You are on page 1of 41


•Inflammation is a defense reaction caused by tissue damage

or injury
•Characterized by redness, heat, swelling, and pain.
•The primary objective of inflammation is to localize and
eradicate the irritant and repair the surrounding tissue.
•For the survival of the host, inflammation is a necessary and
beneficial process.
•The inflammatory response involves three major stages: first,
dilation of capillaries to increase blood flow; second,
microvascular structural changes and escape of plasma
proteins from the bloodstream; and third, leukocyte
transmigration through endothelium and accumulation at the
site of injury.
•The leukocyte adhesion cascade is a sequence of adhesion and
activation events that ends with extravasation of the leukocyte.
•At least five steps of the adhesion cascade are capture, rolling.
slow rolling, firm adhesion, and transmigration.
•Each of these five steps appears to be necessary for effective
leukocyte recruitment, because blocking any of the five can
severely reduce leukocyte accumulation in the tissue.
•These steps are not phases of inflammation, but represent the
sequence of events from the perspective of each leukocyte.
•At any given moment, capture, rolling, slow rolling, firm
adhesion and transmigration all happen in parallel, involving
different leukocytes in the same microvessels.

•The endothelium is located at the interface between the blood and the
vessel wall.
•The cells are in close contact and form a slick layer that prevents
blood cell interaction with the vessel wall as blood moves through the
vessel lumen.
•The endothelium consists of simple squamous epithelium that lines
the lumen of all blood vessels.
•It plays a critical role in the mechanics of blood flow, the regulation of
coagulation, leukocyte adhesion, and vascular smooth muscle cell
growth, and also serves as a barrier to the transvascular diffusion of
liquids and solutes.
•For years the endothelium was thought of as an inert single layer of
cells that passively allowing the passage of water and other small
molecules across the vessel wall.
• However, this dynamic tissue performs many other active functions,
such as the secretion and modification of vasoactive substances and
the contraction and relaxation of vascular smooth muscle.

The cellular components of blood include erythrocytes (red blood cells), leukocytes
(white blood cells), and platelets. Normal human blood contains 4.8 - 5.2 million
erythrocytes/ml and 4000 - 10,000 leukocytes/ml. Leukocytes are divided into five
classes based on morphological and tinctorial characteristics when stained. The
five classes of leukocytes are:

neutrophils (40% - 75%)

eosinophils (1% - 6%)
basophils (less than 1%)
monocytes (2%-10%)
lymphocytes (20%-45%)

Collectively, neutrophils, eosinophils, and basophils are known as granulocytes

due to the presence of granules in their cytoplasm. In addition, monocytes and
lymphocytes are also known as mononuclear cells.
Within 12 hours of being discharged from the marrow into the
bloodstream, neutrophils migrate into the extravascular tissue. Tissue
neutrophils are activated by chemoattractants at the site of injury.
Neutrophils ingest bacteria by phagocytosis and then release enzymes
(such as lysozyme) to destroy the bacteria.

Eosinophils migrate from the marrow through the blood into the
extravascular tissue, and they survive there for weeks. Again,
chemoattractants direct the movement of eosinophils, and like
neutrophils, eosinophils are phagocytic. They do not ingest organisms,
but they do exert cytotoxic effects on them.

Basophils are morphologically similar to mast cells, and along with other
granulocytes, basophils are motile cells with phagocytic properties. They
may migrate into extravascular tissues where they may be stimulated by
complexes of antigens that are bound to IgE.
Monocytes are larger than other leukocytes, and they mature into
macrophages once they are released into the bloodstream. Monocytes then
migrate to tissues, particularly the liver, lymph nodes, and lungs, where they
may stay for days or years. Here, the monocytes are actively phagocytic, and
they ingest particulate matter. Monocytes are also important to the immune
response. They ingest and process antigens and are involved in antigen
presentation, by B- and T-lymphocytes.

Two main types of lymphocytes are B-cells and T-cells. B-cells are
characterized by the presence of immunoglobulins on their surface, and upon
stimulation with antigen, they are transformed into plasma cells. Plasma cells
are then able to secrete antibodies specific to the antigen. T-cells take part in
cell mediated immune response, which does not depend on the presence of
circulating antibodies.

