Chemical Mediators Of Inflammation

Chemical Mediators Of Inflammation

Describe the chemical mediators of acute inflammation.
Or
Describe briefly the chemical mediators of inflammation.
Or
Write a short note on chemical mediators of inflammation.
Or
Write in detail the chemical mediators of inflammation and their role in inflammation.
Or
Mention the names of chemical mediators of acute inflammation and describe the functions of any two of them.
Answer:

Chemical Mediators of Acute Inflammation

There are many biochemical substances in the body which become active in the area of inflammation. These substances mostly increase vascular permeability or the production of pain. They are broadly classified into two groups:

• Mediators released by cell
• Mediators are released by plasma.

Chemical mediators of inflammation list

Cell-Derived Mediators

• Vasoactive amines, i.e. histamine, 5-hydroxytryptamine, neuropeptides
• Arachidonic acid metabolites (eicosanoids)
  • Metabolites via cyclo-oxygenase pathway, i.e. prostate- glands, thromboxane A2, prostacyclin, resolvins
  • Metabolites via the lipo-oxygenase pathway, i.e. 5-HETE, leukotrienes, lipoxins
• Lysosomal components from PMNs, macrophages
• Platelet-activating factor
• Cytokines, i.e. IL-1, IL-6, IL-8, IL-12, IL-17, TNF-a, TNF-β, lFN-?, chemokines
• Free radicals, i.e. oxygen metabolites, nitric oxide

Plasma Protein­Derived Mediators (Plasma Proteases) Products of:

• The kinin system
• The clotting system
• The fibrinolytic system
• The complement system.

1. Vasoactive Amines

• Histamine: It is stored in the granules of mast cells, basophils and platelets. Histamine is released from these cells by various agents as under:
• Stimuli or substances inducing acute inflammation, e.g. heat, cold, irradiation, trauma, irritant chemicals, immunologic reactions, etc.
• Anaphylatoxins like fragments of complement C3a, and C5a, increase vascular permeability and cause edema in tissues.
• Histamine-releasing factors from neutrophils, monocytes, and platelets.
• Interleukins.

The main actions of histamine are vasodilatation, increased vascular permeability, itching and pain.

• 5-­Hydroxytryptamine (5­HT or serotonin): It is present in tissues like chromaffin cells of GIT, spleen, nervous tissue, mast cells and platelets. The actions of 5-HT are similar to histamine but it is a less potent mediator of increased vascular permeability and vasodilatation than histamine.
• Neuropeptides: Another class of vasoactive amines is tach-kinin neuropeptides such as substance P, neurokinin A, vasoactive intestinal polypeptide and somatostatin. These small peptides are produced in central and peripheral nervous systems. The major proinflammatory action of these neuropeptides are:
  • Increased vascular permeability
  • Transmission of pain stimuli
  • Mast cell degranulation

2. Arachidonic Acid Metabolites (Eicosanoids):

Arachidonic acid metabolites or eicosanoids are the most potent mediators of inflammation, much more than oxygen free radicals. Arachidonic acid is released from the cell membrane by phospholipases.

It is then activated to form arachidonic acid metabolites or eicosanoids by one of the following 2 pathways: via cyclo-oxygenase pathway or via lipo-oxygenase pathway:

• Metabolites via cyclo-­oxygenase pathway: Prostaglan- dins, thromboxane A2, prostacyclin
• • Prostaglandins (PGD2, PGE2, and PGF2-α): PGD2 and PGE2 act on blood vessels and cause increased venular permeability, vasodilatation, and bronchodilatation and inhibit inflammatory cell function. PGF2-a induces vasodilatation and bronchoconstriction.
  • Thromboxane A2 (TXA2): Platelets contain the enzyme thromboxane synthetase and hence the metabolite, thromboxane A2, formed is active in platelet aggregation, vasoconstrictor and bronchoconstrictor.
  • Prostacyclin (PGI2): PGI2 induces vasodilatation, and bronchodilatation and inhibits platelet aggregation.
  • Resolvins are another derivative of the COX pathway which act by inhibiting the production of proinflammatory cytokines. Thus, resolvins are actually helpful drugs such as aspirin which act by inhibiting COX activity and stimulating the production of resolvins.
• Metabolites via lipo­oxygenase pathway: 5-HETE, leukotrienes, lipoxins: The enzyme, lipooxygenase, a predominant enzyme in neutrophils, acts on activated arachidonic acid to form hydroperoxy eicosatetraenoic acid which on further peroxidation forms following two metabolites:
• • 5-HETE: It is an intermediate product, is a potent chemotactic agent for neutrophils.
  • Leukotrienes (LT): They are so named as they were fist isolated from leucocytes. Firstly, unstable leukotriene A4 (LTA4) is formed which is acted upon by enzymes to form LTB4 while LTC4, LTD4 and LTE4 have common actions by causing smooth muscle contraction and thereby inducing vasoconstriction, bronchoconstriction and increased vascular permeability.
  • Lipoxins: They act to regulate and counterbalance the actions of leukotrienes. Lipooxygenase-12 present in platelets acts on LTA4, derived from neutrophils and forms LXA4 and LXB4.

