Inflammation

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Chapter 10 Inflammation

Inflammation is the local physiological response to tissue injury. It is not, in itself, a disease, but is usually a manifestation of disease. Inflammation may have beneficial effects, such as the destruction of invading micro-organisms and the walling-off of an abscess cavity, thus preventing spread of infection. Equally, it may produce disease; for example, an abscess in the brain would act as a space-occupying lesion compressing vital surrounding structures, or fibrosis resulting from chronic inflammation may distort the tissues and permanently alter their function.

Inflammation is usually classified according to its time course as:

The two main types of inflammation are also characterised by differences in the cell types taking part in the inflammatory response.

ACUTE INFLAMMATION

Acute inflammation is the initial tissue reaction to a wide range of injurious agents; it may last from a few hours to a few days. The process is usually described by the suffix ‘-itis’, preceded by the name of the organ or tissues involved. Thus, acute inflammation of the meninges is called meningitis. The acute inflammatory response is similar whatever the causative agent.

Causes of acute inflammation

The principal causes of acute inflammation are:

Essential macroscopic appearances of acute inflammation

The essential physical characteristics of acute inflammation were formulated by Celsus (30bcad38) using the Latin words rubor, calor, tumor and dolor. Loss of function is also characteristic.

Early stages of acute inflammation

In the early stages, oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of the damaged tissue. The presence of the cellular component, the neutrophil polymorph, is essential for a histological diagnosis of acute inflammation. The acute inflammatory response involves three processes:

Changes in vessel calibre

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 past 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. 10.3).

In blood vessels larger than capillaries, blood cells flow mainly in the centre of the lumen (axial flow), 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.

Changes in the microcirculation occur as a physiological response; for example, there is hyperaemia in exercising muscle and active endocrine glands. The changes following injury that make up the vascular component of the acute inflammatory reaction were described by Lewis in 1927 as ‘the triple response to injury’: a flush, a flare and a wheal. If a blunt instrument is drawn firmly across the skin, the following sequential changes take place:

The initial phase of arteriolar constriction is transient, and probably of little importance in acute inflammation. The subsequent phase of vasodilatation (active hyperaemia, in contrast to passive hyperaemia due to vascular distension from abnormally high venous pressure) may last from 15 minutes 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 10-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 that 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

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. Oxygen, carbon dioxide and some nutrients transfer across the wall by diffusion, but the main transfer of fluid and solutes is by ultrafiltration, as described by Starling. 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 (Fig. 10.4). 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; hence, the fluid is called the fluid exudate.

Formation of the cellular exudate

The accumulation of neutrophil polymorphs within the extracellular space is the diagnostic histological feature of acute inflammation. The stages whereby leukocytes reach the tissues are shown in Figure 10.5.

Later stages of acute inflammation

Chemical mediators of acute inflammation

The spread of the acute inflammatory response following injury to a small area of tissue suggests that chemical substances are released from injured tissues, spreading outwards into uninjured areas. 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 integrins’ 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. These chemicals, called endogenous chemical mediators, cause:

Chemical mediators released from cells

Plasma factors

The plasma contains four enzymatic cascade systems—complement, the kinins, the coagulation factors and the fibrinolytic system—which are inter-related and produce various inflammatory mediators.

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. The inter-relationships of these systems are shown in Figure 10.6.

Complement system.

The complement system is a cascade system of enzymatic proteins (Ch. 9). It can be activated during the acute inflammatory reaction in various ways:

The products of complement activation most important in acute inflammation include:

Table 10.2 summarises the chemical mediators involved in the three main stages of acute inflammation.

