Chemical Mediators of Acute Inflammation 2
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Chemical mediators of inflammation
Prof. Chandu de SilvaDepartment of Pathology
Faculty of Medicine, Colombo
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Chemical mediators1. Chemical mediators may be circulating in plasma or
may be produced locally at the site of inflammation by cells.
2. Most mediators induce their effects by binding to specific receptors on target cells.
3. Mediators may stimulate target cells to release secondary effector molecules.
4. Mediators may act only on one or a few targets or may have widespread activity.
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5. Mediator function is tightly regulated. Once activated and released from the cell, most mediators quickly decay, are inactivated by enzymes, eliminated or are inhibited.
6. A major reason for the checks and balances is that most mediators have the potential to cause harmful effects.
Chemical mediators
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CHEMICAL MEDIATORS OF INFLAMMATION
Originating from cells Present in Plasma
Performed
1) Amines-Histamine
Serotonin
2) Lysosomal enzymes
Newly Synthesized
1) Arachidonic acid
metabolites
2) Cytokines
3) Platelet activating factor
4) Nitric oxide
1) Complement system
2) Kinin system
3) Clotting / Fibrinolytic systems
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Complement system
• Has 20 component proteins, together with their cleavage products.
• Mediate biologic reactions, all of which serve in the defense against microbial agents.
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CLASSICAL PATHWAY ALTERNATE PATHWAY
Ag-Ab complexes bind to C1
Activated C1
C4+C2
C3 Convertase
(C4b2a)
• Increase Vascular
permeability
• Vasodilation
Bacterial endotoxins, Aggregated globulins
C3 C3b
C3
direct cleavage by plasmin, bacterial proteases C3bBb (C3
convertase)
C3a C3b
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C5
C5 convertase classical Pathway (C4b2a3b)
C3bBb3b (aternate path C5 convertase)
C5a C5b C5b67 Chemotaxis
C5b-9 (Membrane attack complex)
Membrane lysis of cells
Productionof oxygen metabolites
• Chemotaxis
• Adhesions of leukocytes to endothelium
• Leukocyte activation
• Activate Arachidonic Acid pathway
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• C3b acts as an opsonin.
• C3 and C5 can be activated by several proteolytic enzymes present in the inflammatory infiltrate (plasmin, lysoxmal enzymes).
Complement system
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CLOTTING – FIBRINOLYTIC SYSTEM
Hageman factor (Factor XII)
Negatively changed surfaces (collagen, basement membrane)
Activated Hageman Factor (Factor XIIA)
Cofactor HMWK (high molecular weight kininogen)
KININ SYSTEM CLOTTING SYSTEM
FIBRINOLYTIC SYSTEM
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KININ SYSTEM
Prekalikrenin Kalikrein Chemotaxis
Converts C5toC5a
Highmolecular Weight kininogen (HMWK)
Bradykinin
Increase vascular permeability Pain Dilatation of blood vessels Contraction of smooth muscle
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FIBRINOLYTIC SYSTEM
Plasminogen Plasmin Lyse fibrin clots
Activates factor XII Cleaves C3 to produce C3 fragments Degrades fibrin to fibrin split products
Increase vascular permeability
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CLOTTING SYSTEM
XI XIA
X XA
Prothrombin Thrombin
• leukocyte adhesion
• fibroblast proliferation
Fibrinogen Fibrin
Fibrinopeptides
• Increase vascular permeability
• chemotaxis
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ARACHIDONIC ACID METABOLISM • Arachidonic acid metabolites are also called eicosanoids.
Cell membrane phospholipids
Phospholipase
Arachidonic Acid
Cyclooxygenase pathway
Lipoxygenase Pathway
Chemical, physical & other mediators like C5a
Blocked by corticosteroids
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Cyclooxygenase pathway
O2 Blocked by aspirin/ Indomethacin, COX-1 & COX-2 inhibitors PGG2
PGH2+(OX) – Free radical of oxygen
Prostacyclin PGI2
Inhibitor of platelet aggregation Vasodilatation Potentiate oedema
ThromboxaneTXA2
Vasoconstriction Platelet aggregation
PGE2
PGF2
PGD2
pain + fever vasodilatation
Potentiate oedema
Major metabolite in mast cells, causes vasodilatation
Arachidonic Acid
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Lipoxygenase Pathway O2 Lipoxin A4 & B4
Vasodilatation Inhibit chemotaxis
5HPETE HETE
LTA4
Leukotriene
LTB4 Chemotaxis
LTC4 LTD4 LTE4
Vasoconstriction Bronchoconstriction Vascular Permeability
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• HPETE = Hydroperoxy eicosatetraenoic acid
• HETE = Hydroxy eicosaaatetraenoic acid
• SRS – A is a mixture of LTC4 & LTD4
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Prostaglandins • Are best regarded as autocoids or local short range
hormones, which are formed rapidly, exert their effects locally and decay spontaneously or are destroyed enzymatically.
