Week 3 - Inflammation
GENERAL OBJECTIVES OF MODULE:
To acquaint you with an important mechanism of defence and explain and illustrate the various
steps involved in the inflammatory response. We'll also look at the factors that initiate and
modify the course of the inflammatory reaction.
After completing this module you will be able to:
1. Define and describe inflammation.
2. Explain the series of steps that take place in the capillary bed during an acute
inflammatory process (i.e. the vascular events).
3. Describe abnormal permeability at the microcirculation during acute inflammation (in
contrast to normal).
i. Define and contrast exudate and transudate and their characteristics.
4. Illustrate the cellular events of inflammation.
5. Define chemical mediation in inflammation. Explain the mechanisms of action and
effects of: vasoactive amines (e.g. histamine), arachidonic acid metabolites, and plasma
protease systems (e.g. the kinin system, the clotting or coagulation cascade, the
6. Define chemotaxis and list three common chemotactic factors.
7. List the three most common cells involved in inflammation and their role in the
8. Describe the steps involved in phagocytosis.
9. List and explain the mechanism of production of the cardinal signs of inflammation.
10. Classify inflammation based on duration. Give examples for each type.
11. Define granuloma. Give three common etiologies.
12. Classify inflammatory exudates. Give examples.
13. Define abscess, empyema and additional special forms of inflammation.
14.List at least two systemic effects of inflammation.
Inflammation - Key Terms
Acute - of short duration or occurring suddenly.
Cardinal signs of inflammation:
• rubor - redness
• tumor - swelling
• calor - heat
• dolor - pain
• functio laesa - loss of function or impaired function
Chemical mediators - a variety of chemicals secreted by various cells and from injured
tissue involved in the inflammatory response, e.g. histamine. Responsible for mediating
vascular and cellular responses in inflammation. Chemotaxis - phenomenon that guides and attracts WBCs to the site of injury.
Chemotactic agents include some of the chemical mediators, antibodies, products from
bacteria and dead tissue.
Chronic - long-standing; occurring over a long period of time.
Exudate - fluid accumulation outside of a vessel; it has a high protein content and
contains various types of inflammatory cells.
Hyperemia - excess of blood in a part.
Leukocyte - or white blood cell (WBC); the cell type that predominates in acute
inflammation is the polymorphonuclear WBC (PMN) or the neutrophil.
Leukocytosis - a transient increase in the number of leukocytes (WBCs) in the blood.
Monocyte / macrophage - another type of white blood cell; as inflammatory process
continues these cells finish off what the neutrophils begin and continue to clean up the
debris; macro = large; phage = eater.
Permeability - the degree of selectivity a membrane shows in allowing substances to
pass through or in preventing passage; "leakiness"
Phagocytosis - a process in which a cell takes particles and substances into itself for
destruction; phago = eating, cyto = cell. E.g. a neutrophil can engulf (phagocytize)
foreign particles, bacteria, dead material or other debris.
Pyrogen - a fever-producing substance.
Transudate - in this case the fluid contains little, if any protein or cells, and is usually
due to changes in hydrostatic pressure or osmotic pressure in the blood vessel (also see
later module on "Blood Flow and Body Fluids").
Vasodilation - increase in size or diameter of a blood vessel; brought about by chemical
Inflammation: Inflammation is the non-specific, dynamic response of a living organism to tissue
injury. This injury may be the result of physical trauma or chemical injury, infection with a
microorganism, immune reactions or ischemia.
The purpose of the inflammatory reaction is to destroy or limit the spread of the injurious agent
and to allow for repair or replacement of damaged tissue.
Whenever tissues are injured, e.g. cut, burned, or infected by a microorganism - a series of
reactions will occur at the site of injury. That series of reactions constitutes an inflammatory
The purpose of these reactions is:
1. To destroy or limit the spread of the injurious agent.
2. To allow for repair or replacement of the damaged tissue.
The definition of inflammation is very broad. It is perhaps best described as being the
characteristic response of living tissues to an injury. Three points require amplification:
1. Inflammation is a dynamic, ever-changing process consisting of a chain of reactions
which succeed or overlap each other. It is not a static situation. 2. The injury must be non-lethal. If the injury is of such severity to destroy the tissue at the
outset, no inflammatory response can occur in that time.