Selectins are a family of transmembrane molecules, expressed on the surface of leukocytes and
activated endothelial cells. Selectins contain an N-terminal extracellular domain with structural homology
to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor, and two to
nine consensus repeats (CR) similiar to sequences found in complement regulatory proteins. Each of
these adhesion receptors is inserted via a hydrophobic transmembrane domain and possesses a short
cytoplasmic tail. The initial attachment of leukocytes, during inflammation, from the blood stream is
afforded by the selectin family, and causes a slow downstream movement of leukocytes along the
endothelium via transient, reversible, adhesive interactions called leukocyte rolling. Each of the three
selectins can mediate leukocyte rolling given the appropriate conditions.
L-selectin is the smallest of the vascular selectins, and can be found on most leukocytes. P-selectin, the
largest selectin, is expressed on activated platelets and endothelial cells primarily. E-selectin is
expressed on activated endothelium with chemically or cytokine-induced inflammation.


Slow Rolling
•After induction of inflammation by injection of a pro-inflammatory cytokine like
TNF- , leukocyte rolling velocity drops dramatically to an average between 5
and 10 µm/s
•This rolling requires the expression of E-selectin on endothelial cells and
CD18 integrins on the rolling leukocytes and has been termed "slow rolling" to
distinguish it from the much faster rolling without cytokine stimulation.
•Slow rolling can be reproduced in vitro on substrates of E-selectin and, at
equivalent site densities, P-selectin.
•This suggests that slow rolling is not based on a unique property of E-selectin,
but the expression of E-selectin and/or its ligands appears to be sufficiently
high in vivo to support slow rolling..
This slide shows the muscle coats and peritoneum of a
normal appendix. The peritoneal surface runs diagonally
across the upper right hand corner. It is covered by a layer
of mesothelial cells (not apparent in this picture) underlying
which is a layer of pale staining fibrous tissue in which are
a few small blood vessels. The outer longitudinal and inner
circular muscle coats consist of smooth muscle with a few
small blood vessels.

This slide shows the same area in an acutely inflamed

appendix. The changes are striking. The peritoneum is
widened by an increase in tissue fluid (oedema) and by
many inflammatory cells. In addition, the blood vessels are
dilated. The muscle coat also shows oedema which has
caused separation of the muscle fibres. There are
numerous inflammatory cells between the muscle fibres.
Tipos de Inflamación
Serous inflammation
In serous inflammation, there is abundant protein-rich fluid exudate with a
relatively low cellular content. Examples include inflammation of the serous
cavities, such as peritonitis, and inflammation of a synovial joint, acute synovitis.
Vascular dilatation may be apparent to the naked eye, the serous surfaces
appearing injected, i.e. having dilated, blood-laden vessels on the surface, (like
the appearance of the conjunctiva in 'blood- shot' eyes).
Catarrhal inflammation
When mucus hypersecretion accompanies acute inflammation of a mucous
membrane, the appearance is described as catarrhal. The common cold is a good
Fibrinous inflammation
When the inflammatory exudate contains plentiful fibrinogen,
this polymerises into a thick fibrin coating. This is often seen
in acute pericarditis and gives the parietal and visceral
pericardium a 'bread and butter' appearance.
Haemorrhagic inflammation
Haemorrhagic inflammation indicates severe vascular injury
or depletion of coagulation factors. This occurs in acute
pancreatitis due to proteolytic destruction of vascular walls,
and in meningococcal septicaemia due to disseminated
intravascular coagulation.

Suppurative (purulent) inflammation

The terms 'suppurative' and 'purulent' denote the production
of pus, which consists of dying and degenerate neutrophils,
infecting organisms and liquefied tissues. The pus may
become walled-off by granulation tissue or fibrous tissue to
produce an abscess (a localised collection of pus in a
tissue) . If a hollow viscus fills with pus, this is called an
empyema, for example, empyema of the gall bladder or of
the appendix.
Membranous inflammation
In acute membranous inflammation, an epithelium becomes coated by fibrin,
desquamated epithelial cells and inflammatory cells. An example is the grey
membrane seen in pharyngitis or laryngitis due to Corynebaeterium diphtheriae.

Pseudomembranous inflammation
The term 'pseudomembranous' describes superficial mucosal ulceration with an
overlying slough of disrupted mucosa, fibrin, mucus and inflammatory cells. This
is seen in pseudomembranous colitis due to Clostridium difficile colonisation of
the bowel, usually following broad-spectrum antibiotic treatment.