• Prostaglandins also cause pain & fever.
• Arachidonic acid metabolites can pass from one cell to another
• Different cells cooperate with one another to produce different eicosanoids
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• There are two forms of cyclooxygenases called COX-I and COX-2.
• COX-1 is found in the gastric mucosa and mucosal prostaglandins produced by COX-1 are protective against acid induced damage.
• Thus inhibition of cyclooxygenase by aspirin and NSAIDs predisposes to gastric ulceration.
• To prevent this highly selective COX-2 inhibitors are now available
Cyclooxygenase pathway
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Histamin and serotonin Histamin is present in basophils, platelets and mast cells.
It is released in response to
a variety of stimuli such as
1. Leukocyte derived histamine release factors
2. Physical agents
3. Immunologic reactions
4. C3a, C5a
5. Cytokines
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• Histamine causes vasodilatation and is the principal mediator of immediate phase reaction.
• It is inactivated by histaminase.
• Serotonin is found within platelets.
• It is released during platelet degranulation and has actions similar to histamine.
Histamin and serotonin
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Lysosomal constituents
1.Cationic proteins Increase vascular permeability
Chemotaxis of monocytes
Inhibition of movement of neutrophils and eosinophils
2.Acid proteases Degrade bacteria and debris within phagolysosomes
3.Neutral proteases Degrade extracellular components
(eg; elastase, collagenases, Cleave C3 and C5 directly
cathepsin)
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• These harmful proteases are held in check by a system of antiproteases in serum and tissue fluids
eg; alpha-1 antitrypsin inhibits neutrophil elastase.
• Deficiency of alpha-1 antitrypsin lead to sustained activity of leukocyte proteases.
Neutral proteases
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Platelet activating factor [PAF]
1.Sources
Mast cells/Basophils
Neutrophils
Monocytes/Macrophages
Endometrium, Platelets
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Functions
Platelet activation,
Release of histamine from platelets
Increase vascular permeability
Vasoconstriction, bronchoconstriction
Increased leukocyte adhesion to endothelium
Leukocyte degranulation
Stimulates synthesis of other mediators like eicosanoids
Chemotaxis
Platelet activating factor [PAF]
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Cytokines • Cytokines are polypeptide products of activated
lymphocytes (lymphokines) and monocytes (monokines).
• Many non lymphoid cells too produce these.
• Their secretion is transient and tightly regulated
• Their effects tend to be pleiotrophic (different cells are affected differently by the same cytokine).
• They can act on the same cell that produces them (autocrine effect), on other cells in the immediate vicinity (paracrine effect) or systemically (endocrine effect).
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Types of cytokines1. Those regulating lymphocyte function such as
activation, growth and differentiation.
e.g.- IL-2-stimulates lymphocyte growth and transforming growth factor β inhibit lymphocyte growth
2. Cytokines involved in innate immunity- TNF and IL-1
3. Cytokines that activate inflammatory cellsduring cell mediated immune responses, such as interferon ɣ (IFN- ɣ) and IL-12
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4. Chemokines that have chemotactic activity for various leukocytes.