3. The inflammatory reaction is non-specific. Many diverse injuries can cause inflammation
and the initial stages of the inflammatory action are identical in almost all of the tissues,
irrespective of the type of injury. The intensity, duration and outcome of the
inflammatory reaction are modified by factors pertaining to the host as well as to the
Some causes of an inflammatory reaction are:
1. Infection - i.e. invasion and multiplication within tissues by organisms. These, of course,
include various bacteria, fungi, viruses and protozoa, which in many instances, cause damage by
release of toxins which directly or indirectly destroy host cells.
2. Trauma - this includes penetrating injury (e.g. stab wound, a wood sliver), blunt trauma,
thermal injury (excessive heat or cold), chemical injury (acid or alkali).
3. Immunologically-mediated (humoral or cellular).
4. As a result of the loss of blood supply (ischemia).
* Do not confuse inflammation with infection. An infection almost always will cause an
inflammatory reaction. However, as noted above, the etiologies of an inflammatory reaction are
diverse, i.e. infection by a microorganism is one of the triggers of the inflammatory reaction, but
not the only one. Usually, a relatively large inflammatory reaction will occur in response to an
In order to study the inflammatory reaction, it is customary to divide it into its various
components. The sequence can be divided into vascular and cellular events, both of them
mediated by chemical factors (mediators). However, it must be remembered that these events
* There are 3 major components of the inflammatory response:
1) Vascular events (taking place in arterioles, capillaries, venules)
2) Cellular events (major players here are the white blood cells (WBCs)) and
3) Chemical events (release of mediators that cause the changes in cells and vessels).
Immediately following an injury, there is frequently a transient vasoconstriction of arterioles.
This is mediated by nerves to the smooth muscle within the arteriolar walls (i.e. it is
aneurogenic response). This process is brief and usually lasts up to five minutes.
The transient vasoconstriction is followed by the hemodynamically more important
vasodilatation of venules, capillaries, and arterioles.
Opening of precapillary sphincters of arterioles. Opening up of new capillary beds.
Opening of arterial venous shunts in capillary bed.
This results in increased blood flow to the injured area and thus, on gross examination, the area
appears red or hyperemic.
With very mild injuries, the vascular changes may not proceed any further than this stage. With
more severe injury, the vasodilation is soon followed by slowing of the blood flow.
Vascular events occurring in the capillary bed include:
a transient vasoconstriction (neurally-mediated)
followed by vasodilatation of vessels (chemically-mediated)
o opening of precapillary sphincters of arterioles; opening up of new capillary beds;
opening of arterial venous shunts in capillary bed) ---> all of these result in
increased blood flow to the affected area (so clinically we see the redness (rubor)
and heat (calor) of inflammation)
Vasodilatation is often accompanied by increased vascular permeability. This refers to the
outpouring of fluids and proteins from the blood vessels. This affects firstly and predominantly
venules; however, capillaries and arterioles are also involved.
Local hemoconcentration - The viscosity of blood is increased as a result of fluid loss from the
vessel. This will lead to packing or sludging of red blood cells, therefore slowing blood flow.
Occasionally, the blood flow is slowed to the point of stasis or thrombosis (clotting). Thrombosis
in vessels may also occur due to a second mechanism in severe injuries in instances in which
there is direct damage to endothelial cells which, in turn, initiate the formation of blood clots in
the damaged areas.
The cellular elements in a blood vessel normally travel in a stream in the centre of the vessel. As
a result of loss of fluid because of increased vascular permeability and of slowing of blood flow
in the vessel, the circulating cellular elements, including white blood cells, become displaced to
the periphery of vessels where they come in to contact with the endothelial cells. This is referred
to as margination.
The process of the escape of plasma and plasma proteins along with white blood cells from the
vessel is known as exudation. This inflammatory exudate accounts for an increase in the volume
of interstitial fluid (edema) and tissue swelling at the local site of injury.