Table 10.2 Endogenous chemical mediators of the acute inflammatory response

Status of acute inflammatory response Chemical mediators
Vascular dilatation HistamineProstaglandins PGE2/I2 VIP Nitric oxide PAF
Increased vascularpermeability Transient phase—histamineProlonged phase—mediators such as bradykinin, nitric oxide, C5a, leukotriene B4 and PAF, potentiated by prostaglandins
Adhesion of leukocytes to endothelium Up-regulation of adhesion molecules on endothelium, principally by IL-8, C5a, leukotriene B4, PAF, IL-1 and TNF-alpha
Neutrophil polymorph chemotaxis Leukotriene B4, IL-8 and others

Role of the neutrophil polymorph

The neutrophil polymorph is the characteristic cell of the acute inflammatory infiltrate (Fig. 10.8). The actions of this cell will now be considered.

Special macroscopic appearances of acute 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.

Effects of acute inflammation

Acute inflammation has local and systemic effects, both of which may be harmful or beneficial. The local effects are usually clearly beneficial, for example the destruction of invading micro-organisms, but at other times they appear to serve no obvious function, or may even be positively harmful.

Beneficial effects

Both the fluid and cellular exudates may have useful effects. Beneficial effects of the fluid exudate are:

Fibrin formation (Fig. 10.11) from exuded fibrinogen may impede the movement of micro-organisms, trapping them and so facilitating phagocytosis, and serves as a matrix for the formation of granulation tissue.

The role of neutrophils in the cellular exudate has already been discussed. They have a life-span of only 1–3 days and must be constantly replaced. Most die locally, but some leave the site via the lymphatics. Some are actively removed by apoptosis. It is probable that apoptosis and its regulation play a major role in determining the outcome of episodes of inflammation. Blood monocytes also arrive at the site and, on leaving the blood vessels, transform into macrophages, becoming more metabolically active, motile and phagocytic. Phagocytosis of micro-organisms is enhanced by opsonisation by antibodies or by complement. In most acute inflammatory reactions, macrophages play a lesser role in phagocytosis compared with that of neutrophil polymorphs. Macrophages start to appear within a few hours of the commencement of inflammation, but do not predominate until the later stages when the neutrophils have diminished in number and the macrophage population has enlarged by local proliferation. They are responsible for clearing away tissue debris and damaged cells.

Both neutrophils and macrophages may discharge their lysosomal enzymes into the extracellular fluid by exocytosis, or the entire cell contents may be released when the cells die. Release of these enzymes assists in the digestion of the inflammatory exudate.

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 shown in Figure 10.12.

Suppuration

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; this is a manifestation of healing, eventually resulting in granulation tissue and scarring. 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).

Organisation

Organisation of tissues is their replacement by granulation tissue as part of the process of repair. The circumstances favouring this outcome are when:

During organisation, new capillaries grow into the inert material (inflammatory exudate), macrophages migrate into the zone and fibroblasts proliferate under the influence of TGF-beta, resulting in fibrosis and, possibly, scar formation. 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 (Fig. 10.11). 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 (Fig. 10.13). Fibrous adhesions also occur commonly in the peritoneal cavity after surgery or an episode of peritonitis; these can hamper further surgery and can also lead to intestinal obstruction.

Systemic effects of inflammation

Apart from the local features of acute and chronic inflammation described above, an inflammatory focus produces systemic effects.

CHRONIC INFLAMMATION

The word ‘chronic’ applied to any process implies that the process has extended over a long period of time. This is usually the case in chronic inflammation, but here the term ‘chronic’ takes on a much more specific meaning, in that the type of cellular reaction differs from that seen in acute inflammation. Chronic inflammation may be defined as an inflammatory process in which lymphocytes, plasma cells and macrophages predominate. As in acute inflammation, granulation and scar tissue are also formed, but in chronic inflammation they are usually more abundant. Chronic inflammation is usually primary, sometimes called chronic inflammation ab initio, but does occasionally follow acute inflammation.

Causes of chronic inflammation

Primary chronic inflammation

In most cases of chronic inflammation, the inflammatory response has all the histological features of chronic inflammation from the onset, and there is no initial phase of acute inflammation. Some examples of primary chronic inflammation are listed in Table 10.3.

