Mast cells

The mast cell is probably the most important activator of the inflammatory response (see Figure 13-4).³ Mast cells are filled with granules and are located in the loose connective tissues close to blood vessels near the body’s outer surfaces (i.e. in the skin and lining the gastrointestinal and respiratory tracts). Basophils are found in the blood and probably function in the same way as tissue mast cells (see Figure 13-5). A great number of stimuli activate mast cells to release potent soluble inducers of inflammation. These are released by (1) degranulation and (2) synthesis.

FIGURE 13-4 Mast cells and the degranulation and synthesis of inflammatory mediators upon activation.

Mast cells are filled with darkly staining granules that contain a large number of biologically active substances. Among these are histamine, which is a major initiator of vascular changes, and a variety of chemotactic factors. These substances are released immediately after stimulation of mast cells. Other substances are synthesised in response to mast cell stimulation. These include lipid-based molecules that originate from plasma membrane phospholipids as a result of the action of phospholipase A2, including platelet-activating factor and a variety of prostaglandins and leukotrienes.

FIGURE 13-5 Inflammatory cells and their differentiation when migrating into the tissues.

Source: Based on Damjanov I. Pathology for the health professions. 3rd edn. Philadelphia: Saunders; 2006.

In response to a stimulus, biologically active molecules are released from the mast cell granules within seconds and exert their effects immediately. This process is called degranulation, literally meaning that the granules inside the cell are released into the extracellular space. These granules contain molecules that are important to propagating the inflammatory response, called mediators. These molecules include histamine, chemotactic factors and heparin.

In addition to the degranulation of inflammatory mediators, mast cells once activated begin new synthesis (production) of other mediators of inflammation, which are released later than those in the granules. These include leukotrienes, prostaglandins and platelet-activating factor, which are produced from lipids in the plasma membrane.

All of these molecules either released or synthesised by the mast cell are crucial to the inflammatory response, and at the site of tissue damage they are responsible for the hallmarks of inflammation. These chemical mediators are discussed later in the chapter.

Neutrophils

Neutrophils are produced by the bone marrow and are the most prevalent white blood cells, accounting for 50–60% of all white blood cells. They are sometimes referred to as polymorphonuclear neutrophils (see Figure 13-5) due to the multilobed nucleus.⁴ Neutrophils are also the most prominent member of the granulocytes, referring to the granules that are observed when stained. They are also in the group of cells called phagocytes, referring to the process of phagocytosis, which literally means ingesting foreign substances (see later in the chapter for more on phagocytosis). Neutrophils are the predominant phagocytes in the early inflammatory site, arriving 6–12 hours after the initial injury. Several inflammatory mediators specifically and rapidly attract neutrophils from the circulation and activate them.

Neutrophils are short-lived at the inflammatory site as they are mature cells and become a component of the purulent exudate or pus, which is removed from the body through the epithelium or via the lymphatic system (the lymphatic system is described in Chapter 22). The primary roles of neutrophils are the removal of debris and dead cells and phagocytosis of bacteria.

Monocytes and macrophages

Monocytes (the immature form of this white blood cell in the blood) and macrophages (the mature cell in the tissues) have fewer and larger lysosomes (organelles containing digestive enzymes; see Chapter 3) in their cytoplasm than do granulocytes.⁵ Monocytes are the largest normal blood cells and have a nucleus that is often indented or horseshoe-shaped. Monocytes are produced in the bone marrow, enter the circulation and migrate to the inflammatory site, where they develop into macrophages. Monocytes also appear to be the precursors of macrophages that are fixed in tissues (tissue macrophages), including Kupffer cells in the liver, alveolar macrophages in the lungs and microglia in the brain. Macrophages are generally larger and more active as phagocytes than their monocytic precursors (see Figure 13-5).

Macrophages enter the site after 24 hours or later, and they gradually replace the neutrophils. They migrate to the site after the neutrophils because they move more sluggishly and because many of the chemotactic factors that attract them, such as macrophage chemotactic factor, must first be released by neutrophils. Macrophages are better suited than neutrophils to long-term defence against infectious agents because macrophages can survive and divide in the acidic inflammatory site.