There are two events in the inflammatory response that are responsible for the increased vascular
1. Rise in hydrostatic pressure within the microcirculation. Arteriolar vasodilatation is
followed by a rise in pressure within the capillaries and venules. This results in the
passive transport of a large volume of fluid along with small molecules into the
interstitium (space between tissues). 2. Widening of the inter-endothelial cell junctions. These cells contain myofibrils within the
cytoplasm and these allow for contraction of the cells. This is the mechanism by which
large molecules may escape, resulting in a protein-rich exudate.
Vasodilatation of vessels in the inflammatory vascular response is accompanied byincreased
The chemicals (notably histamine in the early stages) that cause vasodilatation also cause
increased permeability within the vessels via an action on the endothelial cells that line the
vessel wall and cause them to contract ---> creating 'spaces' between these cells through which
fluid, proteins, and even cells (aninflammatory exudate) can now escape.
This is the swelling or 'tumor' of inflammation. This flow of fluid out of the vessels is also aided
by the increased blood flow which increases the pressure within capillaries and venules in that
area (recall your Starling's forces from last year's physiology; this is hydrostatic pressure
pushing fluid out of the vessels).
An inflammatory exudate is characterized by having:
1. A high specific gravity (> 1.020).
2. High protein levels - > 2 - 4 gms per dl.
3. Numerous cells or cell fragments.
In contrast, a transudate is due to a rise in hydrostatic pressure, reduced plasma proteins
(oncotic pressure), lymphatic obstruction or Na+ retention. It consists of fluid similar to water
with a low specific gravity (<1.0120) with little to no protein or cells (or cell fragments).
Transudates are NOT associated with inflammation but with clinical situations such as: heart
failure, venous obstruction, malnutrition, among others (also see later Module on Disturbances of
Blood Flow and Body Fluids).
The escape of plasma and plasma proteins, and even cells, from the vessel is known
asexudation. This inflammatory exudate has:
high protein levels (> 2-4 gm/dl)
numerous cells and cell fragments
a high specific gravity
This inflammatory exudate causes an increase in the volume of interstitial or extracellular fluid
(inflammatory edema) and tissue swelling at the local site of injury.
In contrast a transudate, is not related to the inflammatory response, but occurs when there is
a rise in hydrostatic pressure in the vessel, a decrease in plasma proteins (and hence osmotic
pressure) or lymphatic obstruction. It consists of fluid similar to water with NO or little cells or
proteins, and hence a specific gravity close to that of water (<1.012). WHAT MECHANISMS ARE RESPONSIBLE FOR THE VASCULAR EVENTS
(VASODILATATION AND INCREASED PERMEABILITY)?
Operate in the very early phases of inflammatory reaction.
Fleeting arteriolar vasoconstriction.
The mechanism of neurogenic mediation was suggested by Sir Thomas Lewis in l927 and
constitutes the first part (pallor) of Lewis' triple response.
Even without neuroconnections (denervation), the major aspects of acute inflammation
occur. The reason for this is that the main mediators of the vascular changes are
chemical. Neurogenic mediators have probably a secondary and less important role in
A. Cell-Derived Vasoactive Mediators
i. Histamine - This is the major mediator in the early phases of the acute inflammatory
Major source is mast cells - these are ubiquitous throughout the body and occur in
connective tissue often adjacent to blood vessels. Histamine is contained within
granules of the mast cell. Histamine is also found in granules of basophils and
platelets (along with heparin). When mast cells are injured or appropriately
activated, they degranulate, i.e. contents of the granules are released.
Mast cells degranulate in response to:
1. Physical injury - trauma, heat, irradiation.
2. Certain chemical agents - toxins, bee venom, proteins from neutrophils.
3. Immunological process - immune complexes, fragments of the
Histamine has two major functions:
2. Dilatation of arterioles (vasodilatation).
3. Increased permeability in venules and capillaries.
ii. Arachidonic Acid Metabolites - They are derived from cell membrane phospholipids.
Release of arachidonic acid by phospholipases (lysosomes) is induced by mechanical,
chemical and physical stimuli. The end products are prostaglandins and leukotrienes.