5. Cytokines that stimulate haematopoiesis-
Granulocyte-monocyte colony stimulating factor (GM-CSF) and IL-3
Types of cytokines
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Endotoxin, Bacterial products, immune complexes, toxins, physical injury, other cytokines
Macrophage (and other cell) activation Autocrine, paracrine
& endocrine effects IL-I/TNF (Interleukion 1, & Tissue Necrosis Factor act synergistically)
Acute phase reactions
Endothelial effects
Fibroblast effects
Leukocyte effects
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Acute phase reactions 1. Fever2. Increased sleep
(slow wave sleep)3. Decreased appetite4. Increased synthesis of acute phase proteins5. Haemodynamic effects
decrease vascular resistance, hypotension, shock, increase heart rate
3. Neutrophilia 4. Release of ACTH & Corticosteroids
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Endothelial effects
1. Leukocyte adhesion
2. Stimulation of PAF
3. Increase procoagulant activity decrease antico-agulant activity of endothelium making it potentially thrombogenic.
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Leukocyte effects Increase cytokine secretion
(IL-1,IL-6)
Fibroblast effects Collagen synthesis
Proliferation of fibroblasts, release of proteolytic enzymes by mesenchymal cells
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Nitric oxide (NO) NO is a short lived, soluble free radical gas produced
by endothelial cells, macrophages and specific
neurones in the brain
• Causes vascular smooth muscle relaxation.
• Antagonism of platelet aggregation and adhesion.
• Reduction of leukocyte recruitment at inflammatory sites.
• Cytotoxic to certain microbes and tumour cells.
• Uncontrolled NO production by activated macrophages in septic shock can lead to massive peripheral vasodilatation and shock.
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Oxygen derived free radicles
These include superoxide , OH, H2O2 . Their production is
dependent on the activation of the NADPH oxidative
system
They are released by neutrophils and macrophages
They cause,
1. Endothelial cell damage
2. Increase vascular permeability
3. Inactivation of antiproteases, and activation of proteases
4. Injury to other cell types – tumour cells, red cells, parenchymal cells
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Serum, tissue fluids and target cells possess
anti oxidant protective mechanisms
Eg.ceruloplasmintransferinsuperoxide dismutasecatalaseglutathione peroxidas
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Summary of chemical mediators of inflammation 1. Vascular permeability Histamine
C3a, C5aBradykininLeukotrienes-
LTD4,LTC4,LTE4Platelet activating factor
2. Chemotaxis C5aLTB4Bacterial products,
chemokines (IL-8) 3. Acute phase reactions IL-1,TNF
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4. Tissue destruction Lysosomal products,O2 derived free radicles,
NO
5. Vasodilatation Prostaglandins, NO
6. Fever IL-1, IL-6,TNF,prostaglandins
7. Pain Prostaglandin, Bradykinin
• The different mediator systems although discussed separately are intimately intertwined and act together
• With all the mediators, there seems to be an intelligent system of checks and balances
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Systemic effects of inflammation 1) Fever
Infections, toxins Immune complexes, neoplasia,
IL-1/TNF IL-6
Vascular receptors in the thermoregulatory center of the hypothalamus
Prostoglandins (E)
Vasomotor center
Sympathetic nerve stimulation
Vasoconstriction of skin vessels
Reduced heat dissipation
fever
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2. Leukocytosis• usually in infflammation - 15,000 to 20,000
cells/ml• in leukemoid reactions 40,000 to 100,000
cells/ml• IL-T/TNF accelerate release of cells from
bone marrow. This leads to a rise in number of more immature neutrophils in the blood (“ shift to the left”).
Systemic effects of inflammation
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CSF (colony stimulating factor) causes
proliferation of precursors in bone marrow
• Most bacterial infections neutrophilia.
• Infectious mononucleosis and mumps lymphocytosis.
• Parasitic infestations eosinophelia
• Typhoid and viral infections leucopenia
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3. Acute phase reactions• Increase in slow- wave sleep
• Decreased appetite
• Hypotension
• Increased degradation of proteins
• Synthesis of acute – phase proteins by the liver
C reactive protein
Serum amyloid A
Complement
Coagulation proteins
• Most of these are mediated by IL-1, IL-6 and TNF
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Inflammatory reaction
Cardinal features of inflammation
Tests for specific aetiological factors
Culture, gram stained smears
Serum antibody levels, complement levels
Inflammatory mediators
Fever
Biopsy Examination of inflammatory exudate
Increase in total number of neutrophils in peripheral blood
Presence of toxic granules
Presence of immature band forms (shift to the left)
Increase of certain plasma proteins (C-reactive protein, fibrinogen, haptoglobulin)
ESR Measurement of C-reactive protein
Diagnosis of acute inflammation