The bactericidal activity (ability to kill bacteria) of macrophages can increase markedly with the help of inflammatory cytokines produced by cells of the acquired immune system (subsets of T lymphocytes; see Chapter 12). (Cytokines are a family of proteins that are secreted and activate other inflammatory cells. They are discussed in detail later in this chapter.) Macrophages have cell surface receptors for these cytokines and are further activated to become more effective killers of infectious microorganisms.

Eosinophils

Although eosinophils (see Figure 13-5) are only mildly phagocytic, they have two specific functions: (1) they serve as the body’s primary defence against parasites; and (2) they help regulate vascular mediators released from mast cells.⁶

The regulation of mast cell-derived inflammatory mediators is a critical function of eosinophils and helps limit inflammation. Mast cells produce eosinophil chemotactic factor-A, which attracts eosinophils to the site of inflammation. Eosinophil lysosomes contain several enzymes that degrade vasoactive molecules, thereby controlling the vascular effects of inflammation. This role is very important, because if inflammation is not limited to the site of injury or infection, it may damage normal tissue.⁷

Platelets

Platelets are cytoplasmic fragments formed from megakaryocytes (large cells in the bone marrow responsible for platelet production) (see Figure 13-5). They circulate in the bloodstream until vascular injury occurs. After injury, platelets are activated by many products of tissue destruction and inflammation, including collagen, thrombin and platelet-activating factor. Activation results in: (1) their interaction with components of the coagulation cascade to stop bleeding; and (2) degranulation, releasing biochemical mediators such as serotonin, which has vascular effects similar to those of histamine. (Platelet function is described in detail in Chapter 16.)

Phagocytosis

Phagocytosis is the process by which a cell ingests and disposes of foreign material, including microorganisms. This process resembles endocytosis (refer to Chapter 3). Cells that perform this process are called phagocytes. The two most important phagocytes are neutrophils and macrophages. Both cells are circulating in the blood and must first leave the circulation and migrate to the site of inflammation before initiating phagocytosis. During inflammation the endothelial cells of the capillaries move apart (endothelial cell contraction). In addition, the phagocytes produce the surface molecules that increase the adhesion, or stickiness, between leucocytes and endothelial cells, causing the leucocytes to adhere to the walls of the capillaries and venules in a process called margination, or pavementing.⁸ The surface adhesion molecules assist the phagocytes to undergo diapedesis, or emigration of the cells through the endothelial junctions that have retracted in response to inflammatory mediators (see Figure 13-6).

FIGURE 13-6 Phagocytosis.

Phagocytosis is a multistep process that involves diffusion of chemotactic factors from a site of injury. Many additional factors affect the blood vessels and increase adhesion molecules on endothelial cells and phagocytes, resulting in adherence of the neutrophils to the vessel wall (pavementing), retraction of endothelial cells (vascular permeability), and movement of the neutrophils through the opened intercellular junctions (diapedesis) and into the tissue. The cells move along the gradient towards the highest concentration of chemotactic factors (chemotaxis). At the site of injury, phagocytes begin phagocytosis of contaminating bacteria. The actual process of phagocytosis involves several steps (see enlargement). The electron micrographs shows phagocytosis of damaged red blood cells by a macrophage: A Red blood cells (R) attach to the macrophage (M). B The plasma membrane of the macrophage begins to enclose the red blood cells. C The red blood cells are almost totally ingested by the macrophage.

Source: Inset Electron micrograph from Thibodeau GA. The human body in health & disease. 4th edn. St Louis: Mosby; 2005.

Once inside the tissue, leucocytes are attracted to the inflammatory site by chemotactic factors. At the inflammatory site, the process of phagocytosis involves five steps: (1) adherence of the phagocyte to its target; (2) engulfment (ingestion or endocytosis); (3) formation of a phagosome (a vacuole or membrane-bound ‘compartment’ that contains the foreign body); (4) fusion of the phagosome with lysosomal granules within the phagocyte; and (5) destruction of the target (see Figure 13-6) (lysosomes are described in Chapter 3). Throughout the process, both the target and the digestive enzymes are isolated within membrane-bound vesicles. Isolation protects the phagocyte itself from the harmful effects of the target microorganisms, as well as its own enzymes.