Prostaglandins produce vasodilatation and increased permeability. Leukotrienes increase
permeability and have chemotactic activity. Diagram of ARACHIDONIC ACID METABOLISM
B. Plasma-Derived Vasoactive Mediators
i. Kinins - The kinins, of which bradykinin is the most important, are a group of plasma and
tissue proteases which are activated by actions of various clotting or complement system
Bradykinin has four functions:
1. Arteriolar dilatation.
2. Increased capillary and venule permeability.
3. Increased migration of white blood cells to site of injury (chemotaxis).
4. Produce pain.
Like histamine, the effects of bradykinin are transitory and are most important during the
early phases of inflammation.
ii. Complement system - In brief, complement consists of at least 11 different proteins
circulating in the blood in an inactive form. Upon activation of the system - for example,
by contact with antigen-antibody complexes - various by-products of complement are
released. Some of these fragments of complement have the property of increasing vascular permeability, while others are responsible for attracting white blood cells into a
site of inflammation.
iii. Clotting Factors - The clotting (coagulation) system forms a fibrinous exudate or
meshwork at the inflamed site to trap cells, microorganisms and foreign bodies. This
prevents the spread of infection and inflammation into the surrounding tissues; keeps cell
debris, bacteria and foreign bodies at the site of greatest phagocytic activity; and forms a
clot that stops the bleeding and provides a framework for repair and healing. The main
substance of this mesh is an insoluble protein called fibrin which is the end product of
Miscellaneous - There are a wide variety of compounds which have a variable role in the
inflammatory response. Some of these include neutrophil enzymes or lysozymes which are
liberated at the inflammatory site and are responsible for the further release of mediators such as
histamines, kinins, etc. Some of these enzymes also have the property of digesting organic
material. Also of inflammatory significance are cytokines (products of stimulated lymphocytes),
interferon and tumour necrosis factor.
In summary, histamine, perhaps soon followed by the kinins, initiates the early vascular
phenomenon. Fractions of complement are also involved at an early stage. Later, the changes of
increased vascular permeability are due to compounds such as prostaglandins, lysozymes and
SRS (slow reacting substance of anaphylaxis).
Chemical mediators are of two types:
1. those derived from cells (e.g. histamine released by mast cells during initial cell damage)
or breakdown of plasma membranes (e.g. phospholipases that initiate the conversion of
arachidonic acid (AA) to various prostaglandins (PGs) and leukotrienes (LTs) from cell
2. those mediators that are activated in the plasma (e.g. complement fractions, products of
the kinin system, products of the coagulation cascade).
Be familiar with what each of these chemical mediators can do - histamine probably being the
most important promoting vasodilation and increased vascular permeability in the initial
response. PGs - vasodilatation (PGI2 or prostacyclin) and increased permeability; LTs -
increase permeability and are chemotactic factors. Complement factors (C3a and C5a increase
permeability and cause vasodilation; C5a is also a chemotactic factor; C3b is an opsonin and
enhances phagocytosis); kinins, bradykinin - vasodilation, increased permeability, chemotaxis
and pain. There is a nice summary table in the text (8th edition - Table 2-4, see p. 46)
Also in terms of clinical relevance various anti-inflammatory agents we use in treatment act to
inhibit the production or action of these chemical mediators, e.g anti-histamines, aspirin (non-
steroidal anti-inflammatory agents - block AA breakdown to PGs), COX-2 inhibitors (Vioxx -
block cycloxygenase and breakdownof AA to PGs), corticosteroids (block initial breakdown of
membrane phospholipids to AA). Cellular Changes
When we were considering the effects upon blood vessels during the inflammatory process, we
noted that, as a result of stagnation of blood flow, the cellular elements tended to become
arranged around the periphery of the blood vessel, i.e. margination. At this point, the white
blood cells become sticky and actually adhere to the endothelium, i.e.pavementing. The process
of pavementing, is related to, the presence of cell adhesion molecules in both endothelial cells
Diagrammatic representation of the cellular changes taking place in the acute
Margination of WBCs (PMNs or neutrophils) is followed by pavementing and adherence of the
cells to the endothelial basement membrane. Cell adhesion molecules promote adherence. Once
migration through the endothelial cellular junctions has taken place, neutrophils are attracted to
the area of injury by a number of chemotactic factors and there they phagocytose the invading
organism or agent.