Necrotising (gangrenous) inflammation

High tissue pressure due to oedema may
lead to vascular occlusion and thrombosis,
which may result in widespread septic
necrosis of the organ. The combination of
necrosis and bacterial putrefaction is
gangrene. Gangrenous appendicitis is a good
Beneficial effects
Both the fluid and cellular exudates may have useful effects. Beneficial effects of
the fluid exudate are as follows:

•Dilution of toxins. Dilution of toxins, such as those produced by bacteria,

allows them to be carried away in Iymphatics.
•Entry of antibodies. Increased vascular permeability allows antibodies to enter
the extravascular space, where they may lead either to Iysis of microorganisms,
through the participation of complement, or to their phagocytosis by
opsonisation. Antibodies are also important in neutralisation of toxins.
•Drug transport. The fluid carries with it therapeutic drugs such as antibiotics to
the site where bacteria are multiplying.
•Fibrin formation. Fibrin formation from exuded fibrinogen may impede the
movement of micro-organisms, trapping them and so facilitating phagocytosis.
•Delivery of nutrients and oxygen. Delivery of nutrients and oxygen, essential
for cells such as neutrophils which have high metabolic activity, is aided by
increased fluid flow through the area.
•Stimulation of immune response. The drainage of this fluid exudate into the
Iymphatics allows particulate and soluble antigens to reach the local Iymph
nodes where they may stimulate the immune response.
Harmful effects
The release of Iysosomal enzymes by inflammatory cells may also have harmful
•Digestion of normal tissues. Enzymes such as collagenases and proteases may
digest normal tissues, resulting in their destruction. This may result particularly in
vascular damage, for example in type III hypersensitivity reactions and in some
types of glomerulonephritis.
•Swelling. The swelling of acutely inflamed tissues may be harmful: for example,
the swelling of the epiglottis in acute epiglottitis in children due to Haemophilus
influenzae infection may obstruct the airway, resulting in death. Inflammatory
swelling is especially serious when it occurs in an enclosed space such as the
cranial cavity. Thus, acute meningitis or a cerebral abscess may raise intracranial
pressure to the point where blood flow into the brain is impaired, resulting is
ischaemic damage, or may force the cerebral hemispheres against the tentorial
orifice and the cerebellum into the foramen magnum (pressure coning).
•Inappropriate inflammatory response. Sometimes, acute inflammatory
responses appear inappropriate, such as those which occur in type I
hypersensitivity reactions (e.g. hay fever) where the provoking environmental
antigen (e.g. pollen) otherwise poses no threat to the individual. Such allergic
inflammatory responses may be life-threatening, for example extrinsic asthma.
Features of the Fluid Exudate
The increased vascular permeability means that large molecules, such as
proteins, can escape from vessels. Hence, the exudate fluid has a high
protein content of up to 50 g/l. The proteins present include immunoglobulins,
which may be important in the destruction of invading micro-organisms, and
coagulation factors, including fibrinogen, which result in fibrin deposition on
contact with the extravascular tissues. Hence, acutely inflamed organ
surfaces are commonly covered by fibrin: the fibrinous exudate. There is a
considerable turnover of the inflammatory exudate it is constantly drained
away by local Iymphatic channels to be replaced by new exudate.

This slide shows the peritoneal

surface of an acutely inflamed
appendix. The pink layer on the
peritoneal surface consists of fibrin in
which cells are enmeshed.

This slide shows pink staining

threads of fibrin with leucocytes in
Formation of the Cellular Exudate
The accumulation of neutrophil polymorphs within the extracellular space is the
diagnostic histological feature of acute inflammation.

High-magnification of pus in the lumen of the appendix. Pus consists of living

and degenerate neutrophil polymorphs together with liquefied tissue debris.

