COMPLEMENT SYSTEM
Few reminders
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Classical pathway
Alternate pathway
Common pathway
Important inflammatory mediators
– C3a and C5a (anaphylatoxins)
– Cause release of histamine from mast cells
– Lysosomal enzyme release in inflammatory cells
– C5a
– Activates lipoxygenase pathway
– Chemotactic many inflammatory cells
– Increases adhesion of leukocytes
COMPLEMENT SYSTEM
And Inflammation
• C5b-9 membrane attack
complex
– Lyses cells
– Stimulates arachidonic acid
metabolism
– Produces reactive oxygen
metabolites
Complement Cascade
KININ SYSTEM
BRADYKININ
• Activated by Hageman factor (XIIa)
• Bradykinin
– Release of vasoactive nonapeptide bradykinin
– Generated from the plasma
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Potent vasodilator
Increased vascular permeability
Contraction of smooth muscle
Produce pain
Stimulates release of histamine
Activates the arachidonic acid cascade
COAGULATION SYSTEM
Clotting system
• Plasma proteins
– Can be activated by Hageman factor
• Thrombin converts fibrinogen to fibrin
– Fibrinopeptides are formed
– ↑vascular permeability
– Chemotactic for leucocytes
• Plasmin is important in lysing fibrin clots,
– Activates Hageman factor (XII) ⇨ bradykinin
– Cleaves C3 ⇨ C3a
– "fibrin-split products" formed from fibrin breakdown
– ↑ vascular permeability
COAGULATION CASCADE
TF: tissue factor;
HK: high-molecular-weight
kininogen;
PK: prekallikrein;
PL: phospholipid;
PT: prothrombin;
TH: thrombin.
Clotting System
HAGEMAN FACTOR
Dependent Factors
• Factor XII of intrinsic coagulation cascade
• Activated by
– Negatively charged surfaces
– Platelets
– Proteases from inflammatory cells
• Causes
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Coagulation
Activation of fibrinolytic system
Produces bradykinin
Activates complement
Provides an amplification system
IMPORTANT NOTE
• Activated Hageman factor (factor XIIA) initiates the
clotting, fibrinolytic and kinin systems. The products
of this initiation (kallikrein, factor XIIA, and plasmin,
but particularly, kallikrein) can, by feedback, activate
Hageman factor, resulting in significant amplification
of the effects of the initial stimulus.
CYTOKINES
• Transmitters for cell-to-cell chatting
– Modulate cell function
• Primarily from activated macrophages and
lymphocytes
• IL-1, IL-8, TNF
IL-I and TNF
“Master Cytokines”
• Origin
– Monocytes
– Macrophages
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Similar in action
Endothelium
Acute phase proteins
Fibroblasts
Other Cytokines
Chemokines???
• IL-5
– Eosinophils
• IL-6
– B and T cells
• IL-8
– Neutrophils
– Lesser degree monocytes and eosinophils
GROWTH FACTORS
• Platelet derived growth factor
• Transforming growth factor β
– Chemokines
- Leukocytes and Mesenchymal Cells
• Important in regeneration and repair
NITRIC OXIDE (NO)
Just say NO!
• Nitric oxide is synthesized from L-arginine
• 2 enzymes and many factors produce NO
• 3 effects
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♥♥ physical mediator of vascular tone
Host defense (forms perroxynitrite)
Signaling molecule – especially brain
Reduces platelet aggregation and adhesion
Inhibits several features of mast cell induced inflammation
• Uncontrolled NO production
– Can lead to massive peripheral
-Vasodilation
-Shock
LYSOSOMAL CONSTITUENTS
• Neutrophils, Monocyte/Macrophages
– Enzymes and proteins within granules
• Cationic proteins
– ↑ vascular permeability
– Chemotactic
• Neutral proteases
– Degrade ECM
OXYGEN-DERIVED FREE
RADICALS
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Cause endothelial damage
Protein destruction by inhibiting antiproteases
Injury to variety of cells
Don’t forget the antioxidants
– Ceruloplasmin
– Transferrin
– Superoxide dismutase
– Catalase
– Glutathione peroxidase