Emigration - White blood cells are actively motile - they form pseudopods and can move in an
amoeboid fashion. Neutrophils and monocytes are the most rapid travellers and lymphocytes are
the least rapid. These white cells travel along the endothelium until they reach the widened
endothelial cell junction where they are actually able to pass through that space. This process is
active and requires energy. Red blood cells often leave the vascular lumen behind a white blood
cell. This is a passive phenomenon and results from hydrostatic pressures forcing red blood cells
out of the permeable vessel.
The first cells to appear in injured tissues are neutrophils (dependent on C5a generation, in the
first 6 - 24 hours) followed by monocytes (24 - 48 hours). This is due to the various timing of
expression of CAMs & release of chemical mediators at different phases of inflammation. Once
outside the blood vessel, monocytes are referred to as macrophages or histiocytes.
Once fluid starts leaving the vessel during the inflammatory response you now get a relative
concentration of blood cells (red cells and white cells or hemoconcentration) and a general slowing of the blood. These cellular elements, that under normal conditions travel in the centre
of the vessel, now shift towards the margins of the vessel - margination.
* Margination is the first step in the cellular events:
these cells now become sticky and adhere to the sides of the vessel wall (to the
endothelial cells) -->pavementing and adhesion (cell adhesion molecules play a role
cells can then migrate through the spaces opened up between endothelial cells --
> migration (or emigration or transmigration) and
they are attracted to the site of injury by chemotactic factors (that may be released by an
infectious organism, by the damaged host tissue, or as part of the activation of
inflammatory intermediates, e.g. complement fractions) --> chemotaxis
once at the site of damage neutrophils and macrophages can ingest and digest cell debris,
opsonized bacteria or foreign substances (recall examples of opsonins such as IgG, C3b) -
Chemotaxis - The reaction of inflammatory cells to substances in their environment determines
the direction of locomotion of the cell or organism. This movement along a chemical gradient is
a process called chemotaxis.
Chemotactic factors for neutrophils include:
1. Complement fractions.
2. Bacterial and viral products.
3. Collagen breakdown fragments.
4. Components of the kinin system.
5. Breakdown fragments of fibrin
Chemotaxis is the attraction of cells to the site of injury (by the release of factors from injured
cells, infectious organisms or inflammatory mediators). Movement is along a chemical gradient
towards the site of injury.
The finding of a large number of neutrophils at a site of injury constitutes a major histological
feature of acute inflammation. As mentioned above, in most acute reactions, neutrophils appear
first and are followed by macrophages. This is due to their greater mobility and also because
there are many more neutrophils than monocytes in the circulation.
After two or three days, macrophages begin to outnumber neutrophils in most inflammatory
reaction sites (an exception to this would be in those instances in which the injurious stimulus
continues to operate). The normal life span of macrophages is much greater (months to years)
versus the life span of an average neutrophil (2-4 days). Also, macrophages are relatively
resistant to the lower pH (acidity) which is found at inflammatory sites.
During acute inflammation
- neutrophils are the most important cells (produce many substances that augment the inflammatory response - vasodilatation, increased permeability, chemotaxis,phagocytosis, etc
that help to stop or contain the injurious agent)
- followed by macrophages (ingest cellular debris) and
- as inflammation becomes chronic then lymphocytes (humoral and cellular immunity) come
into play and prominence.
The process of ingestion of particulate matter, i.e. bacteria, foreign debris, by the cell. It literally
means "cell-eating". It may be regarded as the culmination of an inflammatory reaction.
Cells with the greatest phagocytotic properties are neutrophils and macrophages. Eosinophils are
also phagocytotic; however, lymphocytes and plasma cells are not.
After foreign material comes in contact with the cell membrane, the cytoplasm of the neutrophil
or macrophage flows around the particle trapping it within a sack. Thus, the foreign material
becomes bound by a membrane derived from the plasma membrane (phagosome). Lysosomes
then fuse to the sack and release their enzymes directly into this sack or vacuole. Phagocytosis is
the process whereby some of the debris at an inflammatory site is removed (this is done
primarily by macrophages), the remainder is removed by lymphatics.