Phagocytosis using innate receptors (phagocyte surface receptors that recognise bacteria) is a relatively slow process. Opsonisation (the coating of foreign bodies with opsonin to attract phagocytes) greatly enhances adherence by acting as a glue to increase the adherence between the phagocyte and the target cell. The most efficient opsonins are antibodies and C3b produced by the complement system. Antibodies are made against antigens on the surface of bacteria and are highly specific to that particular microorganism (see Chapter 12). Alternatively, the complement system is activated during inflammation and deposits C3b on the bacterial surface, which increases phagocytosis (see complement systems later in this chapter). The surface of phagocytes contains a variety of specific receptors that strongly bind to opsonins.

Engulfment (endocytosis) is carried out by small pseudopods that extend from the plasma membrane and surround the adherent microorganism (see Figure 13-6) forming an intracellular phagosome. After the formation of the phagosome, lysosomes converge, fuse with the phagosome and discharge their contents. Destruction of the bacterium (foreign body) takes place inside this compartment.⁹

Often the process of phagocytosis results in the death of the phagocyte. When a phagocyte dies at an inflammatory site, it frequently lyses (breaks open) and releases its cytoplasmic contents, including the lysosomal enzymes, into the tissue. These can be very destructive and digest the surrounding tissue, causing much of the tissue destruction associated with inflammation. The destructive effects of many enzymes released by dying phagocytes are minimised by natural inhibitors found in the blood, such as α₁-antitrypsin, a plasma protein produced by the liver. Released lysosomal products also may contribute to inflammation by increasing vascular permeability, attracting additional monocytes, and activating the complement and kinin systems (see the section on plasma proteins later in the chapter).

Histamine

Histamine is a small weight molecule with potent effects on many other cells, particularly those that control the circulation. Histamine is a vasoactive amine, meaning that its action is on blood vessels. Histamine causes temporary, rapid constriction of smooth muscle and dilation of the post-capillary venules, which results in increased blood flow into the microcirculation. Histamine also causes increased vascular permeability resulting from retraction of endothelial cells lining the capillaries (see Figures 13-1 and 13-7) and increased adherence of leucocytes to the endothelium. Antihistamines are drugs that block the binding of histamine to its receptors, resulting in decreased inflammation.

FIGURE 13-7 Vasodilation of the capillary beds during inflammation induced by histamine and nitric oxide.

Relaxation of the pre-capillary sphincter in the arterioles results in flooding of the capillary network and dilatation of the capillaries and post-capillary venules.

Source: Damjanov I. Pathology for the health professions. 3rd edn. Philadelphia: Saunders; 2006.

Chemotactic factors

Chemotactic factors are released from mast cell granules. Chemotactic factors diffuse from a site of inflammation forming a gradient and causing the directional movement (chemotaxis) of cells towards the inflammation (see Figure 13-8). Mast cells contain two specific chemotactic factors: neutrophil chemotactic factor and eosinophil chemotactic factor of anaphylaxis. These factors provide a strong attraction for neutrophils and eosinophils, which are vital to inflammation. Neutrophils are the predominant cell needed to kill bacteria in the early stages of inflammation, and eosinophils help regulate the inflammatory response.

FIGURE 13-8 Chemotaxis.

This occurs when chemotactic factors are released, which attracts inflammatory cells to site of inflammation. Multiple receptors on the leucocyte’s plasma membrane sense the area of highest concentration of chemotactic factor (dots), and the leucocyte (usually a phagocyte) moves towards this area.

Source: McCance KL, Huether SE. Pathophysiology: the biologic basis for disease in adults and children. 5th edn. St Louis: Mosby; 2006.

Leukotrienes

Leukotrienes are sulfur-containing lipids that produce histamine-like effects: smooth muscle contraction and increased vascular permeability. Leukotrienes appear to be important in the later stages of the inflammatory response because they stimulate slower and more prolonged responses than do histamines.

Nitric oxide

Endothelial cells release nitric oxide (not to be confused with nitrous oxide, or laughing gas), which has at least two effects on inflammation. First, nitric oxide causes vasodilation by inducing relaxation of vascular smooth muscle, a response that is local and short-lived (see Figure 13-7). Second, nitric oxide may suppress mast cell release of inflammatory molecules and decrease platelet adhesion and aggregation. Therefore, nitric oxide has both pro- and anti-inflammatory aspects.

