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Inflammation Acute vs Chronic

Inflammation is usually classified according to its time course as:
• acute inflammation – the initial and often transient series of tissue reactions to injury

• chronic inflammation – the subsequent and often prolonged tissue reactions following the initial response.


Acute inflammation

Initial reaction of tissue to injury

Acute inflammation is the initial tissue reaction to a wide range of injurious agents, lasting from a few hours-few days. Neutrophil polymorph is the predominant cell but mast cells and macrophages are also important

• Vascular phase: dilatation and increased
• Exudative phase: fluid and cells escape from
permeable venules
• Outcome may be resolution, suppuration, organisation, or progression to chronic inflammation.

The acute inflammatory response involves three processes:

• changes in vessel calibre therefore flow
• increased vascular permeability and formation of the fluid exudates
• formation of the cellular exudate – emigration of
the neutrophil polymorphs into the extravascular space.


Macroscopic appearance of acute inflammation: Rubor

Rubor, calor, tumor and dolor. Loss of function is also characteristic.

Redness (rubor)
An acutely inflamed tissue appears red, for example, skin affected by sunburn, cellulitis due to bacterial infection or acute conjunctivitis. This is due to dilatation of small blood vessels within the damaged area.


Macroscopic appearance of acute inflammation: Calor

Heat (calor)
Increase in temperature is seen only in peripheral parts of the body, such as the skin. It is due to increased blood flow (hyperaemia) through the region, resulting in vascular dilatation and the delivery of warm blood to the area. Systemic fever, which results from some of the chemical mediators of inflammation, also contributes to the local temperature.


Macroscopic appearance of acute inflammation: Tumor

See diagram

Swelling (tumor)
Swelling results from oedema – the accumulation of fluid in the extravascular space as part of the fluid exudate – and, to a much lesser extent, from the physical mass of the inflammatory cells migrating into the area.


Macroscopic appearance of acute inflammation: Dolor

Pain (dolor)
For the patient, pain is one of the best-known fea- tures of acute inflammation. It results partly from the stretching and distortion of tissues due to inflammatory oedema and, in particular, from pus under pressure in an abscess cavity. Some of the chemical mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin, are known to induce pain.


Macroscopic appearance of acute inflammation: Loss of function

Movement of an inflamed area is consciously and reflexly inhibited by pain, while severe swelling may physically immo- bilise the tissues.


Stages of acute inflammation: Change in vessel calibre

See diagram

The microcirculation consists of the network of small capillaries lying between arterioles, which have a thick muscular wall, and thin-walled venules.

Capillaries have no smooth muscle in their walls to control their calibre, and are so narrow that red blood cells must pass through them in single file. The smooth muscle of arteriolar walls forms precapillary sphincters which regulate blood flow through the capillary bed.

Flow through the capillaries is intermittent, and some form preferential channels for flow while others are usually shut down (Fig. 2.2).

In blood vessels larger than capillaries, blood cells flow mainly in the centre of the lumen (axial low),
while the area near the vessel wall carries only plasma (plasmatic zone). This feature of normal blood flow keeps blood cells away from the vessel wall.


Triple response: Flush, flare and wheal.

If a blunt instrument is drawn firmly across the skin, the following sequential changes take place:

• a momentary white line follows the stroke: this is due to arteriolar vasoconstriction, the smooth muscle of arterioles contracting as a direct response to injury
• the flush: a dull red line follows due to capillary dilatation
• the flare: a red, irregular, surrounding zone then develops, due to arteriolar dilatation. Both nervous and chemical factors are involved in these vascular changes
• the wheal: a zone of oedema develops due to fluid exudation into the extravascular space.
The initial phase of arteriolar constriction is tran- sient and probably of little importance in acute inflammation.

The subsequent phase of vasodilatation (active hyperaemia) may last from 15 mins to several hours, depending upon the severity of the injury. There is experimental evidence that blood flow to the injured area may increase up to ten-fold.

As blood flow begins to slow again, blood cells begin to flow nearer to the vessel wall, in the plasmatic zone rather than the axial stream. This allows ‘pavementing’ of leukocytes (their adhesion to the vascular epithelium) to occur, which is the first step in leukocyte emigration into the extravascular space.