Phagocytosis is also the main mechanism for bacterial killing and degradation.
Phagocytosis or ingestion of cellular debris or foreign substances by macrophages or
neutrophils. See the figure in the notes for a list of steps.
1. opsonization (e.g. by IgG, C3b)
2. recognition of foreign substance and adherence to WBC membrane
3. engulfment of foreign substance by WBC (to form a phagosome)
4. fusion with lysosome (phagolysosome) in the WBC and release of lytic enzymes
Remember NOT ALL white blood cells are phagocytic. Neutrophils, macrophages (and to a
certain extent eosinophils) are, but lymphocytes and plasma cells ARE NOT Factors affecting phagocytosis:
Opsonins - These are substances which coat bacteria and render them more susceptible to
phagocytosis. They are usually immunoglobulins (e.g. IgG) or complement fractions (e.g. C3b).
What is the fate of the engulfed material?
1. In many instances, the material is destroyed. For example, bacteria may be destroyed and
digested by the lysosomal enzymes within the neutrophil or macrophage.
2. However, in some cases, it is the white blood cell that may be destroyed by the foreign
particle. For example, a particularly virulent bacteria may cause death of the ingesting
3. A third possibility is that the organisms may survive for some time within the
macrophages. This occurs in cases of tuberculosis in which the tuberculous bacillus
remains viable within macrophages for many months or even years and movement of the
macrophage through the lymphatics to the lymph nodes actually results in the spread of
Cardinal Signs of Inflammation
1. Redness or rubor - dilatation and congestion of blood vessels.
2. Swelling or tumor - exudation of fluid (increased vascular permeability) and cells.
3. Heat or calor - mechanisms for this are poorly understood; however, greater blood flow
to the region may be a contributing factor.
4. Pain or dolor - pressure upon nerves by the edema fluid. Also direct effect of
bradykinins and prostaglandins.
5. Loss of function (functio laesa) - secondary to reflex inhibition of muscular movements
associated with pain. Also, mechanical disability may be produced by the swelling and
READ CASE STUDY Classifications of Inflammation
Inflammation may be classified according to:
B. Type of exudate formed
C. Location and special forms
1. Type of Inflammation Based on Duration
- Acute or chronic.
- No sharp line of division exists between these forms.
o In a clinical sense, acute inflammation is usually of sudden onset and
accompanied by one or more of the cardinal signs. It also generally lasts a matter
of hours or days. Acute reactions occur when the injury is transient, e.g. physical
trauma, burn, or an infection in which the organism is rapidly eradicated by the
body's defence mechanisms.
o In a pathological sense, acute inflammation has, as its dominant morphological
changes, the vascular and exudative changes described, i.e. exudation of fluid and
accumulation of cells. The cellular infiltrate contains numerous neutrophils.
sudden onset, accompanied by 1 or more of cardinal signs (redness, swelling, heat, pain,
Duration - hours to days.
Morphologically - vascular and exudative changes (vasodilatation and increased
permeability, inflammatory exudate), numerous neutrophils (review case of acute
inflammation - acute appendicitis)
Examples: a cut or scrape, a burn, a bee sting, acute pneumonia.
B. Chronic Inflammation: This results from an injurious agent which persists in the tissues
and continues to cause damage, e.g. foreign body (wood splinter) which remains in the
tissue, organisms which are not eradicated.
Chronic inflammation can arise basically under two different sets of circumstances:
a. Evolution of acute to chronic inflammation: This occurs characteristically in
certain infections. As the agent persists in the tissue, so does the inflammatory
reaction to that agent. An example of chronic inflammation would be a
staphylococcal infection of bone (osteomyelitis). At first, one sees the typical
changes associated with an acute inflammatory reaction. However, usually there
is a mass of bone that becomes necrotic and this becomes a suitable place in
which the bacteria can persist and which is very difficult for the body defences to
reach. Also, it is difficult for antibiotics to reach the bacteria in necrotic tissue.
Thus, the battle between organisms and host continues to rage for many weeks or even years.
The inflammatory reaction with chronicity takes on two new facets:
i. A proliferation of connective tissue (predominantly fibroblasts)
and vessels (angiogenesis).