CHEMICAL MEDIATORS OF INFLAMMATION
The events in the inflammatory response are initiated by a complex series of interactions
involving several chemical mediators; whose interactions are still only partially understood.
These mediators are any messenger that acts on blood vessels, inflammatory cells and other cells to contribute to the inflammatory response.
Origin of these chemical mediators is variable:
Some are derived from the invading organism,
Some are released by the damaged tissue,
Some are generated by several plasma enzyme systems
Some are products of various white blood cells participating in the inflammatory response.
1. Histamine
This is the most potent of the mediators of inflammation. It initiates the early vascular responses. Its effects last only up to an hour. Other mediators sustain the response. It is released from basophils and mast cells. Its release is stimulated by complement components C3a and C5a and by lysosomal proteins released from neutrophils.
Functions:
(i) Dilatation of capillaries that leads to hyperemia and increased vascular permeability.
(ii) Contraction of non vascular smooth muscle e.g. smooth muscle constriction in
bronchi.
(iii) Chemotaxis for Eosinophils.
2. Serotonin (5-Hydroxytryptamine 5HT)
It is also involved in initiating vascular changes, but is of less significance. It is also capable of increasing vascular permeability, dilating capillaries and producing contraction of nonvascular smooth muscle. It is stored platelets as well enterochromaffin cells (a type of enteroendocrine cell occurring in the epithelial lining the lumen of the digestive tract) and in the CNS.
3. Kinins
These are from serum precursor proteins, the a-2 globulins called kininogens. Tissue injury induces their activation. The major ones are Bradykinin and kallidin. The kinins are potent vasoactive peptides. They increase vascular permeability, cause vasodilation, pain and contraction of smooth muscle. They also stimulate arachidonic acid metabolism. They are short lived; (The precursors are also unstable).
4. Complement system
Complement (C) is a self assembling extracellular system of protein present in inactive form in plasma and body fluids. They are activated on cell or microbial surface membranes by immune complexes. They are therefore particularly important in bacterial infections. They cause lysis and clumping of bacteria. There are several components of the system that can be cleaved. Various components have different factors. e.g. C3a and C5a induce release of histamine from mast cells.
C3a and C5a are anaphylatoxins. C5a induces chemotaxis of neutrophils Ag-Ab-C3b complex - adheres to leukocytes causing lysosomal release C3b causes platelet aggregation, monocytes chemotaxis and B-Iymphocyte transformation.
5. Prostaglandins
These are small fatty acid derivatives, a result of the arachidonic acid pathway. They are released from phospholipids during cell injury. They are released from almost all cells of the body! The major ones are PGEI and PGE2. They potentiate the effects of histamine and Bradykinin i.e., increases vasodilation, increases vascular permeability and serves as a chemo attractant for neutrophils. They are also pyrogenic (cause fever).
6. Others
(a) Leukotrienes - also a result of the arachidonic acid pathway. They increase smooth muscle contraction and serve as a chemoatractant for neutrophils. .
Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of the Leukotrienes
L TC4, LTD4 and L TE4. Mast cells secrete it during the anaphylactic reaction, inducing
inflammation. It can be found in basophils. It induces prolonged, slow contraction of
smooth muscle and has a major bronchoconstrictor role in asthma.
(b) Epinephrine/norepinephrine and glucocorticoids - these are anti-inflammatory. They
control severe inflammation.
(c) Platelet activating factors (PAF) - cause platelet aggregation and serve as chemoattractant for neutrophils.
(d) Cytokines - these are substances secreted by specific cells of the immune system which
carry signals locally between cells and have an effect on other cells therefore coordinating and controlling the inflammatory response. IL 1 - 10 (interleukin), TNF-a (tumor necrosis factor) and INF-y (interferon) are produced predominantly by macrophages and lymphocytes but can be produced by other cell types as well. These cytokines are pyrogenic.