The slowing of blood flow which follows the phase of hyperaemia is due to increased vascular permeability, allowing plasma to escape into the tissues while blood cells are retained within the vessels. The blood viscosity is, therefore, increased.


Increased vascular permeability

1) Small blood vessels are lined by a single layer of endothelial cells. In some tissues, these form a complete layer of uniform thickness around the vessel wall, while in other tissues there are areas of endothelial cell thinning, known as fenestrations. The walls of small blood vessels act as a microfilter, allowing the passage of water and solutes but blocking that of large molecules and cells.

2) The high colloid osmotic pressure inside the vessel, due to plasma proteins, favours fluid return to the vascular compartment. Under normal circumstances, high hydrostatic pressure at the arteriolar end of capillaries forces fluid out into the extravascular space, but this fluid returns into the capillaries at their venous end, where hydrostatic pressure is low.

3) In acute inflammation, however, not only is capillary hydrostatic pressure increased, but there is also escape of plasma proteins into the extravascular space, increasing the colloid osmotic pressure there. Consequently, much more fluid leaves the vessels than is returned to them. The net escape of protein-rich fluid is called exudation


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, acute 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 lymphatic channels to be replaced by new exudate.


Ultrastructural basis of increased vascular permeability

Injection of histamine causes:

Electron microscopic examination of venules and small veins during this period showed that gaps of 0.1–0.4μm in diameter had appeared between endothelial cells.

The endothelial cells are not damaged during this process. They contain contractile proteins such as actin, which, when stimulated by the chemical mediators of acute inflammation, cause contraction of the endothelial cells, pulling open the transient pores.

The leakage induced by chemical mediators, such as histamine, is confined to venules and small veins.

Although fluid is lost by ultrafiltration from capillaries, there is no evidence that they too become more permeable in acute inflammation.


Leukocyte surface adhesion molecule expression is increased by:

• complement component C5a
• leukotriene B4
• tumour necrosis factor


Tissue sensitivity to chemical mediators

Vessels in the central nervous system are relatively insensitive to the chemical mediators, while those in the skin, conjunctiva and bronchial mucosa are exquisitely sensitive to agents such as histamine.


Endothelial cell expression of endothelial-leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1), to which the leukocytes’ surface adhesion molecules bond, is increased by:

• interleukin-1
• endotoxins
• tumour necrosis factor


Margination of neutrophils

See diagram neutrophils

In the normal circulation, cells are confined to the central (axial) stream in blood vessels, and do not flow in the peripheral (plasmatic) zone near to the endothelium.

However, loss of intravascular fluid and increase in plasma viscosity with slowing of flow at the site of acute inflammation allow neutrophils to flow in this plasmatic zone.


Adhesion of neutrophils

The adhesion of neutrophils to the vascular endothelium which occurs at sites of acute inflammation is termed ‘pavementing’ of neutrophils. Neutrophils randomly contact the endothelium in normal tissues, but do not adhere to it. However, at sites of injury, pavementing occurs early in the acute inflammatory response and appears to be a specific process occurring independently of the eventual slowing of blood flow.

The phenomenon is seen only in venules.
Increased leukocyte adhesion results from interaction between paired adhesion molecules on leukocyte and endothelial surfaces. Leukocyte surface adhesion molecule expression is increased by:

• complement component C5a
• leukotriene B4
• tumour necrosis factor

Endothelial cell expression of endothelial-leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1), to which the leukocytes’ surface adhesion molecules bond, is increased by:

• interleukin-1
• endotoxins
• tumour necrosis factor


Neutrophil emigration and diapedesis

Leukocytes migrate by active amoeboid movement through the walls of venules and small veins, under the influence of C5a and leukotriene-B4, but do not commonly exit from capillaries. Electron microscopy shows that neutrophil and eosinophil polymorphs and macrophages can insert pseudopodia between endothelial cells, migrate through the gap created between the endothelial cells, and then on through the basal lamina into the vessel wall. The defect appears to
be self-sealing, and the endothelial cells are not damaged by this process.

Red cells may also escape from vessels, but in this case the process is passive and depends on hydrostatic pressure forcing the red cells out. The process is called diapedesis, and the presence of large numbers of red cells in the extravascular space implies severe vascular injury, such as a tear in the vessel wall.


