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
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
The Basics
• Fever
– IL-1, IL-6, TNF, Prostaglandins
• Pain
– Prostaglandins, Bradykinin
• Tissue Damage
– Neutrophil and Macrophage products
– Lysosomal enzymes
– Oxygen metabolites
– NO
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
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
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
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
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 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
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.
ARACHIDONIC ACID
METABOLITES
• Roles in many biologic and
pathologic processes
– Inflammation
• 20-carbon polyunsaturated fatty
acid
– Derived directly from dietary
sources or by conversion of
essential fatty acid linoleic acid
• Esterified in membrane
phospholipids
– Must first be released from
phospholipids
• Via activation of cellular
phospholipases
– By mechanical, chemical and
physical stimuli or by other
mediators
• 2 major pathways
– Cyclooxygenase pathway
– Lipoxygenase pathway.
CYCLOOXYGENASE PATHWAY
• 2 cyclooxygenase enzymes
– COX-1
– COX-2
• 3 important products
– Thromboxane A2
– Aggregates platelets and causes vasoconstriction
– Prostacyclin (PGI2)
– Endothelial cells inhibits platelet aggregation and causes vasodilation
– Prostaglandins PGE2, PGF2 and PGD2
– Variety of actions on vascular tone and permeability
LIPOXYGENASE PATHWAY
Leukotrienes
• Leukotrienes
• Leukotriene B4 is a potent chemotactic agent
• Leukotrienes C4, D4, E4
– Potent vasoconstrictors
– Potent mediators of increased vascular permeability on
venules only
– Up to 1000 times as potent as histamine in producing
increased vascular permeability
• NOTE:
– Some anti-inflammatory properties interfere with
arachidonic acid metabolism
– Corticosteroids interfere with phospholipase
– Aspirin interferes with cyclooxygenase
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PLATELET ACTIVATING
FACTOR
Aggregate platelets and cause release
Bronchoconstriction and Vasoconstriction
Vasodilation and ↑ vascular permeability
↑ leukocyte adhesion
Leukocyte chemotaxis
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