Chemokines - a specific class of cytokines that mediate chemotaxis, i.e. activation and
migration of specific leukocytes in acute inflammation. E.g. lL-8
(e) Nitric oxide, peroxidases and oxygen radicals - also produced by the process of
phagocytosis. They are highly toxic to microorganisms.
EVENTS IN ACUTE INFLAMMATION
Vasodilatation:
Histamine
Prostaglandins
Nitric oxide
Increased vascular permeability:
Histamine
Anaphylatoxins C3a and C5a
Kinins
Leukotrienes C, D, and E
PAF
Chemotaxis:
Complement fragment C5a
Lipoxygenase products, lipoxins & leukotrines (LTB4)
Chemokines
Tissue Damage
Lysosomal products
Oxygen-derived radicals
Nitric Oxide
Fever
IL-l
TNF
Prostaglandins
Pain
Prostaglandins
Bradykinin
Summary of mediators of acute inflammation
Chemical mediators of inflammation, EC-endothelial cells;
A.4 EXUDATES IN ACUTE INFLAMMATION
The escape of fluid, proteins and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.
The accumulated protein-rich extravascular fluid is known as the inflammatory exudate.
The exudate is composed of five major constituents:
(1) the irritant,
(2) injured tissue cells,
(3) Leukocytes,
(4) Plasma constituents (water, protein, fibrin and antibodies) and
(5) erythrocytes.
These components give the exudate a very characteristic appearance and composition which differentiate it from a transudate.
The exudates associated with inflammatory reactions vary in their fluid, plasma protein and cell content.
In general, the nature of the exudate is dictated by the severity of the reaction and its
specific cause.
Transudate is an extravascular fluid, an ultrafiltrate of blood plasma and thus larger molecules such as proteins and cell debris are absent. The most common causes of pathologic transudate include conditions which either increase hydrostatic pressure in vessels or decrease osmotic pressure from tissues: embolism, left ventricular heart failure, cirrhosis (Cirrhosis leads to hypoalbuminaemia and decreasing of osmotic pressure that causes edema.), and Nephrotic syndrome (also due to hypoalbuminaemia caused by proteinuria).
A.4.1 FUNCTIONS OF THE EXUDATE
Dilution of the irritant: The irritant is changed from severe to mild, and thus less damage is caused to the tissues. Moreover, irritants like bacteria are dispersed and so better phagocytized.
The exudate also mechanically carries the irritant away, especially to the exterior (in the case of cutaneous or mucous surfaces). This helps in getting rid of the irritant from the body.
It brings phagocytes (neutrophils, macrophages etc) to the area to destroy the irritant.
Exudate also brings fibrin to the area.
Fibrin performs several useful functions:
It entraps the irritant and thus retards its spread. This facilitates their phagocytosis
It forms a layer around the cells, thus protecting them from the damaging effect of the irritant
It seals the lumen of the lymphatics effectively. This keeps irritants like bacteria from entering into lymphatics, thus stopping their spread to regional lymph nodes
It facilitates healing and repair
Fibrin also has a stimulating effect on the proliferation of fibroblasts. This further
helps in healingFor the movement of leukocytes, fibrin is required and acts as a scaffold. Otherwise they cannot move in a fluid medium.
The exudate brings antibodies to the area of inflammation; these are most effective
against bacteria and viruses.The exudate brings to the area of inflammation increased amounts of nutrients and
oxygen needed for tissue regeneration and repair.Exudate also drains the area of products of tissue destruction and altered metabolism
which are acidic in nature.Exudate also provides a suitable medium for the working of phagocytes, enzymes and
antibodies under optimum conditions.
Sequel of acute inflammation
Acute inflammation may end up in either in:
Complete resolution, with restoration of the site of acute inflammation to normal. This is the usual outcome when injury is mild, e.g. a superficial bum or limited trauma, or when there is little tissue destruction.
Healing by scarring: this occurs after substantial tissue destruction, or when the
inflammation occurs in tissues that do not regenerate, or when there is abundant fibrin
exudation.Abscess formation: this occurs particularly in infections with pyogenic organisms.
Progress to chronic inflammation.
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