Chemotaxis of neutrophils

Neutrophil polymorphs are attracted towards certain chemical substances in solution – a process called chemotaxis-migration of neutrophils along a concentration gradient.

It is not known whether chemo-taxis is important in vivo.

Neutrophils may possibly arrive at sites of injury by random movement, and then be trapped there by immobilising factors (a process analogous to the trapping of macrophages at sites of delayed type hypersensitivity by migration inhibitory factor


Chemical mediators of acute inflammation

Early in the response, histamine and thrombin released by the original inflammatory stimulus cause upregulation of P-selectin and platelet activating factor (PAF) on the endothelial cells lining the venules.

Adhesion molecules, stored in intracellular vesicles, appear rapidly on the cell surface. Neutrophil polymorphs begin to roll along the endothelial wall due to engagement of the lectin-like domain on the P-selectin molecule with sialyl Lewisx carbohydrate ligands on the neutrophil polymorph surface mucins.

This also helps platelet activating factor to dock with its corresponding receptor which, in turn, increases expression of the integrals lymphocyte function-associated molecule-1 (LFA-1) and membrane attack complex-1 (MAC-1). The overall effect of all these molecules is very firm neutrophil adhesion to the endothelial surface.


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
- eosinophil leukocytes
- platelets

Histamine release from these sites (for example, mast cell degranulation) is stimulated by complement components C3a and C5a, and by lysosomal proteins released from neutrophils.


Complement activation most important in acute inflammation include:

The products of complement activation most important in acute inflammation include:
• C5a: chemotactic for neutrophils; increases vascular permeability; releases histamine from mast cells;
• C3a: similar properties to those of C5a, but less active;
• C5,6,7: chemotactic for neutrophils;
• C5,6,7,8,9: cytolytic activity; and
• C4b,2a,3b: opsonisation of bacteria (facilitates
phagocytosis by macrophages).


Chemical mediators released from cells: Prostaglandins

Some prostaglandins potentiate the increase in vascular permeability caused by other compounds.

Others include platelet aggregation (prostaglandin I2 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.


Chemical mediators released from cells: Leukotrienes

These are also synthesised from arachidonic acid, especially in neutrophils, and appear to have vasoactive properties. SRS-A (slow reacting sub- stance of anaphylaxis), involved in type I hypersensitivity, is a mixture of leukotrienes.


Chemical mediators released from cells: Serotonin and chemokines

Serotonin: This is present in high concentration in mast cells and platelets. It is a potent vasoconstrictor.

Chemokines This large family of 8–10kDa proteins selectively attracts various types of leukocytes to the site of inflammation. Some chemokines such as IL-8 are mainly specific for neutrophil polymorphs and to a lesser extent lymphocytes whereas other types of chemokines are chemotactic for monocytes, natural killer (NK) cells, basophils and eosinophils. The various chemokines bind to extracellular matrix components such as heparin and heparan sulphate glycosaminoglycans, setting up a gradient of chemotactic molecules fixed to the extracellular matrix.


Complement system

The complement system is a cascade system of enzymatic proteins. It can be activated during the acute inflammatory reaction in various ways:

• in tissue necrosis, enzymes capable of activating complement are released from dying cells

• during infection, the formation of antigen- antibody complexes can activate complement via the classical pathway, while the endotoxins of Gram-negative bacteria activate complement via the alternative pathway

• products of the kinin, coagulation and fibrinolytic systems can activate complement.


Kinin system

See diagram

The kinins are peptides of 9–11 amino acids; the most important vascular permeability factor is bradykinin. The kinin system is activated by coagulation factor XII (Fig. 2.5). Bradykinin is also a chemical mediator of the pain which is a cardinal feature of acute inflammation.


Coagulation system

The coagulation system is responsible for the conversion of soluble fibrinogen into fibrin, a major component of the acute inflammatory exudate.

Coagulation factor XII (the Hageman factor), once activated by contact with extracellular materials such as basal lamina, and various proteolytic enzymes of bacterial origin, can activate the coagulation, kinin and fibrinolytic systems.


