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.
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.
One of the commonest causes of inflammation is microbial infection. Viruses lead to death of individual cells by intracellular multiplication. Bacteria release specific exotoxins – chemicals synthesised by them which specifically initiate inflammation – or endotoxins, which are associated with their cell walls. Additionally, some organisms cause immunologically-mediated inflammation through hypersensitivity reactions (Chapter 6). Parasite infections and tuberculous inflammation are instances where hypersensitivity is important.
A hypersensitivity reaction occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction which damages the tissues. The types of reaction are classified in Chapter 6 but all have cellular or chemical mediators similar to those involved in inflammation.
Corrosive chemicals (acids, alkalis, oxidising agents) provoke inflammation through gross tissue damage. However, infecting agents may release specific chem-ical irritants which lead directly to inflammation.
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.
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.
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 phys-ical mass of the inflammatory cells migrating into the area (Fig. 2.1).
For the patient, pain is one of the best-known features 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 prosta-glandins and serotonin, are known to induce pain.
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:
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).
Source: Stephenson T J, Inflammation. In: Underwood J C E (ed) General and systemic pathology, 4th edn, Churchill Livingstone, Edinburgh (2004).
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.
Changes in the microcirculation occur as a physio-logical response; for example, there is hyperaemia in exercising muscle and active endocrine glands. The changes following injury which 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 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.
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. 2.3). 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; hence, the fluid is called the fluid exudate.
Normally, fluid leaving and entering the vessel is in equilibrium. In acute inflammation, there is a net loss of fluid together with plasma protein molecules (P) into the extracellular space, resulting in oedema.
Source: Stephenson op. cit.
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 immunoglobu-lins, 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.
The ultrastructural basis of increased vascular permeability was originally determined using an experimental model in which histamine, one of the chemical medi-ators of increased vascular permeability, was injected under the skin. This caused transient leakage of plasma proteins into the extravascular space. Electron microscopic examination of venules and small veins during this period showed that gaps of 0.1–0.4 μm in diameter had appeared between endothelial cells. These gaps allowed the leakage of injected particles, such as carbon, into the tissues. 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.
In addition to the transient vascular leakage caused by some inflammatory stimuli, certain other stimuli, e.g. heat, cold, ultraviolet light and x-rays, bacterial toxins and corrosive chemicals, cause delayed prolonged leakage. In these circumstances, there is direct injury to endothelial cells in several types of vessels within the damaged area (Table 2.1).
|Immediate transient||Chemical mediators, e.g. histamine, bradykinin, nitric oxide, C5a, leukotriene B4, platelet activating factor|
|Immediate sustained||Severe direct vascular injury, e.g. trauma|
|Delayed prolonged||Endothelial cell injury, e.g. x-rays, bacterial toxins|
The relative importance of chemical mediators and of direct vascular injury in causing increased vascular permeability varies according to the type of tissue. For example, 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.
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 Fig. 2.4.
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.
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. There are several classes of such adhesion molecules: some of them act as lectins which bind to carbohydrates on the partner cell. Leukocyte surface adhesion molecule expression is increased by:
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:
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 so 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.
It has been long known from in vitro experiments that neutrophil polymorphs are attracted towards certain chemical substances in solution – a process called chemotaxis. Video microscopy shows apparently purposeful migration of neutrophils along a concentration gradient. Compounds which appear chemotactic for neutrophils in vitro include certain complement components, cytokines and products produced by neutrophils themselves. 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; Chapter 6).
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:
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 these sites (for example, mast cell degranulation) is stimulated by complement components C3a and C5a, and by lysosomal proteins released from neutrophils.
These are a group of long-chain fatty acids derived from arachidonic acid and synthesised by many cell types. Some prostaglandins potenti-ate 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.
These are 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 (Chapter 6), is a mixture of leukotrienes.
This large family of 8–10 kDa 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, nat-ural 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.