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Chemical Mediators of Inflammation

  1. Chemical Mediators of Inflammation are:
    1. Plasma Cells Q
      1. Plasma -Precursor form – activated
      2. Cell derived → sequestered - histamine
                          → De novo synthesis - prostaglandins
        1. Production triggered by microbial products or host proteins.
        2. Binding to specific receptors on target cells
        3. Mediator can stimulate the release
        4. One/few target cell types
        5. Short lived
        6. Potential to cause harmful effects
    2. Preformed -                      
      1. Histamine - Mast cell, Basophil, Platelets
      2. Serotonin – Platelets
      3. Lysosomal - Neutrophils, macrophage enzymes
    3. Newly synthesized                
      1. PGs - All leukocytes, Platelets, Endometrial cells Q
      2. LT- AI leukocytes      
      3. PAF- All leukocytes, EC Q
      4. Activated O2 species - All leukocytes
      5. Nitric oxide - Macrophages
      6. Cytokines - Lymphocytes, Macrophages, EC
      7. F XII activation - Kinin system           
HISTAMINE (Hist. & Serotonin):   
  1. Preformed stores     
  2. First to be released
  3. Widely distributed
  4. Richest: mast cells (present in connective tissue adjacent to BVs)Q
  5. Basophils, Platelets
  1. Factor Causing
    1. Release: Q of Mediators
      1. Physical injury (trauma, heat, cold)            
      2. Immune react. (Ab. binding to mast cells)
      3. C comp. (C3a & C5a)                               
      4. Histamine rel. proteins
      5. Neuropeptides (substance P)                     
      6. Cytokines (IL-1, IL -8)
    2. Functions: Q
      1. Dilatation of arterioles (constricts large arteries)      
      2. Increase Vascular permeability of venules
      3. Immediate transient phase of increased vascular permeability (via H1 recept)
Actions similar to histamine present in platelets, enterochromaffin cells (Platelet aggregation ž Release) Q
    1. Complement System:
      1. 20 component proteins
      2. Present in greatest concentration in plasma
      3. Present in inactive forms (C1 to C9)
      4. Most critical step: Activation of C3 by 3 pathways - classical, lectin and alternative
      5. C3 and C5 can also be activated by Plasmin and lysosomal enzymes
    2. C3a, C5a - Anaphylatoxins
      - Release histamine from mast cells
    3. C5a- active lipoxygenase pathway of AA metals
      It is Chemotactic to -
      Neutrophils, monocytes, eosinophils, basophils
      -  ↑adhesion to lymphocytes to endothelium
  1. C3a, & C3bi - Opsonins
    Regulation of complement activation
  1. Complement system:
    1. Closely controlled by protein inhibitors                     
    2. Present in host cell membrane'
    3. Reg. of C3 & C5 convertase:
      1. DAF (Decay accelerating factor)
      2. Proteolytic cleaving of C3b Q
      3. Binding to active C comp. by specific proteins in plasma:
      4. C1 INH (absent C1 binding to immune complex and also inhibits serine proteases like
      5. kallikrein and Hageman factor) Q
      6. MIRL (Memb. inhibitor of reactive lysis) - inhibit Membrane attack complex (C5-9)
        i. PNH: Q
        Inability to express phosphatidyl-inositol- linked membrane proteins (Decay accelerating factor DAF, MIRL)
        ii. Hereditary Angioneurotic oedema: Def. of C1 INH (1ptd. by emotional stress/trauma)
Episodic edema- skin, extremities, larynx and intestinal mucosa,     
Mediator of edema - C2 kinin and bradykinin
  1. Kinin System:                             
  1. Bradykinin:
    1. Contraction of smooth muscle       
    2. Dilation of blood vessels (venules)
    3. Pain
  2. Kallikrein:
    1. Activation of F XII → Autocatalytic action                     
    2. Chemotactic activity          
    3. Converts C5 to C5a  
  1. Clotting system
    1. Thrombin:
      1. Main link between coagulation system and inflammation.
      2. Thrombin binds to PARs - mobilization of P selectin,
      3. production of chemokines, (Type 1 receptor by proteases)/Protease activated receptor -1
      4. expression of endothelial adhesion molecules for integrins,
      5. induction of COX 2 and production of PGs, PAF, NO
    2. Fibrinogen  
      1. Fibrin                                  
      2. Fibrinopeptide: ↑ vascular permeability
      3. Chemotaxis            
      4. Xa ↑ vascular permeability & leukocyte exudation

