Tissue damage caused by a wound or by invasion by a pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response.  The clinical signs were described as early as 1600 B.C.

    rubor (redness)
    tumor (swelling)
    calor (heat)
    dolor (pain)

The functions of the inflammatory response include:
    1)  The delivery of effector molecules and cells to the sites of infection.
    2)  The formation of a physical barrier to the spread of the tissue damage or infection.
    3)  Wound healing and tissue repair.

The major physiological events which occur during an inflammatory response include:
    1)  immediate vasoconstriction of the blood vessels leading away from the site.
    2)  increased volume of blood flow to the site [vasodilation]
    3)  decreased velocity of blood flow to the site [leucocytes are able to slow down and adhere to vascular endothelium]
    4)  increased expression of vascular endothelial adhesion molecules [leucocytes are able to attach to vascular endothelium]
    2)  increased vascular permeability [fluid enters tissues]
    3)  influx of phagocytic cells into tissues [due to increased margination and extravasation]

Within a very short time period following trauma to the tissue or infection, blood vessels carrying blood away from the sight constrict, resulting in engorgement of the capillary network.  Engorged capillaries produce the tissue redness and an increase in temperature.  An increase in capillary permeabilty facilitates an influx of fluid and cells from the engorged capillaries into the surrounding tissue.  The fluid that accumulates [exudate] has a much higher protein content than fluid normally released.  Accumulation of this fluid results in swelling [edema].  The increased capillary permeability, decreased blood velocity, and increased expression of adhesion molecules also facilitates the migration of various leucocytes from the capillaries into the tissues.

Phagocytic cells are the first major type of leucocytes to emigrate [first neutrophils, followed by macrophages]
Neutrophils are short-lived cells which die within the tissues.  Macrophages are much longer-lived.

Later, lymphocytes (B and /or T) may also enter the site.

 Margination- the adherence of the cells to the endothelial wall
 Diapediesis / extravasation - emigration between the capillary  endothelial cells into the tissue.
 Chemotaxis - directed migration through the tissue to the site of the inflammatory response.

Phagocytic cells accumulate at the site -  release lytic enzymes and damage nearby cells -
Pus forms - accumulation of dead cells, digested materials, fluid

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.
Some of these are derived from the invading organsim,
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.

Histamine

[Released by a wide variety of cell types following tissue injury - stimulate vasodilation and increased capillary permeability]

Lipid-Derived Chemical Mediators

Cell membrane phospholipids are hydrolyzed by phospholipases at a fairly high rate during inflammation.  The
arachidonic acid pathway leads to the production of leukotrienes and prostaglandins.  A second pathway leads to the production of platelet aggregating factors.

prostaglandin - increases vasodilation, increases vascular permeability, serves as chemoattractant for neutrophils
leukotrienes - increase smooth muscle contraction, serve as chemoattractant for neutrophils
platelet-activating factors - cause platelet aggregation and serve as chemoattractant for neutrophils)

Chemokines
Chemokines are small proteins (only 90-130 amino acids in length)
Presently, over 50 different chemokines have been described
They all contain 4 conserved cysteines
Two families of chemokines have been designated, depending on whether each pair of cysteines is contiguous (CC) or separated by some other amino acid (CXC).
Chemokines are produced by a wide variety of cell types.
Chemokines are the major regulators of leukocyte traffic and help to attract leucocytes to the actual site of inflammation.
These proteins bind to proteoglycans on the endothelial cell surface and within the extracellular matrix and set up chemokine gradients for the migrating leucocytes to follow.  Importantly, only leucoctyes which bear the appropriate receptors are attracted to particular chemokines.

Chemokine Receptors

Chemokine Receptors are designated as serpentine receptors, due to the fact that the polypeptide chain "snakes through" the cell
membrane with 7 transmembrane segments.
The 2 subgroups of receptors are designated CCR (those which bind CC chemokines) and CXCR (those which bind CXC chemokines)

Examples of well characterized chemokines are:
IL-8 (interleukin-8)
RANTES (regulated upon activation normal T cell expressed and secreted)
MCP (monocyte chemoattractant protein)

Pro-inflammatory Cytokines

Responding to the presence of chemokines, phagocytes enter the site of inflammation within a few hours.  These cells release a variety of soluble factors, many of which have potent pro-inflammatory properties.