Fibrinolytic system

Plasmin is responsible for the lysis of fibrin into fibrin degradation products, which may have local effects on vascular permeability.



Terminal lymphatics are blind-ended, endothelium-lined tubes present in most tissues in similar numbers to capillaries.

The terminal lymphatics drain into collecting lymphatics which have valves and so propel lymph passively, aided by contraction of neighbouring muscles, to the lymph nodes. The basal lamina of lymphatic endothelium is incomplete, and the junction between the cells are simpler and less robust than those between capillary endothelial cells.

Hence, gaps tend to open up passively between the lymphatic endothelial cells, allowing large protein molecules to enter.

In acute inflammation, the lymphatic 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 lymphatics to carry large molecules and some particulate matter is important in the immune response to infecting agents; antigens are carried to the regional lymph nodes for recognition by lymphocytes.



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, whereby the micro-organism becomes coated with antibody, C3b and certain acute phase proteins while phagocytic cells such as neutrophil polymorphs and macrophages have upregulated C3 and Ig receptors under the influence of inflammatory mediators, enhancing adhesion of the microorganism. 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 microorganisms occurs.


Intracellular killing of micro-organisms
Oxygen-dependent and independent mechanisms

Neutrophil polymorphs are highly specialised cells, containing noxious microbicidal agents, some of which are similar to household bleach. The microbicidal 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 C1, to produce a potent microbicidal agent. Other products of oxygen reduction also contribute to the killing, such as perox- ide anions (O2), hydroxyl radicals (.OH) and singlet oxygen (1O2).

Oxygen-independent mechanisms
These include lysozyme (muramidase), lactoferrin which chelates iron required for bacterial growth, cationic proteins, and the low pH inside phagocytic vacuoles.


Special macroscopic appearances of inflammation: Serous inflammation

The cardinal signs of acute inflammation are modified according to the tissue involved and the type of agent provoking the inflammation. Several descriptive terms are used for the appearances.

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 (Fig. 2.1), i.e. having dilated, blood-laden vessels on the surface (like the appearance of the con- junctiva in ‘blood-shot eyes’).


Special macroscopic appearances of inflammation: Catarrhal inflammation

When mucus hypersecretion accompanies acute inflammation of a mucous membrane, the appearance is described as catarrhal. The common cold is a good example.


Special macroscopic appearances of inflammation: 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.


Special macroscopic appearances of inflammation: 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.


Special macroscopic appearances of inflammation: Suppurative (purulent) inflammation

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 gallbladder or of the appendix.


Special macroscopic appearances of inflammation: 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 Corynebacterium diphtheriae.


Special macroscopic appearances of inflammation: 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.


Special macroscopic appearances of inflammation: Necrotising inflammation

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 example



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 system)
• rapid destruction of the causal agent (e.g. phagocytosis of bacteria)
• rapid removal of fluid and debris by good local vascular drainage.



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).


Abscess and Fistula

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 gallbladder) the mucosal layers of the outflow tract of the viscus may become fused together by fibrin, resulting in an empyema (Fig. 2.8).

Such deep-seated abscesses sometimes discharge their pus along a sinus tract. 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 (an abnormal passage, lined by granulation tissue, between two mucosal surfaces). .

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.

The fibrous walls of long-standing abscesses may become complicated by dystrophic calcification.



Organisation of tissues is their replacement by granulation tissue. The circumstances favouring this outcome are when:
• large 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 and fibroblasts proliferate under the influence of TGFà, 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 eas- ily 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.


Features of chronic inflammation

The principal features of chronic inflammation are as follows.
• lymphocytes, plasma cells and macrophages predominate
• usually primary, but may follow recurrent acute inflammation
• granulomatous inflammation is a specific type of chronic inflammation;
• a granuloma is an aggregate of epithelioid histiocytes
• may be complicated by secondary (reactive) amyloidosis.


Primary chronic inflammation

In most cases of chronic inflammation, the inflam- matory response has all the histological features of chronic inflammation from the onset, and there is no initial phase of acute inflammation.


Acute to chronic inflammation

Most cases of acute inflammation do not develop into the chronic form, but resolve completely. The commonest variety of acute inflammation to progress to chronic inflammation is the suppurative type.

