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:

• 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.

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

ACUTE INFLAMMATION

Initial reaction of tissue to injury

Vascular component: dilatation of vessels

Exudative component: vascular leakage of protein-rich fluid

Neutrophil polymorph is the characteristic cell recruited to the tissue

Outcome may be resolution, suppuration (e.g. abscess), organisation, or progression to chronic 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:

• microbial infections, e.g. pyogenic bacteria, viruses

• hypersensitivity reactions, e.g. parasites, tubercle bacilli

• physical agents, e.g. trauma, ionising radiation, heat, cold

• chemicals, e.g. corrosives, acids, alkalis, reducing agents, bacterial toxins

• tissue necrosis, e.g. ischaemic infarction.

Essential macroscopic appearances of acute inflammation

The essential physical characteristics of acute inflammation were formulated by Celsus (30bc–ad38) using the Latin words 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 (Fig. 10.1).

Fig. 10.1 Cellulitis. The skin over the lateral part of the foot is red (erythema) due to vascular dilatation associated with acute inflammation.

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.

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 (Fig. 10.2). As the inflammation response progresses, formation of new connective tissue contributes to the swelling.

Fig. 10.2 Early acute appendicitis. The appendix is swollen due to oedema, the surface is covered by fibrinous exudate (arrowed), and the blood vessels are prominent because they are dilated.

Pain (dolor)

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 prostaglandins and serotonin, are known to induce pain.

Loss of function

Loss of function, a well-known consequence of inflammation, was added by Virchow (1821–1902) to the list of features drawn up by Celsus. Movement of an inflamed area is consciously and reflexly inhibited by pain, while severe swelling may physically immobilise the tissues.

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 and, consequently, flow

• increased vascular permeability and formation of the fluid exudate

• formation of the cellular exudate—emigration of the neutrophil polymorphs into the extravascular space.

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).

Fig. 10.3 Vascular dilatation in acute inflammation. Normally, most of the capillary bed is closed down by precapillary sphincters. In acute inflammation, the sphincters open, causing blood to flow through all capillaries.

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:

• 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 enabled by relaxation of precapillary sphincters.

• 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 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.

Fig. 10.4 Ultrafiltration of fluid across the small blood vessel wall. 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.

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 lymphatic channels to be replaced by new exudate.

Ultrastructural basis of increased vascular permeability

The ultrastructural basis of increased vascular permeability was originally determined using an experimental model in which histamine, one of the chemical mediators 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.

Other causes of increased vascular permeability

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 circum-stances, there is direct injury to endothelial cells in several types of vessel within the damaged area (Table 10.1).

Table 10.1 Causes of increased vascular permeability

Time course	Mechanisms
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