Prostaglandins

Prostaglandins cause increased vascular permeability, neutrophil chemotaxis and pain by direct effects on nerves. They are long-chain, unsaturated fatty acids and are produced when the enzyme cyclo-oxygenase converts arachidonic acid to prostaglandin. Two particular types of prostaglandins, E₁ and E₂, cause increased vascular permeability and smooth muscle contraction. The enzyme cyclo-oxygenase (commonly abbreviated to COX) and arachidonic acid are important to remember because aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, block the synthesis of prostaglandins by inhibiting cyclo-oxygenase, thereby inhibiting inflammation.

Platelet-activating factor

Platelet-activating factor is produced from a lipid of the phospholipid plasma membrane. Although mast cells are a major source of platelet-activating factor, this molecule can also be produced during inflammation by neutrophils, monocytes, endothelial cells and platelets. The biological activity of platelet-activating factor is virtually identical to that of leukotrienes, namely causing endothelial cell retraction to increase vascular permeability, leucocyte adhesion to endothelial cells and platelet activation.

Cytokines

Cytokines are a large group of proteins that provide a means of communication for the inflammatory and immune cells. Cytokines can be pro-inflammatory or anti-inflammatory, depending on whether they tend to induce or inhibit the inflammatory response. These molecules diffuse over short distances, bind to the appropriate target cells and affect the function of the target cells. Some effects occur over long distances, such as the systemic induction of fever by some cytokines (i.e. endogenous pyrogens) away from where they are produced at an inflammatory site (see the section on fever later in the chapter). Cytokine effects on other cells are mediated through specific cell-surface receptors. The binding of cytokines to a target cell often induces synthesis of additional cellular products. These are detailed in Table 13-1. Below we list some of the cytokines that strongly influence inflammation.

Table 13-1 THE ACTIONS OF THE PRIMARY INFLAMMATORY MEDIATORS

Source: Based on Kumar V. Robbins & Cotran pathologic basis of disease. 8th edn. Philadelphia: Saunders; 2009.

Interleukins

The interleukins are produced predominantly by macrophages and lymphocytes in response to their recognition of a pathogen or stimulation by other products of inflammation. Interleukin-1 (IL-1) is a pro-inflammatory cytokine (which means that it encourages the inflammatory process) produced mainly by macrophages. It is endogenous, meaning that it is produced from within the body. This endogenous pyrogen (i.e. fever-causing cytokine) reacts with receptors on cells of the hypothalamus and affects the body’s thermostat, resulting in fever. It also activates phagocytes and lymphocytes, thereby enhancing both innate and adaptive immunity, and acts as a growth factor for many cells. It has several effects on neutrophils, including induction of proliferation (resulting in an increase in the number of circulating neutrophils), chemotaxis, increased cellular respiration and increased lysosomal enzyme activity.

Interleukin-6 (IL-6) is produced by macrophages, lymphocytes, fibroblasts and other cells. It directly induces hepatocytes (liver cells) to produce many of the proteins needed in inflammation (acute-phase reactants, discussed later in this chapter). IL-6 also stimulates growth and differentiation of precursors of blood cells in the bone marrow and the growth of fibroblasts.

Interleukin-10 (IL-10) is an example of an anti-inflammatory cytokine and is primarily produced by lymphocytes to slow both the inflammatory and the acquired immune responses. It achieves this through suppressing the growth of lymphocytes and the production of pro-inflammatory cytokines by macrophages.

More than 30 interleukins have been identified. Their varied effects include the following:

alteration of adhesion molecule expression on many types of cells

induction of leucocyte chemotaxis

induction of proliferation and maturation of leucocytes in the bone marrow

general enhancement or suppression of inflammation.

Tumour necrosis factor-alpha

Macrophages secrete tumour necrosis factor-alpha (TNF-α) in response to recognition of foreign materials. Other cells, such as mast cells, are additional and crucial sources of this pro-inflammatory cytokine. TNF-α induces a multitude of pro-inflammatory effects, including enhancement of endothelial cell adhesion molecule expression, which results in increased adherence of neutrophils. When secreted in large amounts, TNF-α has the following systemic effects:

inducing fever by acting as an endogenous pyrogen

causing increased synthesis of inflammation-related serum proteins by the liver

causing muscle wasting (cachexia) and intravascular thrombosis in cases of severe infection and cancer.