Table 10.3 Some examples of primary chronic inflammation

Cause of inflammation Examples
Resistance of infective agent to phagocytosis and intracellular killing Tuberculosis, leprosy, brucellosis, viral infections
Endogenous materials Necrotic adipose tissue, bone, uric acid crystals
Exogenous materials Silica, asbestos fibres, suture materials, implanted prostheses
Some autoimmune diseases

Specific diseases of unknown aetiology Chronic inflammatory bowel disease, e.g. ulcerative colitis Primary granulomatous diseases Crohn’s disease, sarcoidosis

Progression from acute 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 that 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.

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

Another feature that favours progression to chronic inflammation is the presence of indigestible material. This may be keratin from a ruptured epidermal cyst, or fragments of necrotic bone as in the sequestrum of chronic osteomyelitis (Ch. 25). These materials are relatively inert, and are resistant to the action of lysosomal enzymes. The most indigestible forms of material are inert foreign body materials, for example some types of surgical suture, wood, metal or glass implanted into a wound, or deliberately implanted prostheses such as artificial joints. It is not known why the presence of foreign body materials gives rise to chronic suppuration, but it is a well-established fact that suppuration will not cease without surgical removal of the material.

Foreign bodies have in common the tendency to provoke a special type of chronic inflammation called ‘granulomatous inflammation’ (p. 216), and to cause macrophages to form multinucleate giant cells called ‘foreign body giant cells’.

Macroscopic appearances of chronic inflammation

The commonest appearances of chronic inflammation are:

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 (Figs 10.1510.17). 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. It is not usually possible to predict the causative factor from the histological appearances in chronic inflammation.

Paracrine stimulation of connective tissue proliferation

Healing involves regeneration and migration of specialised cells, while the predominant features in repair are angiogenesis followed by fibroblast proliferation and collagen synthesis resulting in granulation tissue. These processes are regulated by low molecular weight proteins called growth factors which bind to specific receptors on cell membranes and trigger a series of events culminating in cell proliferation (Table 10.4).

Table 10.4 Growth factors involved in healing and repair associated with inflammation

Growth factor Abbreviation Main function
Epidermal growth factor EGF Regeneration of epithelial cells
Transforming growth factor-alpha TGF-alpha Regeneration of epithelial cells
Transforming growth factor-beta TGF-beta

Platelet-derived growth factor PDGF Mitogenic and chemotactic for fibroblasts and smooth muscle cells Fibroblast growth factor FGF Stimulates fibroblast proliferation, angiogenesis and epithelial cell regeneration Insulin-like growth factor-1 IGF-1 Synergistic effect with other growth factors Tumour necrosis factor TNF Stimulates angiogenesis

Cellular co-operation in chronic inflammation

The lymphocytic tissue infiltrate contains two main types of lymphocyte (described more fully in Ch. 9). 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.

These pathways of cellular co-operation are summarised in Figure 10.18.

Macrophages in chronic inflammation

Macrophages are relatively large cells, up to 30 μm in diameter, that move by amoeboid motion through the tissues. They respond to certain chemotactic stimuli (possibly cytokines and antigen–antibody complexes) and have considerable phagocytic capabilities for the ingestion of micro-organisms and cell debris. When neutrophil polymorphs ingest micro-organisms, they usually bring about their own destruction and thus have a limited life-span of up to about 3 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 that can survive inside macrophages include mycobacteria, such as Mycobacterium tuberculosis and M. leprae, and organisms such as Histoplasma capsulatum. When macrophages participate in the delayed-type hypersensitivity response (Ch. 9) 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 inflamed tissues are derived from blood monocytes that have migrated out of vessels and have become transformed in the tissues. They are thus part of the mononuclear phagocyte system (Fig. 10.19), also known as the reticulo-endothelial system.

The mononuclear phagocyte system, shown in Figure 10.19, is now known to include macrophages, fixed tissue histiocytes in many organs and, probably, the osteoclasts of bone. All are derived from monocytes, which in turn are derived from a haemopoietic stem cell in the bone marrow.