Three of these cytokines in particular have very well-characterized activity:

IL-1
IL-6
TNF-a [tumor necrosis factor alpha]

-All three of these cytokines are known to be endogenous pyrogens due to the fact that they induce fever by acting upon the
hypothalamus.
-These three cytokines also induce the production of acute phase proteins by the liver.
-They also trigger increased hematopoiesis (blood cell production) in the bone marrow, leading to leukocytosis.

Other Mediators

The process of phagocytosis also leads to the production of a variety of additional mediators of inflammation including:
nitric oxide
peroxides
oxygen radicals
[These oxygen and nitrogen intermediates are highly toxic to microorganisms]

Acute Phase Proteins
As mentioned previously, the synthesis of acute phase proteins is triggered by the pro-inflammatory cytokines IL-1, TNF-alpha, and IL-6.  The majority of these proteins are synthesized by the liver.
Well characterized examples include:
C-reactive protein (CRP)
mannose-binding protein

CRP and mannose-binding protein are both capable of triggering complement fixation leading to formation of the membrane attack complex and the release of complement components (such as C3b) which function as opsonins.  CRP mimics the binding of antibody to the surface of microorganisms whereas MBL (mannan-binding lectin) triggers the lectin pathway of complement fixation.
 
CRP binds to phosphorylcholine portion of certain bacterial and fungal cell wall lipopolysaccharides  (interestingly, mammalian phosphorylcholine is not bound by CRP)
 

Products of the 4 major plasma enzyme systems also serve as chemical mediators:
Kinin System -  Complement System  -  Clotting System  -  Fibrinolytic System

Vasodilation and increased capillary permeability that occur in injured tissue also enable the components of these enzyme systems to enter the tissues.

The 4 pathways are interconnected.These four enzyme systems generate factors that induce constriction of the blood vessels, vasodilation, increased capillary permeability, extravasation, chemotaxis, and clearance of the pathogen.

The initial tissue damage triggers the activation of -
Hageman Factor (one of the plasma clotting factors)

In turn, Hageman Factor triggers the Kinin cascade (see below) the Clotting Cascade (which leads to fibrin deposition and clot formation -Fibrin clots wall off the injured area from the rest of the body and serve to prevent the spread of infection).  Finally,  the Fibrinolytic System leads to the synthesis of plasmin.  Plasmin functions to degrade/dissolve the fibrin clot
and also triggers Complement activation.

Kinins
-small peptides
-present in an inactive form in the blood plasma
-tissue injury induces activation of these peptides
-this causes vasodilation and increased permeability

bradykinin - stimulates pain receptors [pain normally causes an individual to protect an injured area.
 

The inflammatory response must be closely regulated to prevent extensive tissue damage.
As the inflammatory response subsides the following events occur:
 

Capillaries grow into the fibrin clots, new connective tissue cells [fibroblasts] replace the fibrin as the clot dissolves.
-the fibrinolytic system degrades clots which have formed
-debris is cleared from the area by phagocytes
-fibroblasts enter the area and form connective tissue
-scar tissue forms and wound healing occurs

If antigen is not cleared away and the inflammatory process continues------>
Chronic inflammation occurs

Chronic inflammation (characterized by low numbers of neutrophils, high numbers of T lymphocytes (espec. CD4+), and macrophages) can lead to the build up of scar tissue, fibrosis, and granuloma formation.  Over time, the
resulting tissue damage can lead to organ failure.

Infection by parasitic helminths can lead to chronic inflammation.  The inflammatory cell infiltrate in such cases contains high numbers of eosinophils.

In cases of asthma, the inflammatory cell infiltrate is composed of eosinophils, basophils, and macrophges.  

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