If the pus forms an abscess cavity which is deep-seated, and drainage is delayed or inadequate, then by the time that drainage occurs the abscess will have developed thick walls composed of granulation and fibrous tissues. The rigid walls of the abscess cavity, therefore, fail to come together after drainage, and the stagnating pus within the cavity becomes organised by the ingrowth of granulation tissue, eventually to be replaced by a fibrous scar.


Chronic abscesses

Good examples of such chronic abscesses include: an abscess in bone marrow cavity (osteomyelitis), which is notoriously difficult to eradicate; and empyema thoracis which has been inadequately drained.

Some bacterial infections lead to chronic inflammation because the microbes have evolved defence mechanisms to phagocytosis. Some virulent organisms synthesise an outer capsule, which resists adhesion to phagocytes and covers carbohydrate molecules on the bacterial surface preventing their recognition by phagocyte receptors.

Some bacterial capsules physically block access of phagocytes to C3b deposited on the bacterial cell wall. Other organisms have positively antiphagocytic cell surface molecules or even secrete exotoxins which poison the leukoytes.

Some bacteria bind to the surface of non-phagocytic cells to ‘hide’ from phagocytes. Poor activation of complement by some bacterial capsules, acceleration of complement breakdown by bacterial surface molecules such as sialic acid and secretion of enzymes which degrade C5a are ways in which the complement system can be prevented from clearing infections.


Macroscopic appearance of chronic inflammation

The commonest appearances of chronic inflammation are:

• chronic ulcer: such as a chronic peptic ulcer of the stomach with breach of the mucosa, a base lined by granulation tissue and with fibrous tissue extending through the muscle layers of the wall:
• chronic abscess cavity: for example, osteomyelitis, empyema thoracis
• thickening of the wall of a hollow viscus: by fibrous tissue in the presence of a chronic inflammatory
cell infiltrate, for example Crohn’s disease, chronic • cholecystitis.
granulomatous inflammation: with caseous necrosis as in chronic fibrocaseous tuberculosis of the lung; and
• fibrosis: which may become the most prominent feature of the chronic inflammatory reaction when most of the chronic inflammatory cell infiltrate has subsided. This is commonly seen in chronic cholecystitis, ‘hour-glass contracture’ of the stomach, where fibrosis distorts the gastric wall and may even lead to acquired pyloric stenosis, and in the strictures which characterise Crohn’s disease


Microscopic features of chronic inflammation

The cellular infiltrate consists characteristically of lymphocytes, plasma cells and macrophages. A few eosinophil polymorphs may be present, but neutrophil polymorphs are scarce. Some of the macrophages may form multinucleate giant cells.

Exudation of fluid is not a prominent feature, but there may be production of new fibrous tissue from granulation tissue. There may be evidence of continuing destruction of tissue at the same time as tissue regeneration and repair. Tissue necrosis may be a prominent feature, especially in granulomatous conditions such as tuberculosis.


Cellular cooperation in chronic inflammation (See diagram)

The lymphocytic tissue infiltrate contains two main types of lymphocyte

B-lymphocytes, on contact with antigen, become progressively transformed into plasma cells, which are cells specially adapted for the production of antibodies. The other main type of lymphocyte, the T-lymphocyte, is responsible for cell-mediated immunity. On contact with antigen, T-lymphocytes produce a range of soluble factors called cytokines, which have a number of important activities:

• Recruitment of macrophages into the area.
It is thought that macrophages are recruited into the area mainly via factors such as migration inhibition factor (MIF) which trap macrophages in the tissue. Macrophage activation factors (MAF) stimulate macrophage phagocytosis and killing of bacteria.

• Production of inflammatory mediators. T-lymphocytes produce a number of inflammatory mediators, including cytokines, chemotactic factors for neutrophils, and factors which increase vascular permeability.

• Recruitment of other lymphocytes. Interleukins stimulate other lymphocytes to divide and confer
on other lymphocytes the ability to mount cell- mediated immune responses to a variety of antigens. T-lymphocytes also co-operate with B-lymphocytes, assisting them in recognising antigens.

• Destruction of target cells. Factors, such as perforins, are produced which destroy other cells by damaging their cell membranes.

