Chemical mediators of inflammation
Contents
• Chemical mediators of inflammation
• Cell derived mediators
• Plasma derived mediators
Objectives
At the end of this lecture, student will be able to
• List various chemical mediators of inflammation
• Describe the
formation and functions of cell derived mediators
• Describe the formation and functions of plasma
derived mediators
Chemical
mediators of inflammation
• Endogenous compounds
• Released during inflammation
• Increases vascular permeability
• Edema, Destruction of inflammatory agents
Cell derived mediators of inflammation
• Vasoactive amines – Histamine, Serotonin,
Neuropeptides
• Arachidonic acid metabolites
– Via COX pathway – Prostaglandins, Thromboxane A2, prostacyclin
– Via LOX pathway – 5-HETE, leukotrienes
• Lysosomal system
• Platelet activating factor
• Nitric oxide and oxygen metabolites
Plasma
derived mediators of inflammation
• The kinin system
• The clotting system
• The fibrinolytic system
• The complement system
Vasoactive amines (Autocoids)
Amine autocoids
• Histamine
• 5 – HT / Serotonin
Released within 1 hour
of inflammatory response
Histamine
• Stored in mast cells, basophills &
platelets
Released due to –
Heat/cold radiations
– Chemical irritant & immunological reactions
– Anaphyla toxins
Main actions of
Histamine
• Vaso dilation
• ↑ permeability of venules
• Itching & pain
• Release of other cell derived mediators
• Broncho constriction
Serotonin
• Present in chromaffin cells of GIT
• In spleen, nervous system, mast cells &
platelets
Actions
• Vasodilation
• ↑vascular permeability
• Less potent than histamine
Neuropeptides
• Tachykinin neuropeptides – substance P, neurokinin A, vasoactive
intestinal polypeptide (VIP) & somatostatin
• Produced in the central and peripheral nervous systems
Actions
• Increased vascular permeability
• Transmission of pain stimuli
• Mast cell degranulation
Arachdonic acid Metabolite
• Tissue injury – Phospholipase A2
activation
• Conversion of phospholipids into arachdonic
acid
Metabolism of
arachdonic acid follows 2 pathway
• COX (Cyclo-oxygenase) – Pathway
• LOX (Lipo- oxygenase) – Pathway
COX Pathway
LOX Pathway
Lysosomal components
Granules of
Neutrophills
Primary granules
·
Myeloperoxidase
·
Acid
hydrolase
·
Neutral
proteases
Secondary granules
·
Lactoferrin
·
Lysozyme
·
Alkaline
phosphatase
·
Collagenase
Granules of
Monocytes & Tissue macrophages
• Cells on degranulation releases mediators like
• Acid proteases
• Collagenase
• Elastase
• Plasminogen activator
More involved in
chronic inflammation
Platelet Activating Factor (PAF)
IgE-sensitised
basophils or mast cells, other leucocytes, endothelium and platelets
•
↑ vascular permeability
•
Vasodilatation in low concentration and vasoconstriction
•
Broncho constriction
•
Adhesion of leucocytes to endothelium
•
Chemotaxis
Cytokines
•
Group of polypeptide substances
•
Produced by activated lymphocytes/ monocytes
•
Interleukin 1 & 8
•
Tumor necrosis factor
•
Interferon
•
Platelet factor
Actions:
•
IL –I, TNF α
& β
– ↑ leucocyte adherence, Platelet aggregation, proliferation of fibroblast
•
Interferon gamma – activation of macrophages & neutrophils
•
IL-8 – Chemotactic of neutrophills
•
PF – 4 – Chemotactic for neutrophills, monocytes & eosinophills
Nitric oxide & oxygen metabolites
•
Released by activated macrophages from vascular endothelium
•
Vasodilation
•
Inhibiton of platelet aggregation
•
Killing of micro organism
•
O2 free radicals released from activated neutrophills &
macrophages
•
Endothelial damage
•
↑vascular permeability
•
Tissue matrix damage
Plasma derived mediators
•
Interlinked system
•
Include
–
Clotting system
–
Kinin system
–
Fibrinolytic system
–
Complement system
•
Hageman factor (Factor XII) – connects the other 4 system
Clotting system
•
Results in formation of fibrinogen
•
Thrombin converts fibrinogen to fibrin & fibrinopeptide
–
↑ vascular permeability
–
Chemotaxis of leucocytes
–
Anticoagulant activity
Fibrinolytic system
•
Activated by plasminogen
•
Plasminogen activator – plasminogen – plasmin- breakdown of fibrin – fibrinopeptides or fibrin split products
Actions
–
Activation of factor XII
–
Splits complement fraction C3to C3a– permeability factor
–
Degrade fibrin to form fibrin split products
Complement system
Involves
2 pathways
•
Classic pathway through antigen-antibody complexes
•
Alternate pathway via non-immunologic agents such as bacterial toxins,
cobra venoms and IgA
Anaphylatoxins
(C3a, C5a, C4a)
–
Activate mast cells and basophils to release of histamine
–
cause increased vascular permeability
–
augments phagocytosis
•
C3b – an opsonin
•
C5a – chemotactic for leucocytes
•
Membrane attack complex (MAC) (C5b-C9) is a lipid dissolving agent and
causes holes in the phospholipid membrane
Chemical mediators of inflammation
Summary
•
Chemical mediators are endogenous compounds released during inflammation
which increases vascular permeability, bring about edema and destruction of
inflammatory agents
•
Chemical mediators of inflammation are derived from cell and plasma
•
Cell derived mediators include histamine, serotonin, leukotrienes,
platelet activating factors, cytokinines, prostaglandins
•
Plasma derived mediators include kinin system, cltting and fibrinolytic
system and clotting system