The neutrophil is the main cell to mediate the effects of acute inflammation. If
tissue damage is slight, an adequate supply is derived from normal numbers
circulating in blood. If tissue damage is extensive, stores of neutrophils,
including some immature forms, are released from bone marrow to increase the
absolute count of neutrophils in the blood. To maintain the supply of neutrophils,
growth factors derived from the inflammatory process stimulate division of
myeloid precursors in the bone marrow, thereby increasing the number of
developing neutrophils.
Chemical mediators released from cells
•Histamine. This is the best-known chemical mediator in acute inflammation. It causes
vascular dilatation and the immediate transient phase of increased vascular
permeability. It is stored in mast cells, basophil and eosinophil leukocytes, and
platelets. Histamine release from those sites (for example, mast cell degranulation) is
stimulated by complement components C3a and C5a, and by Iysosomal proteins
released from neutrophils.
•Lysosomal compounds. These are released from neutrophils and include cationic
proteins, which may increase vascular permeability, and neutral proteases, which may
activate complement.
•Prostaglandins. These are a group of long-chain fatty acids derived from arachidonic
acid and synthesised by many cell types. Some prostaglandins potentiate the increase
in vascular permeability caused by other compounds. Others include platelet
aggregation (prostaglandin 1. is inhibitory while prostaglandin A2 is stimulatory). Part of
the anti-inflammatory activity of drugs such as aspirin and the non-steroidal anti-
inflammatory drugs is attributable to inhibition of one of the enzymes involved in
prostaglandin synthesis.
•Leukotrienes. These arc also synthesised from arachidonic acid, especially in
neutrophils, and appear to have vasoactive properties. SRS-A (slow reacting substance
of anaphylaxis), involved in type I hypersensitivity, is a mixture of leukotrienes.
•5-hydroxytryptamine (serotonin). This is present in high concentration in mast cells
and platelets. It is a potent vasoconstrictor.
•Lymphokines. This family of chemical messengers released by Iymphocytes. Apart
from their major role in type IV hypersensitivity, Iymphokines may also have vasoactive
or chemotactic properties.
Role of the Neutrophil Polymorph

The neutrophil polymorph is the characteristic cell of the acute inflammatory infiltrate. The actions of
this cell will now be considered.
Contraction of cytoplasmic microtubules and gel/sol changes in cytoplasmic fluidity bring
about amoeboid movement. These active mechanisms are dependent upon calcium ions and
are controlled by intracellular concentrations of cyclic nucleotides. The movement shows a
directional response (chemotaxis) to various chemicals.
Adhesion to micro-organisms
Micro-organisms are opsonised (from the Greek word meaning 'to prepare for the table'), or
rendered more amenable to phagocytosis, either by immunoglobulins or by complement
components. Bacterial lipopolysaccharides activate complement via the alternative pathway,
generating component C3b which has opsonising properties. In addition, if antibody binds to
bacterial antigens, this can activate complement via the classical pathway, also generating
C3b. In the immune individual, the binding of immunoglobulins to micro-organisms by their
Fab components leaves the Fc component exposed. Neutrophils have surface receptors for
the Fc fragment of immunoglobulins, and consequently bind to the micro-organisms prior to
The process whereby cells (such as neutrophil polymorphs and macrophages) ingest solid
particles is termed phagocytosis. The first step in phagocytosis is adhesion of the particle to
be phagocytosed to the cell surface. This is facilitated by opsonisation. 'The phagocyte then
ingests the attached particle by sending out pseudopodia around it. These meet and fuse so
that the particle lies in a phagocytic vacuole (also called a phagosome) bounded by cell
membrane. Lysosomes, membrane-bound packets containing the toxic compounds described
below, then fuse with phagosomes to form phagolysosomes. It is within these that intracellular
killing of micro-organisms occurs.
Intracellular killing of micro-organisms
Neutrophil polymorphs are highly specialised cells, containing noxious microbial
agents, some of which are similar to household bleach. The microbial agents may be
classified as:
those which are oxygen-dependent
those which are oxygen-independent.
Oxygen-dependent mechanisms. The neutrophils produce hydrogen peroxide which
reacts with myeloperoxidase in the cytoplasmic granules in the presence of halide,
such as Cl, to produce a potent microbial agent. Other products of oxygen reduction
also contribute to the killing, such as peroxide anions (O2-), hydroxyl radicals (.OH)
and singlet oxygen (1O2).
Oxygen-independent mechanisms. These include Iysozyme (muramidase), lactoferrin
which chelates iron required for bacterial growth, cationic proteins, and the low pH
inside phagocytic vacuoles.
Release of lysosomal products
Release of Iysosomal products from the cell damages local tissues by proteolysis by
enzymes such as elastase and collagenase, activates coagulation factor XII, and
attracts other leukocytes into the area. Some of the compounds released increase
vascular permeability, while others are pyrogens, producing systemic fever by acting
on the hypothalamus.
Role of the Lymphatics
Terminal Iymphatics are blind-ended, endothelium-lined tubes present in most tissues in
similar numbers to capillaries. The terminal Iymphatics drain into collecting Iymphatics
which have valves and so propel Iymph passively, aided by contraction of neighbouring
muscles, to the Iymph nodes. The basal lamina of Iymphatic endothelium is incomplete,
and the junctions between the cells are simpler and less robust than those between
capillary endothelial cells. Hence, gaps tend to open up passively between the Iymphatic
endothelial cells,allowing large protein molecules to enter.
In acute inflammation, the Iymphatic channels become dilated as they drain away the
oedema fluid of the inflammatory exudate. This drainage tends to limit the extent of
oedema in the tissues. The ability of the Iymphatics to carry large molecules and some
particulate matter is important in the immune response to infecting agents; antigens are
carried to the regional Iymph nodes for recognition by Iymphocytes.

