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