Very high levels of TNF-α can be lethal and may be responsible for fatalities from shock caused by gram-negative bacterial infections. (The distinction between gram-positive and gram-negative is discussed in Chapter 14.)

FOCUS ON LEARNING

1. Describe the function of inflammatory mediators.

2. List and describe the actions of histamine, platelet-activating factor, chemotactic factor and prostaglandin E₂.

3. Discuss how cytokines act to influence both innate and adaptive immune responses.

The complement system

The complement system consists of a large number of proteins (sometimes called complement components) that together constitute about 10% of the total circulating serum protein.¹⁰ The complement system is extremely important because activated components can destroy pathogens directly and can activate or collaborate with virtually every other component of the inflammatory response. For these reasons, proteins of the complement system are among the body’s most potent defenders against bacterial infection.

The most important portion of the complement cascade is activation of C3 and C5, which results in a variety of subunits that are opsonins, chemotactic factors or anaphylatoxins. Opsonins are molecules that coat bacteria and increase their susceptibility to being eaten and killed by inflammatory cells, such as neutrophils and macrophages. Anaphylatoxins are molecules that induce rapid degranulation of mast cells, thus increasing inflammation. The most potent complement products are C3b (opsonin), C3a (anaphylatoxin) and C5a (anaphylatoxin, chemotactic factor).

Complement components C5b to C9 (membrane attack complex, or MAC) form a complex that creates pores in the outer membranes of cells or bacteria. The pores disrupt the cell’s membrane and permit water to enter, causing lysis and death of the cell. This is a particularly effective mechanism for destroying foreign cells that have entered the body.

Complement activation can be accomplished in three different ways (see Figure 13-9):

The classical pathway is primarily activated by proteins of the acquired immune system, antibodies.¹¹ When antibodies bind to antigens they activate the first component of complement, C1, which through other complement components leads to activation of C3 and C5. Thus, the acquired immune response can use the complement system to kill bacteria and activate inflammation.

The lectin pathway is similar to the classic pathway but is independent of antibody. Thus, infectious agents that do not activate the alternative pathway may be susceptible to complement through the lectin pathway.

The alternative pathway is activated by several substances found on the surface of infectious organisms. This pathway uses unique proteins to form a complex that activates C3, which leads to C5 activation and convergence with the classical pathway. Thus, the complement system can be directly activated by certain infectious organisms without antibody being present.

In summary, the complement cascades can be activated by at least three different means and its products have four functions: (1) opsonisation, (2) anaphylatoxic activity resulting in mast cell degranulation, (3) leucocyte chemotaxis and (4) cell lysis.

The coagulation system

The coagulation (clotting) system is a group of plasma proteins that, when activated sequentially, form a fibrinous meshwork at an injured or inflamed site.¹² This: (1) forms a clot that stops bleeding; (2) traps infectious organisms and prevents their spread to adjacent tissues; (3) keeps microorganisms and foreign substances at the site of greatest inflammatory cell activity; and (4) provides a framework for future repair and healing. The main substance in this fibrinous mesh is fibrin, an insoluble protein produced by the coagulation cascade.

Like the complement cascade, the coagulation cascade can be activated through different pathways that converge and result in the formation of a clot (see Figure 13-9). The coagulation cascade converges at factor X. From that point on, a common pathway results in fibrin formation. The coagulation cascade is discussed further in Chapter 16.

Many substances that are released during tissue destruction and infection, such as bacterial products (e.g. endotoxin), collagen and cellular proteases, can activate the coagulation system. Activation of some clotting factors produces fragments that enhance the inflammatory response.

The kinin system

The third plasma protein system, the kinin system, interacts closely with the coagulation system (see Figure 13-9). Both the coagulation and kinin systems are activated through activated factor XII (factor XIIa). Another name for factor XIIa is prekallikrein activator because it enzymatically activates the first component of the kinin system, prekallikrein. The final product of the kinin system is a small-molecular-weight molecule, bradykinin. At low doses, bradykinin causes dilation of blood vessels, acts with prostaglandins to induce pain, causes smooth muscle cell contraction and increases vascular permeability (see Figure 13-3). Bradykinin induces smooth muscle contraction more slowly than histamine and may be more important during the later phases of inflammation.