If the lymphatic system becomes blocked either as a result of

acute inflammation or in filariasis (infection by parasitic larvae),
severe tissue oedema may occur, resulting in elephantiasis.
Sequelae of Acute Inflammation
The sequelae of acute inflammation depend upon the type of tissue involved and the
amount of tissue destruction, which depend in turn upon the nature of the injurious agent.
The possible outcomes of acute inflammation are:
Chronic Inflammation
Resolution of Acute Inflammation
The term resolution means the complete restoration of the tissues to normal after an episode of
acute inflammation. The conditions which favour resolution are:
•minimal cell death and tissue damage occurrence in an organ or tissue which has regenerative
capacity (e.g. the liver) rather than in one which cannot regenerate (e.g. the central nervous
•rapid destruction of the causal agent (e.g. phagocytosis of bacteria)
•rapid removal of fluid and debris by good local vascular drainage.
•A good example of an acute inflammatory condition which usually resolves completely is acute
lobar pneumonia. The alveoli become filled with acute inflammatory exudate containing fibrin,
bacteria and neutrophil polymorphs. The alveolar walls are thin and have many capillaries (for gas
exchange) and Iymphatic channels. The sequence of events leading to resolution is usually:
•phagocytosis of bacteria (e.g. pneumococci) by neutrophils and intracellular killing
•phagocytosis of debris, especially by macrophages, and carriage through Iymphatics to the hilar
Iymph nodes
•disappearance of vascular dilatation.
•Following this, the lung parenchyma would appear histologically normal.
Suppuration is the formation of pus, a mixture of living, dying and dead neutrophils and
bacteria, cellular debris and sometimes globules of lipid. The causative stimulus must be fairly
persistent and is virtually always an infective agent, usually pyogenic bacteria (e.g.
Staphylococcus aureus, Streptococcus pyogenes, Neisseria species or coliform organisms).
Once pus begins to accumulate in a tissue, it becomes surrounded by a 'pyogenic membrane'
consisting of sprouting capillaries, neutrophils and occasional fibroblasts. Such a collection of
pus is called an abscess, and bacteria within the abscess cavity are relatively inaccessible to
antibodies and to antibiotic drugs (thus, for example, acute osteomyelitis, an abscess in the
bone marrow cavity, is notoriously difficult to treat).
An abscess (for example, a boil) usually 'points', then bursts; the abscess cavity collapses and
is obliterated by organisation and fibrosis, leaving a small scar. Sometimes, surgical incision
and drainage is necessary to eliminate the abscess. If an abscess forms inside a hollow
viscus (e.g. the gall bladder) the mucosal layers of the outflow tract of the viscus may become
fused together by fibrin, resulting in an empyema.
Such deep-seated abscesses sometimes discharge their pus along a sinus tract (an abnormal
connection, lined by granulation tissue, between the abscess and the skin or a mucosal
surface). If this results in an abnormal passage connecting two mucosal surfaces or one
mucosal surface to the skin surface, it is referred to as a fistula. Sinuses occur particularly
when foreign body materials are present, which are indigestible by macrophages and which
favour continuing suppuration. The only treatment for this type of condition is surgical
elimination of the foreign body material.
Organisation of tissues is their replacement by granulation tissue. The circumstances
favouring this outcome are when:
•Iarge amounts of fibrin are formed, which cannot be removed completely by fibrinolytic
enzymes from the plasma or from neutrophil polymorphs
•substantial volumes of tissue become necrotic or if the dead tissue (e.g. fibrous tissue) is not
easily digested
•exudate and debris cannot be removed or discharged.
During organisation,
•new capillaries grow into the inert material (inflammatory exudate),
•macrophages migrate into the zone
•fibroblasts proliferate, resulting in fibrosis.
A good example of this is seen in the pleural space following acute lobar pneumonia.
Resolution usually occurs in the lung parenchyma, but very extensive fibrinous exudate fills
the pleural cavity. The fibrin is not easily removed and consequently capillaries grow into the
fibrin, accompanied by macrophages and fibroblasts (the exudate becomes 'organised').
Eventually, fibrous adhesion occurs between the parietal and visceral pleura.