3. Lysosomal Components:

The inflammatory cells neutrophils and monocytes contain lysosomal granules which on release elaborate a variety of mediators of inflammation. These are as under:

• Granules of neutrophils: Neutrophils have 3 types of granules: primary or azurophil, secondary or specific, and tertiary.
  Primary or azurophil granules are large azurophil granules that contain functionally active enzymes. These are myeloperoxidase, acid hydrolases, acid phosphatase, lysozyme, defensin (cationic protein), phospholipase, cathepsin G, elastase, and protease.
  • Secondary or specific granules contain alkaline phosphatase, lactoferrin, gelatinase, collagenase, lysozyme, vitamin-B12 binding proteins, and plasminogen activator.
  • Tertiary granules or C particles contain gelatinase and acid hydrolases.
  • Myeloperoxidase causes oxidative lysis by the generation of oxygen free radicals, acid hydrolases act within the cell to cause the destruction of bacteria in phagolysosome while proteases attack on the extracellular constituents such as basement membrane, collagen, elastin, cartilage, etc.
• Granules of monocytes and tissue macrophages: These cells on degranulation also release mediators of inflammation like acid proteases, collagenase, elastase and plasminogen activators. However, they are more active in chronic inflammation than acting as mediators of acute inflammation.

4. Platelet Activating Factor:

It is released from IgE-sensitised basophils or mast cells, other leucocytes, endothelium and platelets. Apart from its action on platelet aggregation and release reaction, the actions of platelet-activating factor as a mediator of inflammation are:

• Increased vascular permeability
• Vasodilatation in low concentration and vasoconstriction otherwise
• Bronchoconstriction
• Adhesion of leucocytes to the endothelium
• Chemotaxis.

5. Cytokines:

Cytokines are polypeptide substances produced by activated lymphocytes and activated monocytes. Major cytokines and their role in inflammation are:

1. Interleukins (IL­1, IL­6, IL­8, IL­12, IL­17): IL-l and IL-6 are active in mediating acute inflammation, IL-12 and IL-17 play a potent role in chronic inflammation. IL-8 is a chemokine for acute inflammatory cells:

• IL-1 is elaborated by several body cells—monocytes and macrophages, B lymphocytes, fibroblasts, endothelial, and some epithelial cells. Similarly, it can target all body cells. Its major actions are:

• • Expression of adhesion molecules
  • Emigration of neutrophils and macrophages
  • Role in fever and shock
  • Hepatic production of acute phase protein.
• IL-6 is similar in its sources and target cells of action. Its major role is:
  • Hepatic production of acute phase protein
  • Differentiation and growth of T and B cells.
  • IL-8 is a chemokine and its major actions are:
  • Induces migration of neutrophils, macrophages, and T cells
  • Stimulates release of histamine from basophils
  • Stimulates angiogenesis.
• IL-12 is synthesized by macrophages, dendritic cells, and neutrophils while it targets T cells and NK cells. Its actions in chronic inflammation are as under:
  • Induces the formation of T helper cells and killer cells
  • Promotes cytolytic activity
  • Increases production of IFN-?
  • Decreases production of IL-17.
• IL-17 is formed by CD4+T cells while it targets fibroblasts, endothelial cells, and epithelial cells. Its action in chronic inflammation are:
  • Increased secretion of other cytokines
  • Migration of neutrophils and monocytes.

2. Tumor necrosis factor (TNF­a and β): TNF-a is a mediator of acute inflammation while TNF-β is involved in cellular cytotoxicity and in the development of spleen and lymph nodes. Major actions of TNF-a are:

• Hepatic production of acute phase proteins
• Systemic features (fever, shock, anorexia)
• Expression of endothelial adhesion molecules
• Enhanced leucocyte cytotoxicity
• Induction of pro-inflammatory cytokines.

3. Interferon (IFN)­?: It is produced by T cells and NK cells and may act on all body cells. It acts as a mediator of acute inflammation as under:

• Activation of macrophages and NK cells
• Stimulates secretion of immunoglobulins by B cells
• Role in the differentiation of T helper cells.

Inflammatory mediators

6. Free Radicals: Oxygen Metabolites and Nitric Oxide

Free radicals act as potent mediators of inflammation:

• Oxygen-derived metabolites are released from activated neutrophils and macrophages and include superoxide oxygen, H2O2, OH- and toxic NO products. These oxygen-derived free radicals have the following actions in inflammation:
  • Endothelial cell damage and thereby increased vascular permeability.
  • Activation of protease and inactivation of antiprotease causing tissue matrix damage.
  • Damage to other cells.
• Nitric oxide (NO): Nitrous oxide plays the following roles in mediating inflammation
  • Vasodilatation
  • Anti-platelet activating agent
  • Possibly microbicidal action.

Chemical Mediators of Acute Inflammation Plasma Derived Mediators

There include various products derived from the activation and interaction of interlinked systems, kinin, clotting, fibrinolytic, and complement.

• The Kinin system: This system on activation by factor XII generates bradykinin. Bradykinin acts in the early stage of inflammation.
  • Smooth muscle contraction
  • Vasodilatation
  • Increase vascular permeability
  • Pain
• The clotting system: The action of fibrin peptides in inflammation are:
  • Increase permeability
  • Chemotaxis for leukocyte
  • Anticoagulant activity.
• The fibrinolytic system: This system on activation by a plasminogen activator generates plasmin.
  • The action of plasmin in inflammation is:
    • Activation of factor XII to form a pro-kallikrein activator that stimulates the kinin system to generate bradykinin.
    • Splits of complement C3 to form C3a which is a permeability factor.
    • Degrades the firin to form firin split products which increase vascular permeability and are chemotactic of leucocytes.
• The complement system: The complement system on activation yields anaphylatoxins, C3a, C4a, C5a and membrane attack complex.
  • The action of anaphylatoxins is as follows:
    • Release histamine from mast cells and basophils
    • Increase vascular permeability causing edema.
    • C3 augments phagocytosis.
    • C5a is chemotactic for leucocytes.