Interaction of the plasma protein systems

The three plasma protein systems are highly interactive so that activation of one results in secondary activation of the other two. It is beneficial to the individual to activate all three systems, but it would be detrimental if the systems continued producing potent pro-inflammatory molecules indefinitely. Therefore, the systems are tightly regulated to control and localise inflammation to the appropriate sites.

Temperature regulation

We regulate body temperature within a relatively narrow range using both autonomic and behavioural mechanisms. Behavioural responses are very powerful — for instance, when we are cold, we can apply more clothing or move towards a heat source. This increases skin temperature, which in turn increases core temperature. In contrast, autonomic responses (those we do not have conscious control over) are mediated through our nervous system and act to maintain homeostasis.

In all homeothermic animals (animals with the ability to maintain a stable core temperature independent of environmental temperature), temperature regulation is achieved through precise balancing of heat production and heat loss. Maintenance of body temperature within the normal range is necessary for life. In humans, core temperature is maintained in a range around 37°C — the normal range being about 36.2 to 37.5°C — and rarely exceeds 41°C. However, this is dependent on many factors — for instance, stages in the menstrual cycle and time of day both influence core temperature. In addition, an individual’s body parts will vary in temperature, which means that finding a representative core temperature is difficult. Skin temperature is strongly associated with air temperature and varies according to anatomical location: the extremities are generally cooler than the trunk and the temperature at the core of the body (as measured by the rectal temperature) is generally 0.5°C higher than at the surface (as measured by oral temperature). The daily fluctuating temperature in both sexes peaks at around 6 pm and is at its lowest during sleep.

Disorders of temperature regulation

The pathogenesis of fever

Fever (also called febrile response) is a temporary ‘resetting of the hypothalamic thermostat’ to a higher level. Usually, thermoregulatory mechanisms adjust heat production and heat loss to maintain body core temperature within a narrow range. During fever, this is re-set to a higher level, so that the thermoregulatory centre in the hypothalamus adjusts heat production and loss to maintain the core temperature at the new, higher temperature.¹⁶ Fever is usually characterised by an increase in core temperature of 1–4°C. However, the primary difference between fever and hyperthermia is that in fever the increase in temperature is a response to an endogenous or exogenous pyrogen. A pyrogen is a substance that causes fever. There are two broad classifications of pyrogens: exogenous pyrogens arise from outside of the body; and endogenous pyrogens arise from inside the body.

Exogenous pyrogens, or endotoxins produced by pathogens, stimulate inflammatory cells, mainly macrophages and neutrophils, to release substances such as TNF-α, IL-1, IL-6 and interferon. These pyrogenic cytokines induce the synthesis of prostaglandins in the hypothalamus and this increases the level of hypothalamic temperature. In reality, the hypothalamus does not regulate body temperature from a ‘set-point’ temperature, but rather a range of temperatures called the interthreshold zone.¹⁷ This is elevated in fever. In response, the hypothalamus signals an increase in heat production and decreases heat-loss avenues to raise body temperature (see Figure 13-12).¹⁸ The individual feels colder, dresses more warmly, decreases body surface area by curling up and may go to bed in an effort to get warm. Body temperature is maintained at the new higher level until the fever ‘breaks’, when the interthreshold zone begins to return to normal. This response is mediated in part by cytokines associated with the inflammatory response.¹⁹ There are decreased heat-production and increased heat-loss mechanisms. The individual feels very warm, dons cooler clothes, throws off the covers and stretches out. Once the body has returned to a normal temperature the individual feels more comfortable and the hypothalamus adjusts thermoregulatory mechanisms to maintain the new temperature. Therefore, fever is mediated from exogenous and endogenous pyrogens and elevates the core temperature as a defence mechanism.

FIGURE 13-12 The pathogenesis of fever.

Exogenous pyrogens stimulate cells that release cytokines that stimulate fever (exogenous pyrogens). These pyrogenic cytokines stimulate the hypothalamus (pre-optic of anterior hypothalamus) to synthesise and release prostaglandin E₂, which acts on the cells locally in the hypothalamus to increase heat production area and decrease heat-loss avenues. This causes an increase in core temperature, which is manifest as fever.