Progression to Chronic Inflammation

If the agent causing acute inflammation is not removed, the acute inflammation may progress
to the chronic stage. In addition to organisation of the tissue just described, the character of
the cellular exudate changes, with Iymphocytes, plasma cells and macrophages (sometimes
including multi nucleate giant cells) replacing the neutrophil polymorphs. Often, however,
chronic inflammation occurs as a primary event, there being no preceeding period of acute
Examples of Organisms which can be Associated with Chronic
Inflammatory Processes

• Mycobacterium tuberculosis.
The red - stained, elongated organisms shown here are
M. tuberculosis within macrophages in a tuberculous
abscess. Mycobacteria have a thick, waxy cell wall that
protects them against the enzymic and other
mechanisms used by macrophages to inactivate
organisms. They are thus able to survive for prolonged
periods within macrophages and so are also protected
against other cellular and humoral mechanisms for
dealing with invading organisms. (Ziehl-Neelsen stain).

2. Streptococci in chronic abscess.

Streptococci can survive within pus in a chronic abscess
cavity where they are protected from other mechanisms
for disposal of bacteria, e.g. macrophages, opsonising
antibodies, complement and, of course, theraputically
administered antibiotics.(Gram stain).
3. Fungi.
This is an illustration of mycelial filaments of the
fungus Mucor in a chronic abscess. The presence of
the fungus has stimulated vigorous fibrosis and this
has enabled the organism to become surrounded by
dense collagenous tissue and thus protected from
phagocytosis, antibodies, complement, etc.

4. Syphilis.
This illustration shows the organisms Treponema
pallidum in a syphilitic lesion in the brain. Such
lesions are now rare, since the disease is treatable
with antibiotics such as the penicillins. (Levaditi
silver stain).
Chronic Inflammation

Chronic inflammation is an inflammatory response of prolonged duration - weeks, months,

or even indefinitely - whose extended time course is provoked by persistance of the
causative stimulus to inflammation in the tissue. The inflammatory process inevitably
causes tissue damage and is accompanied by simultaneous attempts at healing and
repair. The exact nature, extent and time course of chronic inflammation is variable, and
depends on a balance between the causative agent and the attempts of the body to
remove it.

Chronic inflammation may develop in the following ways:

• as a progression from acute inflammation if the original stimulus persists,

• after repeated episodes of acute inflammation,
• de novo if the causative agent produces only a mild acute response.
Aetiological agents producing chronic inflammation include:

• Infectious organisms that can avoid or resist host defences and so persist in the tissue for a prolonged
period. Examples include Mycobacterium tuberculosis, Actinomycetes, and numerous fungi, protozoa
and metazoal parasites. Such organisms are in general able to avoid phagocytosis or survive within
phagocytic cells, and tend not to produce toxins causing acute tissue damage.

• Infectious organisms that are not innately resistant but persist in damaged regions where they are
protected from host defences. The common example here is of bacteria which grow in the pus within an
undrained abscess cavity, where they are protected both from host immunity and from blood-borne
theraputic agents, e.g. antibiotics. Some locations are particularly prone to chronic abscess formation,
e.g. bone, pleural cavities.

• Irritant non-living foreign material that cannot be removed by enzymic breakdown or phagocytosis.
Examples include a wide range of materials implanted into wounds (wood splinters, grit, metals and
plastics), inhaled (silica dust and other particles or fibres), or deliberately introduced (surgical
prostheses, sutures, etc.). Dead tissue components that cannot be broken down may have similar
effects, e.g. keratin squames from a ruptured epidermoid cyst or fragments of dead bone (sequestrum)
in osteomyelitis.

