1.1.3 The phases of inflammation

The main purpose of inflammation, this immensely complex response seems to be to bring fluid, proteins, and cells from the blood into the damaged tissues. It should be remembered that the tissues are normally bathed in a watery fluid (extracellular lymph) that lacks most of the proteins and cells that are present in blood, since the majority of proteins are too large to cross the blood vessel endothelium. Thus there have to be mechanisms that allow cells and proteins to gain access to extravascular sites where and when they are needed if damage and infection has occured.

The main features of the inflammatory response are, therefore: vasodilation, i.e. widening of the blood vessels to increase the blood flow to the infected area; increased vascular permeability, which allows diffusible components to enter the site; cellular infiltration by chemotaxis, or the directed movement of inflammatory cells through the walls of blood vessels into the site of injury; changes in biosynthetic, metabolic, and catabolic profiles of many organs; and activation of cells of the immune system as well as of complex enzymatic systems of blood plasma. Of course, the degree to which these occur is normally proportional to the severity of the injury and the extent of infection.

Inflammation can be divided into several phases. The earliest, gross event of an inflammatory response is temporary vasoconstriction, i.e. narrowing of blood vessels caused by contraction of smooth muscle in the vessel walls, which can be seen as blanching (whitening) of the skin. This is followed by several phases that occur over minutes, hours and days later, outlined below.

1. The acute vascular response follows within seconds of the tissue injury and last for some minutes. This results from vasodilation and increased capillary permeability due to alterations in the vascular endothelium, which leads to increased blood flow ( hyperaemia) that causes redness ( erythema) and the entry of fluid into the tissues ( oedema). This phase of the inflammatory response can be demonstrated by scratching the skin with a finger-nail. The ''wheal and flare reaction'' that occurs is composed of (a) initial blanching of the skin due to vasoconstriction, (b) the subsequent rapid appearance of a thin red line when the capillaries dilate; (c) a flush in the immediate area, generally within a minute, as the arterioles dilate; and (d) a wheal, or swollen area that appears within a few minutes as fluid leaks from the capillaries. It is usually terminates after several tens minutes.

2. If there has been sufficient damage to the tissues, or if infection has occured, the acute cellular response takes place over the next few hours. The hallmark of this phase is the appearance of granulocytes, particularly neutrophils, in the tissues. These cells first attach themselves to the endothelial cells within the blood vessels ( margination) and then cross into the surrounding tissue ( diapedesis). During this phase erythrocytes may also leak into the tissues and a haemorrhage can occur (e.g. a blood blister). If the vessel is damage, fibrinogen and fibronectin are deposited at the site of injury, platelets aggregate and become activated, and the red cells stack together in what are called ''rouleau'' to help stop bleeding and aid clot formation. The dead and dying cells contribute to pus formation.

3. If the damage is sufficiently severe, a chronic cellular response may follow over the next few days. A characteristic of this phase of inflammation is the appearance of a mononuclear cell infiltrate composed of macrophages and lymphocytes. The macrophages are involved in microbial killing, in clearing up cellular and tissue debris, and they also seem to be very important in remodelling the tissues.

4. Over the next few weeks, resolution may occur, meaning that the normal tissue architecture is restored. Blood clots are removed by fibrinolysis, and if it is not possible to return the tissue to its original form, scarring results from in-filling with fibroblasts, collagen, and new endothelial cells. Generally, by this time, any infection will have been overcome. However, if it has not been possible to destroy the infectious agents or to remove all of the products that have accumulated at the site completely, they are walled off from the surrounding tissue in granulomatous tissue. A granuloma is formed when macrophages and lymphocytes accumulate around material that has not been eliminated, together with epitheloid cells and gigant cells (perhaps derived from macrophages) that appear later, to form a ball of cell.

Inflammation is often considered in terms of acute inflammation that includes all the events of the acute vascular and acute cellular response (1 and 2 above), and chronic inflammation that includes the events during the chronic cellular response and resolution or scarring (3 and 4).

In addition, a large number of more distant effects occur during inflammation. These include: the production of acute phase proteins, including complement components, by the liver; fever, caused by pyrogens acting on the hypotalamus in the brain; and systemic immunity, resulting in part from lymphocyte activation in peripheral lymphoid tissues.