The benefits of fever

Fever is usually beneficial and assists the immune system to respond to pathogenic microorganisms.

It does this through several mechanisms:^20,21

Conversely, fever can also be harmful to the individual as it may augment the body’s susceptibility to the effects of endotoxins associated with gram-negative bacterial infections (bacterial toxins are described in Chapter 14).

Suppression of fever by pharmacological treatment with antipyretic medications, such as aspirin or paracetamol, occurs via inhibition of the cyclo-oxygenase enzyme, which is required for the production of prostaglandin. Therefore, prostaglandin does not influence the hypothalamus and an increase in heat production does not occur. However, antipyretics should be used only if a fever (> 38.5°C) produces or is high enough to produce serious side effects, such as cardiovascular stress, nerve damage or convulsion.²²

Clinical patterns of fever

Although fever is accompanied by an increase in core temperature, the patterns can be varied. Four categorised patterns are seen in clinical practice (see Figure 13-13).

During sustained fever, the core temperature remains elevated, often for days, and there is very little variation.

Intermittent fever occurs when the core temperature returns to normal levels periodically.

Remittent fever occurs when there are minor fluctuations in body temperature but the fever is sustained.

Relapsing fever is associated with days of normal temperature following fever, with an increase in core temperature, often associated with increasing severity of illness.

FIGURE 13-13 Different patterns of fever.

See text for details.

Source: McGee S. Evidence-based physical diagnosis. 2nd edn. St Louis: Saunders; 2007.

Unfortunately, despite differing patterns, these fever patterns are not usually associated with any particular condition or disease. They represent fever mediated through pyrogens from both infectious and non-infectious agents.

The reconstructive phase

Surgical and penetrating wounds are useful models of both normal and abnormal (dysfunctional) healing. Bleeding is initially sealed off by a blood clot containing a cross-linked mesh of fibrin and trapped platelets. Most surgical wounds are completely sealed within hours after closure. This sealing helps unite the wound edges and creates a physical barrier to bacterial invasion. The fibrin mesh acts as a scaffold for fibroblasts and collagen deposition, which ultimately fills the wound.

For healing to proceed, the fibrin clot must be replaced by normal tissue or scar tissue.²⁴ Macrophages invade the dissolving clot and clear away debris and dead cells. Macrophages also secrete biochemical mediators that promote healing. Granulation tissue grows into the wound from the surrounding healthy connective tissue. Granulation tissue is filled with new capillaries (called angiogenesis, meaning growing new blood vessels) derived from capillaries in the surrounding tissue, giving the granulation tissue a red, granular appearance. New lymphatic vessels also grow into the granulation tissue by a similar process.

During this process the healing wound must be protected. Epithelialisation is the process by which epithelial cells grow into the wound from surrounding healthy tissue. Epithelial cells migrate under the clot or scab to unravel collagen. Migrating epithelial cells contact similar cells from all sides of the wound and seal it, thereby halting migration and proliferation. The epithelial cells remain active, undergoing differentiation to give rise to the various epidermal layers (see Chapter 18). Epithelialisation of a skin wound can be hastened if the wound is kept moist (as opposed to allowing the wound to dry out), preventing the fibrin clot from becoming a scab.

Fibroblasts are the most important cells during healing because they secrete collagen and other connective tissue proteins, which are deposited in debrided areas about 6 days after the fibroblasts have entered the lesion. Collagen is the most abundant protein in the body. It contains high concentrations of the amino acids. As healing progresses, collagen undergoes chemical reactions to form collagen fibres. The complete process takes several months.

Wound contraction is necessary for closure to all wounds, especially those that heal by secondary intention. Contraction is noticeable 6–12 days after injury. The granulation tissue contains myofibroblasts — specialised cells that are responsible for wound contraction. Myofibroblasts have features of both smooth muscle cells and fibroblasts. They appear microscopically similar to fibroblasts but differ in that their cytoplasm contains bundles of parallel fibres similar to those found in smooth muscle cells. Wound contraction occurs as extensions from the plasma membrane of myofibroblasts establish connections between neighbouring cells, contract their fibres and exert tension on the neighbouring cells while anchoring themselves to the wound bed.