• In some cases the stimulus to chronic inflammation may be a "normal" tissue component. This occurs
in inflammatory diseases where the disease process is initated and maintained because of an
abnormality in the regulation of the body's immune reponse to its own tissues - the so-called auto-
immune diseases.

• For many diseases characterised by a chronic inflammatory pathological process the underlying cause
remains unknown. A good example here is Crohn's disease of the intestine.
Histological appearances in chronic inflammation:

The microscopic appearances of chronic inflammation vary considerably according to the site involved
and the causative stimulus. However, the general features are:

• A mixed inflammatory cell infiltrate containing predominantly macrophages, lymphocytes and

plasma cells, with neutrophil and eosinophil polymorphs as possible minor components (compare
with the predominance of neutrophils in acute inflammation). Lymphoid cells can proliferate at the
site of inflammation as well as in local lymph nodes; in severe cases this can give rise to lymphoid
follicles with germinal centres in the inflammatory lesion.

• Tissue destruction (necrosis) caused both by the causative agent and by the inflammatory process

• Attempts at reconstructing the damaged tissue occur simultaneously with the inflammatory
process. These can be considered under the general title of healing and repair. The attempts at
reconstruction may have different outcomes. If there is little tissue destruction then some organs
may be able to regenerate their original structure, or mild inflammation may terminate by resolution
without causing any structural damage. Commonly, however, the original structure cannot be re-
created and the damaged area undergoes repair.This involves removal of the destroyed tissue by
phagocytosis with proliferation of capillary blood vessels and lymphatics into the lesion together
with fibroblasts and collagen production (so-called granulation tissue), ending up with a dense
fibrous scar.

• Granulomatous inflammation is a histologically distinctive form of chronic inflammation that

occurs in particular circumstances in response to certain organisms or foreign material and merits
description in a separate section. N.B. This term (granuloma, granulomatous inflammation) is not
to be confused with granulation tissue. Look at the links explaining both processes and be sure
you understand the distinction.
Types of Chronic Inflammatory Cells.

1. Lymphocytes and macrophages:

This illustration shows a mixed chronic
inflammatory cell infiltrate containing mainly
lymphocytes and macrophages. The
lymphocytes have small, round, very darkly
staining nuclei and little surrounding
cytoplasm; the macrophages have larger,
paler, oval or bean shaped nuclei and a
somewhat larger amount of cytoplasm.
Plasma cells are not obvious in this field.

2. Lymphocytes around a blood vessel:

Perivascular cuffingis a common pattern of
lymphocytic infiltration in chronic inflammmatory
reactions. Lymphocytes emerge from the
circulating blood mostly through the walls of small
venules and tend to aggregate around the
vessels. This example is from an inflammatory
disease of the brain - multiple sclerosis.
3. Macrophages in infarcted brain:
Macrophages are highly phagocytic, as the name
implies, and will engulf and degrade all sorts of debris
in areas of damage. This example shows
macrophages which have phagocytosed lipid material
from broken - down myelin in an area of infarcted
brain. The macrophage cell bodies are large and
round, distended with pale, foamy looking lipid - filled
vacuoles (lysosomes). This foamy appearance is also
seen in other sites where lipid debris is being removed
(fat necrosis, for example).

4. Plasma cells:
These distinctive looking cells have an
eccentrically placed nucleus with coarse, blotchy
staining of the chromatin, said to resemble a clock
face. The cytoplasm is rather blue staining
(basophilic), reflecting its high content of rough
endoplasmic reticulum with large numbers of
ribosomes containing ribosomal RNA. There is also
a prominent pale area of cytoplasm next to the
nucleus - the Golgi apparatus. Plasma cells are
mature, end-stage cells of the B-lymphocyte
lineage, specialised for antibody production and
5.Lymphoid follicles:
This is a lymphoid follicle producing lymphocytes
within thyroid tissue during the chronic inflammatory
process which destroys the gland in Hashimoto's
Disease. The inflammation is triggered and maintained
by abnormal sensitivity of the immune system against
its own thyroid tissue - i.e. an auto-immune disease.
The follicle is a structured aggregate of lymphoid cells,
with a central region of large, pale - staining, actively
proliferating precursor cells and a mantle zone of
closely packed mature lymphocytes recognizable by
their small, round, intensely blue/black nuclei.