Fibrinolytic System

  1. Hageman factor activates Q
    1. Kinin system          
    2. Clotting system      
    3. Fibrinolytic system             
    4. Complement system
  2. Arachidonic Acid Metabolites:
    A: 20 C polyunsaturated FA (5, 8,11,14 - eicosapentaenoic acid)
    Source:   Dietary, Linoleic acid conversion
    1. Found normally esterified in membrane phospholipids (in Carbon 2 position of phosphatidylcholine, phosphatidylinositol & phosphatidylethanolamine) Q
    2. Activation of phospholipases by:
      Mechanical, chemical, physical stimuli, or other mediators (e.g., C5a)
3. AA metabolites → Eicosanoids- bind to G-protein coupled receptors on many cells
            and this mediate inflammation.

4. Cyclo-oxygenase → PG & Tx- inhibited by NSAID

5. Lipoxygenase → Leukotrienes & Lipoxins

Cyclooxygenase Pathway

Initiated by 2 enzymes COX 1 & COX 2 produce - prostaglandins
  1. COX1 –
    1. Constitutively expressed in most tissues,
    2. Also produced in response to inflammatory stimuli.
    3. In addition to role in inflammation, also has homeostatic function (eg: Fluid and electrolyte balance in kidneys, cytoprotection of GI tract). Q
  2. COX2- produced only in response to inflammatory stimul
    1. Thromboxane A2:
      1. in Platelets (Thromboxane synthetase) Q
      2. Causes Platelet aggregation; vasoconstriction
    2. PGI2:
      1. in endothelium (Prostacyclin synthetase)
      2. vasodilator, inhibits platelet aggregation; ↑vascular permeability chemotactic effects – end product PGF1:
    3. PGE2 – hyperalgesic
  1. Lipoxins:        
    1. Most recent addition. Involve transcellular biosynthesis (involving 2 cell population)
    2. Platelets alone can't form lipoxins (interact with leukocytes) Q
    3. LXA4 & LXB4 → generated by action to platelet 12- lipoxygenase on neutrophil LTA4
    4. LX: Proinflammatory & anti inflammatory actions
    5. Inhibit neutrophil chemotaxis & adhesion
    6. Stimulate monocyte adhesion
    7. Vasodilatation. endogenous negative regulators of leukotriene activity
  2. Resolvins :      
    1. New class of AA mediators
    2. Inhibit leucocytes recruitment and activation by inhibiting cytokine production.
    3. Aspirin also acts by stimulating resolvin production. Q
Table: Inflammatory Actions of Eicosanoids
Action Metabolite
Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4
Vasodilation PGI2, PGE1, PGE2, PGD2
Increased vascular permeability Leukotrienes C4, D4, E4
Chemotaxis, Leukocyte adhesion Leukotriene B4, HETE, lipoxins

