General principles77
9.2 Vascular events in inflammation79
9.3 Cellular processes of inflammation79
Inflammatory processes are part of the body’s natural defence and repair mechanisms. However, their beneficial effects can be accompanied by significant tissue damage. Inflammation involves the coordination of many different functions by a wide variety of cells. Soluble molecules called inflammatory mediators (e.g. cytokines) are important in this process, as are cell–cell and cell–matrix interactions. To help conceptualise this complex web of activity, it is helpful to think about these processes as vascular events (changes in blood vessels) and cellular events (the activities of inflammatory cells).
9.1. General principles
Inflammation is the local response to injury in living, vascularised tissues. Its purpose is to localise and eliminate the injurious agent, such as infecting organisms, and then, as far as possible, to restore the tissue to normal structure and function. However, inflammation may be seen as a two-edged sword. On the one hand, it has beneficial effects by localising and eliminating an injurious agent; on the other, the consequent tissue damage may be detrimental to the host. Inflamed tissues are named with the suffix ‘-itis’; thus appendicitis is inflammation of the appendix and hepatitis is inflammation of the liver.
Chemical inflammatory mediators
Chemical inflammatory mediators have an important role in orchestrating the inflammatory response. They are widely distributed throughout the body (Table 15). Some circulate as plasma proteins (the clotting factors, fibrinolytic factors, kinin system and complement proteins); the others are released, synthesised or activated locally. Inactivation occurs rapidly after release, which is important for the control and localisation of inflammation.
| Mediator | Common sources | Important functions |
|---|---|---|
| Histamine and serotonin | Mast cells and basophils, platelets | Vasodilatation and early increase in vascular permeability |
| Cytokines | Lymphocytes, macrophages, many other cells | Activation and modulation of inflammatory cell activity, chemotaxis of inflammatory cells (chemotactic cytokines are called chemokines) |
| Platelet activating factor (PAF) | Most white cells, vascular endothelium | Increases vascular permeability, increases adhesion of white cells to endothelium and induces platelet aggregation |
| Prostaglandins (PG) and PG-like substances | Mast cells, endothelium, platelets | PGE2 causes pain, PGE2 and PGI2 cause vasodilatation, thromboxane A2 (produced by platelets) causes vasoconstriction |
| Leukotrienes | Neutrophils | Neutrophil chemotaxis, increased vascular permeability, vasoconstriction |
| Nitric oxide | Vascular endothelium, macrophages | Vasodilatation, toxic to bacteria |
| Lysosomal compounds (proteases, acid hydrolases) | Neutrophils, macrophages | Increased vascular permeability, activation of complement, increased tissue damage |
| Coagulation factors | Plasma proteins | Thrombin activates many cells, including platelets, endothelial cells and smooth muscle cells; fibrin forms a clot-like mesh in the inflammatory exudate |
| Fibrinolytic system | Plasma proteins | Plasmin dissolves fibrin but also activates C3 |
| Kinin system | Plasma proteins | Pain, vasodilatation, increased vascular permeability |
| Complement cascade | Plasma proteins | See Chapter 5 |
Clinical features of inflammation
There are four clinical features that have been known to be associated with inflammation since antiquity. They are known as the ‘cardinal signs’:
• redness (from dilatation of blood vessels)
• pain (from oedema and inflammatory mediators)
• heat (from vasodilatation)
• swelling (from oedema).
In addition, patients with inflammation frequently experience systemic effects due to circulating cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin 1 (IL-1) released from the inflamed tissue. Malaise and loss of appetite are common, and fever is due to re-setting of the set-point of the thermostat in the hypothalamus to a higher temperature. The liver releases a variety of proteins called acute-phase reactants that can have a role in the inflammatory response, e.g. C-reactive protein and serum amyloid-A protein (SAA), which have antibacterial effects, and clotting factors such as fibrinogen. The numbers of circulating leucocytes increase as leucocytes are released from the bone marrow. When neutrophils are released from the bone marrow in this way, the proportion of less mature forms in the blood increases; haematologists describe this as a ‘shift to the left’ in neutrophil morphology. Weight loss is common in long-standing inflammation due to a negative nitrogen balance caused by a combination of increased metabolic activity and loss of appetite.