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 lamellipodia, 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 interferon-alpha and -beta, interleukin-1, -6 and -8, and tumour necrosis factor-alpha (TNF) (see Ch. 9).

Specialised forms of macrophages and granulomatous inflammation

A granuloma is an aggregate of epithelioid histiocytes (Fig. 10.20). It may also contain other cell types such as lymphocytes and histiocytic giant cells. Granulomatous diseases comprise some of the most widespread and serious diseases in the world, such as tuberculosis and leprosy.

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 granulomatous 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. The association of granulomas with eosinophils often indicates a parasitic infection (e.g. worms). A common feature of many of the stimuli that induce granulomatous inflammation is indigestibility of particulate matter by macrophages. In other conditions, such as the systemic granulomatous disease 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. Some of the commoner granulomatous conditions are shown in Table 10.5.

Table 10.5 Causes of granulomatous disease

Cause Example
Specific infections

Materials that resist digestion

Specific chemicals Beryllium Drugs Hepatic granulomas due to allopurinol, phenylbutazone, sulphonamides Unknown

Histiocytic giant cells

Histiocytic giant cells tend to form where particulate matter that 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 that resist enzymatic digestion. Histiocytic giant cells form particularly when foreign particles are too large to be ingested by just one macrophage. 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.

Role of inflammation in systemic and organ-specific diseases

Acute inflammation is involved in the cardiovascular system in the response to acute myocardial infarction (Ch. 13) and the generation of some complications of myocardial infarction such as cardiac rupture. It is also involved in infective endocarditis, pericarditis and myocarditis, and in some vasculitic syndromes. One mechanism of vasculitis is that immune complexes deposit in the vessel wall, activate complement, and thus excite an inflammatory response.

Commonly confused conditions and entities relating to inflammation

Commonly confused Distinction and explanation
Acute and chronic In inflammation, acute and chronic denote both the dynamics and character of the process. Acute inflammation has a relatively rapid onset and, usually, resolution, and neutrophil polymorphs are the most abundant cells. Chronic inflammation has a relatively insidious onset, prolonged course and slow resolution, and lymphocytes, plasma cells and macrophages (sometimes with granuloma formation) are the most abundant cells.
Exudate and transudate Exudates have a high protein content because they result from increased vascular permeability. Transudates have a low protein content because the vessels have normal permeability characteristics.
Granuloma and granulation tissue A granuloma is an aggregate of epithelioid histiocytes and a feature of some specific chronic inflammatory disorders. Granulation tissue is an important component of healing and comprises small blood vessels in a connective tissue matrix with myofibroblasts.
Monocytes, macrophages and histiocytes Monocytes are the newly formed cells of the mononuclear phagocyte system. After a few hours in the blood, they enter tissues and undergo further differentiation into macrophages. Some macrophages in tissues have specific features and names (e.g. Kupffer cells); others are referred to as histiocytes.
Fibrin and fibrous Fibrin is deposited in blood vessels and tissues or on surfaces (e.g. in acute inflammation) as a result of the action of thrombin on fibrinogen. Fibrous describes the texture of a non-mineralised tissue of which the principal component is collagen (e.g. scar tissue).

Chronic inflammation is involved in myocardial fibrosis after myocardial infarction.

Inflammation makes an important contribution to development of atheroma (Ch. 13). Macrophages adhere to endothelium, migrate into the arterial intima and, with T-lymphocytes, express cell adhesion molecules which recruit other cells into the area. The macrophages are involved in processing the lipids that accumulate in atheromatous plaques.

Inflammation also features in the tissue injury associated with neurodegenerative disorders of the central nervous system. Multiple sclerosis is a relatively common chronic demyelinating neurodegenerative disorder in which chronic inflammation plays an important role. Perivascular cuffing by plasma cells and T lymphocytes is seen in zones of white matter where macrophages break down myelin.

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