Antiinflammatory Therapy

  1. → Cyclooxygenase inhibitors Aspirin & NSAIDS - inhibit COX (not LO)
  2. COX2 inhibitors - newer class of drugs, produce less toxicity than COX1 inhibitors.Q
  3. → Lipoxygenase inhibitors- newer drugs that inhibit leukotriene production / block leukotriene Receptors used in treatment of asthma. Q
  4. → Broad spectrum inhibitors -Glucocorticoids: Down regulate expression of genes for
    1. COX2                                
    2. Proinflammatory, CKs(IL-1 & TNF a)
    3. Phospholipase A2  
    4. INOS
    5. Up regulate gene for anti-inflammatory proteins such as lipocortin I (inhibits release of AA from membrane phospholipids)
  5. → Modify dietary lipids: fish oil
    [(LTs from FA in fish oil (Linoleic acid) are less potent than those derived from AA found in most animal / vegetable fats)]
  6. Cytokines:
    1. Secreted by mononuclear phagocytes, lymphocytes, endothelial cells etc.
    2. Local & systemic effect
  1. Mononuclear Phagocytes                               
    1. Endothelial effects             
    2. leucocyte adherence
    3. PGI synthesis                                 
    4. procoagulant, ↓ anti coagulant
    5. Il1, IL8
  2. IL1 – TNFa
    1. Fibroblast Effects   ↑fibroblast, ↑collagen,âprotease,
    2. Leucocyte Effects   ↑ Cytokine secretion (IL1, IL6)
Chemokines- - Family of small proteins. Chemo attractants to leucocytes
C-X-C chemokines (α - chemokines) C-C chemokines (β- chemokines) C- chemokines (γ-chemokines) CX3C chemokines
• Act primarily on neutrophils
• IL-l & TNF, IL-8
• Monocyte chemoattractant protein (MCP-1)
• Eotaxin
• Macrophage inflammatory protein -1a(MIP-1a)
• Attract monocytes, basophils, Eosinophils and lymphocytes but not neutrophils
• Specific for
• Lymphotactin
• Fructalkine
• Promotes strong
adhesion between
monocytes and T cell
  1. Four major classes
    1. CXC or a chemokineQ - act on neutrophils e.g. IL8  
    2. C-C or ß chemokines Q- monocyte chemo attractant protein (MCP-1), macrophage inflammatory protein 1 a (MIP-1a eotaxin, RANTES
      a. Acts on eosinophils, monocytes, basophils and lymphocytes.
      b. Eotaxin Qselectively recruits eosinophiles.
    3. C/γ chemokines Q - specific on lymphocyte
    4. CX3C
  2. Fractalkine -'both adhesion & chemotactic agent
  1. Mediate their activities by binding to G protein linked receptor (CXCR/CCR)
  2. Serpentine receptors
  3. Act as viral Co-receptor for HIV (CXCR4, CCR-5)
  4. Nitrous oxide - 3 different types endothelial, neuronal, cytokine inducible. Vasodilator, ↓ platelet adhesion, regulates leucocyte recruitment
a. Lysosomal constituents - specific granules & Azurophil granules

Out Comes Of Acute Inflammation

A. Resolution-
  1. Clearance of injurious stimuli          
  2. Clearance of mediators & acute inflammatory Cells
  3. Replacement of injured cells.           
  4. Normal function
B. Pus formation (Abscess)
C. Healing with fibrosis
D. Chronic inflammation

Fig: Major effects of interleukin-1 and TNF in inflammation.

Table: Summary of mediators of Acute inflammation
Mediator Source Principal Actions
Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation
Serotonin Platelets Vasodilation, increased vascular permeability
Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
Platelet-activating factor Leukocytes, endothelial cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Reactive oxygen species Leukocytes Killing of microbes, tissue damage
Nitric oxideDescription: View drug information Endothelium, macrophages Vascular smooth muscle relaxation; killing of microbes
Cytokines (e.g. TNF, IL-1) Macrophages, lymphocytes, endothelial cells, mast cells Local endothelial activation (expression of adhesion molecules), systemic acute-phase response; in severe infections, septic shock
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation
Plasma Protein-Derived
Complement Plasma (produced in liver) Leukocyte chemotaxis and activation, opsonization, vasodilation (mast cell stimulation)
Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction, vasodilation, pain
Proteases activated during coagulation Plasma (produced in liver) Endothelial

Table: Role of mediators in different reactions of inflammation
Vasodilation Prostaglandins

Nitric oxideDescription: View drug information

Increased vascular permeability Histamine and serotonin
C3a and C5a (by liberating vasoactive amines from mast cells)
Leukotrienes C4, D4, E4
Substance P
Leukocyte recruitment and activation TNF, IL-1
C3a, C5a
Leukotriene B4
(Bacterial products, e.g., N-formyl methyl peptides)
Fever IL-1, TNF

Pain Prostaglandins


Tissue damage Lysosomal enzymes of leukocytes

Reactive oxygen species

Nitric oxideDescription: View drug information

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