Acute inflammation
Acute inflammation is defined as the early inflammatory response to an injurious agent, and is characterised by the presence of neutrophil polymorphs and later macrophages. Acute inflammation usually lasts for a few hours or days.
Causes of acute inflammation
• Hypersensitivity reactions: types I–IV
• Physical agents: physical trauma, burns, UV light, radiation
• Chemicals: acids, alkalis, oxidising agents
• Tissue necrosis: e.g. infarction
The acute inflammatory response is characterised by increased blood flow, exudation of protein-rich fluid, and the accumulation of neutrophils (Figure 22). The mechanisms responsible are discussed later in this chapter. Within tissues, the exudate accumulates as oedema fluid, but exudate from inflamed serous membranes can accumulate in body cavities such as the pleural, pericardial and peritoneal cavities. The exudate contains large amounts of fibrin that can cause clots to form. Histologically, the presence of neutrophils is an important feature indicating the presence of acute inflammation to the pathologist.
 |
| Figure 22 |
Outcomes of acute inflammation
Healing by resolution
Acute inflammation may disappear after a few days and the tissue returns to normal. Fluid and degraded proteins are drained by the lymphatic channels and the exudate, cell debris and fibrin are removed by neutrophils and monocytes. To prevent further acute inflammation, the inflammatory cells are finally removed by apoptosis. The end result is that the tissue returns to normal and normal anatomy is restored. Resolution is only possible if there is minimal destruction of the extracellular matrix and the tissue has cells capable of dividing by mitosis to replace cells lost in the inflammatory process.
Healing by fibrosis
This is the process of organisation by granulation tissue (see Ch. 10).
Progression to chronic inflammation
Chronic inflammation
Chronic inflammation is an inflammatory response lasting more than a few days and is characterised by the presence of lymphocytes, plasma cells and macrophages. It is generally associated with significant tissue damage and so healing occurs by granulation tissue formation and fibrosis (see Ch. 10).
Clinically, chronic inflammation may occur as a result of:
• progression from acute inflammation due to persistence of the inflammatory stimulus, such as a foreign body or persistent microorganisms
• chronic inflammation ab initio (i.e. without preceding acute inflammation): typically seen as the response to intracellular organisms (e.g. mycobacteria, viruses), in many autoimmune diseases (e.g. rheumatoid arthritis, contact dermatitis), and in cases of chronic rejection of transplants.
9.2. Vascular events in inflammation
Vasodilatation
This occurs rapidly in the early acute inflammatory response and leads to increased blood flow into the damaged tissue. It is principally due to relaxation of arterioles.
Increased vascular permeability
Venules and capillaries are lined by a continuous layer of endothelium which keeps blood cells and large proteins within the vessel; water, oxygen and carbon dioxide pass freely through the vessel wall. In inflamed tissue, there is an increase in hydrostatic pressure due to the relaxation of arterioles. There is also an increase in the permeability (‘leakiness’) of the blood vessel to proteins, which can occur in a number of ways:
• gaps between endothelial cells induced by histamine, leukotrienes, etc.
• direct injury to the endothelial cells by the injurious agent (toxins, ischaemia, burns, etc.)
• increased transport of proteins across cell membranes stimulated by cytokines.
The increased intravascular hydrostatic pressure and increased permeability allow fluid and proteins to leak into the extracellular tissues. This protein-rich fluid is called exudate and is responsible for the oedema of inflammation. Within the dilated vascular beds, blood flow will slow dramatically as exudate is lost from the vascular space into tissues. Many of the proteins in the exudate are important in the inflammatory reaction, e.g. antibodies and acute-phase reactants.
9.3. Cellular processes of inflammation
Cells of the inflammatory response
Neutrophil polymorphs
Neutrophils are the first cells to appear at the site of acute inflammation. They are phagocytes, and their function is to degrade cell debris and to ingest and kill microbes. Neutrophils originate in the bone marrow and have a short tissue lifespan of only 3–4days.
They kill microorganisms by two main mechanisms: digestive enzymes in lysosomes and oxygen-dependent production of free radicals (see Box 12 and Figure 23). Neutrophils are an important component of pus (Box 13).
Box 12
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