The maturation phase

Collagen matrix assembly, tissue regeneration and wound contraction continue into the maturation phase — a phase that can persist for years. Scar tissue is remodelled and capillaries disappear, leaving the scar avascular — that is, without a blood supply (the ‘a’ in front of the word vascular means without). Within 2 to 3 weeks after maturation has begun, the scar tissue has gained about two-thirds of its eventual maximum strength.

Epidermal wounds that heal by secondary intention and unsutured internal lesions are not completely restored by healing. At best, repaired tissue regains 80% of its original tensile strength. Essentially, this means that the scar tissue is never as strong as the original tissue. Only epithelial, hepatic (liver) and bone marrow cells are capable of the complete mitotic regeneration of the normal tissue known as compensatory hyperplasia (hyperplasia is described in Chapter 4). In fibrous connective tissue such as joints and ligaments, normal healing results in replacement of the original tissue with new tissue that does not have exactly the same structure or function as that of the original. In some cases this leads to recurrent injury, such as that experienced by athletes. For instance, an athlete sustains a knee injury, undergoes rehabilitation, but re-injures the same knee when competing again. This may occur because the new tissue is not quite as effective as the original tissue, leading to future problems. Some tissues heal without the replacement of cells. For example, damage resulting from myocardial infarction heals with a scar composed of fibrous tissue rather than with cardiac muscle, which can lead to cardiac conduction abnormalities as action potentials cannot propagate through the cardiac muscle tissue.

Dysfunctional wound healing

Dysfunctional healing may occur during any phase of the process and may involve insufficient repair, excessive repair or infection. The cause of dysfunctional healing can be related to a predisposing disorder, such as diabetes mellitus; to an acquired condition, such as hypoxaemia (insufficient oxygen in arterial blood); or to numerous drugs and nutrients. Wound repair delays healing by reactivating inflammatory processes.

Dysfunction during the reconstructive phase

Impaired collagen synthesis

Most of the factors that interfere with the production of collagen in healing tissues are nutritional.²⁴ Protein and other nutrients are required for collagen synthesis. These include iron, oxygen, copper and calcium. Usually such minute amounts of these substances are required as cofactors that deficiencies are not clinically significant.

Dysfunctional collagen synthesis also may involve excessive production of collagen, causing surface overhealing leading to abnormal scarring. Hypertrophic scars are large, red scars that are often hard and raised compared to normal scars. They may form when excessive collagen tissue is produced but the defining characteristic is that the tissue remains within the wound edges. Hypertrophic scars tend to regress over time, usually years. Keloid scars, on the other hand, are raised scars that extend beyond the original boundaries of the wound and invade surrounding tissue. They are permanent and are often associated with tenderness and pain. Figure 13-15 shows hypertrophic and keloid scars.

FIGURE 13-15 Different types of scars.

A Hypertrophic scars: (i) a 5-month-old scar that is still pink; and (ii) a 1-year-old scar that has reduced in size and lost colour (hypopigmented). B A keloid scar. Keloids on the chest and extremities are raised with a flat surface, and the base is wider than the top.

Source: A Courtesy of Jean L Bolognia MD. Bolognia JL. Dermatology. 2nd edn. St Louis: Mosby; 2008. B Habif TP. Clinical dermatology: a color guide to diagnosis and therapy. 5th edn. St Louis: Mosby; 2010.

Impaired epithelialisation

Epithelialisation is suppressed by anti-inflammatory steroids and hypoxaemia. Wound care technique may greatly influence epithelial cell migration. External wounds that are draining or healing by secondary intention often are debrided and protected with dressings. The ideal dressing absorbs some drainage without being incorporated into the clot or granulation tissue. Because epithelial cells must migrate across the wound during healing, dressings that debride healthy epithelial cells along with necrotic tissue prolong epithelialisation.

Many solutions that traditionally have been used to clean or irrigate wounds are deleterious to the fragile new cells in the wound bed. Normal saline and potable tap water are the most innocuous solutions that can be used to cleanse or irrigate a wound that is healing primarily by epithelialisation. Solutions such as iodine and hydrogen peroxide are very drying and subsequently inhibit rather than promote epithelial cell migration.