• Interferon production. Interferon , produced by activated T-cells, has antiviral properties and, in turn, activates macrophages. Interferons " and à, produced by macrophages and fibroblasts, have antiviral properties and activate NK cells and macrophages.


Macrophages in chronic inflammation I

When neutrophil polymorphs ingest microorganisms, they usually bring about their own destruction and thus have a limited life-span of up to about three days. Macrophages can ingest a wider range of materials than can polymorphs and, being long-lived, they can harbour viable organisms if they are not able to kill them by their lysosomal enzymes.

Examples of organisms which can survive inside macrophages include mycobacteria, such as Mycobacterium tuberculosis and Mycobacterium leprae, and organisms such as Histoplasma capsulatum. When macrophages participate in the delayed type hypersensitivity response to these types of organism, they often die in the process, contributing to the large areas of necrosis by release of their lysosomal enzymes.


Macrophages in chronic inflammation II

Macrophages in inflamed tissues are derived from blood monocytes which have migrated out of vessels and have become transformed in the tissues. They are thus part of the mononuclear phagocyte system.

The ‘activation’ of macrophages as they migrate into an area of inflammation involves an increase in size, protein synthesis, mobility, phagocytic activity and content of lysosomal enzymes. Electron microscopy reveals that the cells have a roughened cell membrane bearing filopodia, while the cytoplasm contains numerous dense bodies – phagolysosomes (formed by the fusion of lysosomes with phagocytic vacuoles).
Macrophages produce a range of important cytokines, including interferons alpha and beta, interleukins 1, 6 and 8, and tumour necrosis factor (TNF) alpha


Specialised forms of macrophages
and granulomatous inflammation: Epithelioid histiocytes

A granuloma is an aggregate of epithelioid histiocytes.

Named for their vague histological resemblance to epithelial cells, epithelioid histiocytes have large vesicular nuclei, plentiful eosinophilic cytoplasm and are often rather elongated. They tend to be arranged in clusters. They have little phagocytic activity, but appear to be adapted to a secretory function. The full range, or purpose, of their secretory products is not known, although one product is angiotensin converting enzyme.

Measurement of the activity of this enzyme in the blood can act as a marker for systemic granulo- matous disease, such as sarcoidosis.
The appearance of granulomas may be augmented by the presence of caseous necrosis (as in tuberculosis) or by the conversion of some of the histiocytes into multinucleate giant cells.

A common feature of many of the stimuli which induce granulomatous inflammation is indigestibility of particulate matter by macrophages. In other conditions, such as the systemic granulomatous condition sarcoidosis, there appear to be far-reaching derangements in immune responsiveness favouring granulomatous inflammation. In other instances, small traces of elements such as beryllium induce granuloma formation, but the way in which they induce the inflammation is unknown.


Histiocytic giant cells

Histiocytic giant cells tend to form where particulate matter which is indigestible by macrophages accumulates, for example, inert minerals such as silica, or bacteria such as tubercle bacilli which have cell walls containing mycolic acids and waxes which resist enzymatic digestion. The multinucleate giant cells, which may contain over 100 nuclei, are thought to develop ‘by accident’ when two or more macrophages attempt simultaneously to engulf the same particle; their cell membranes fuse and the cells unite. The multinucleate giant cells resulting have little phagocytic activity and no known function. They are given specific names according to their microscopic appearance.


Langhans’ giant cells

Langhans’ giant cells have a horseshoe arrangement of peripheral nuclei at one pole of the cell and are characteristically seen in tuberculosis, although they may be seen in other granulomatous conditions. (They must not be confused with Langerhans’ cells, the den- dritic antigen-presenting cells of the epidermis.)


Foreign-body giant cells

So-called ‘foreign-body giant cells’ are large cells with nuclei randomly scattered throughout their cytoplasm. They are characteristically seen in relation to particu- late foreign-body material.


Touton giant cells

Touton giant cells have a central ring of nuclei while the peripheral cytoplasm is clear due to accumulated lipid. They are seen at sites of adipose tissue break- down and in xanthomas (tumour-like aggregates of lipid-laden macrophages).

Although giant cells are commonly seen in granulomas, they do not constitute a defining feature. Solitary giant cells in the absence of epithelioid histiocytes do not constitute a granuloma.