Other cell types involved in the inflammatory reaction:

3. Mast cell

5. Platelet

7. Vascular endothelium
Granulomatous Inflammation:

Structure of a granuloma.
Granulomas are aggregates of particular types of chronic inflamatory cells which form nodules in the
milimetre size range. Granulomas may be confluent, forming larger areas.The essential components
of a granuloma are collections of modified macrophages, termed epithelioid cells, usually with a
surrounding zone of lymphocytes. (Epithelioid cells are so named by tradition because of their
histological resemblance to epithelial cells, but are not in fact epithelial; they are derived from blood
monocytes, like all macrophages.) Epithelioid cells are less phagocytic than other macrophages and
appear to be modified for secretory functions. The full extent of their functions is still unclear.

Macrophages in granulomas are commonly further modified to form multinucleate giant cells.These
arise by fusion of epithelioid macrophages without nuclear or cellular division forming huge single cells
which may contain dozens of nuclei. In some circumstances the nuclei are arranged round the
periphery of the cell, termed a Langhans-type giant cell (characteristically seen in tuberculosis); in
other circumstances the nuclei are randomly scattered throughout the cytoplasm - for example in the
foreign body type of giant cell which is formed in response to the presence of other indigestible foreign
material in the tissue.

Areas of granulomatous inflammation commonly undergo necrosis. The prototype example here is
caseous necrosis in tuberculosis.

Conditions for formation of granulomas.

Formation of granulomatous inflammation seems to require the presence of indigestible foreign
material (derived from bacteria or other sources) and/or a cell-mediated immune reaction against the
injurious agent (type IV hypersensitivity reaction). The finding of granulomatous infammation in a
biopsy specimen can be very useful in limiting the number of possible causes of the inflammatory
Examples of granulomatous inflammation:

• Specific Infections:Mycobacteria (tuberculosis, leprosy, others),

syphilis, brucellosis, fungi, parasites (e.g. Schistosoma).

• Foreign bodies:
Endogenous: e.g. keratin, necrotic boneor adipose tissue, uric acid
crystals (gout).
Exogenous: e.g. wood, grit, silica or asbestos dust, talc, suture
material, silicone, prostheses.

• Specific chemicals: Beryllium.

• Drugs: Hepatic granuloma due to allopurinal, phenylbutazone,


• Unknown: Sarcoidosis, Crohn's disease.

Cell Types in Granulomatous Inflammation:

1. Langhans type giant cell and epithelioid

macrophages in tuberculous granuloma.
The central giant cell has a peripheral ring of
nuclei in the cytoplasm. A second group of similar
nuclei just to the right of this cell represents a
second giant cell, probably smaller and cut rather
tangentially in the plane of section. The
surrounding cells are almost all epithelioid

2. Giant cells in the wall of an artery in giant

cell arteritis (temporal arteritis).
Giant cell arteritis involves an abnormal
inflammatory attack on elasic tissue in the walls
of some arteries, commonly the temporal artery
and other branches of the external carotid
circulation. The elastic tissue is not easily
degraded and stimulates the formation of
multinucleate giant cells as part of the
granulomatous chronic inflammatory process.
3. Foreign body type giant cells (a).
These giant cells have formed as a reaction to
keratinous material forced into the dermis when
an epidermoid cyst underwent rupture.

4. Foreign body type giant cells (b).

These foreign body giant cells contain distinctive
elongated, apparently empty, clefts which result
from the ingestion of crystalline material, largely
cholesterol, in an atheromatous plaque. The clefts
appear empty in the histological preparation
because the lipid-rich ingested material has been
dissolved out of the tissue by the solvents used in
histological processing.
5. Structure of a granuloma (a).
This low power photomicrograph shows
numerous discrete, uniformly sized, round
granulomas scattered throughout a lymph
node. They are composed of epithelioid cells
which stand out pale against the darkly staining
lymphocytes in which thay are set. Giant cells
are not obvious. The capsule of the lymph node
can be seen at the top, giving a clue to the size
of the structures - probably 0.5 to 1.0 mm
across. The disease process here is
sarcoidosis, a chronic granulomatous disease
of unknown aetiology.

6. Structure of a granuloma (b).

This image shows pale staining granulomas
composed of rather irregular, confluent
aggregates of epithelioid cells with Langhans-
type giant cells centrally and a surrouding
infiltrate of lymphocytes, seen on the right of
the picture. Tuberculous meningitis.