Acute inflammation, healing and repair


Inflammation is an almost universal response to tissue damage by a wide range of harmful stimuli, including mechanical trauma, tissue necrosis and infection. The purpose of inflammation is to destroy (or contain) the damaging agent, initiate repair processes and return the damaged tissue to useful function. Inflammation is somewhat arbitrarily divided into acute and chronic inflammation , but, in reality, the two often form a continuum. Many causes of tissue damage provoke an acute inflammatory response but some types of insult may bring about a typical chronic inflammatory reaction from the outset (e.g. viral infections, foreign body reactions and fungal infections). Acute inflammation may resolve or heal by scarring but may also progress to chronic inflammation and it is common for a mixed acute and chronic response to co-exist. This chapter describes acute inflammation and its sequelae, while chronic inflammation is discussed in Ch. 4 . Many examples of acute and chronic inflammation are illustrated throughout this book.

There are three major and interrelated components of the acute inflammatory response

  • Vascular dilatation

    • Relaxation of vascular smooth muscle leads to engorgement of tissue with blood (hyperaemia)

  • Endothelial activation

    • Increased endothelial permeability allows plasma proteins to pass into tissues

    • Expression of adhesion molecules on the endothelial surface mediates neutrophil adherence

    • Production of factors that cause vascular dilatation

  • Neutrophil activation and migration

    • Expression of adhesion molecules causes neutrophils to adhere to endothelium

    • Chemotactic factors drive emigration from vessels into surrounding tissues

    • Increased capacity for bacterial killing

      Fig. 3.1, Outline of acute inflammation.

      Fig. 3.2, Formation of the acute inflammatory exudate. (A) Early vascular changes (HP); (B) migration of neutrophils (HP); (C) early formation of exudate (LP).

      Fig. 3.3, Established acute inflammation: lobar pneumonia. (A) LP; (B) MP.

These are outlined in Fig. 3.1 .

Key to Figures

A alveolus C alveolar capillary F interlobar fissure Fi fibrin M alveolar macrophage N neutrophils

Morphological patterns of acute inflammation

While the basic process of acute inflammation is the same in all tissues, there are frequently qualitative differences in the inflammatory response seen under different circumstances. Terms describing these variations are widely used in clinical practice and are summarised below:

  • Suppurative inflammation (purulent inflammation) refers to acute inflammation in which the acute inflammatory exudate is rich in neutrophils. Suppurative inflammation is most commonly seen due to infection by bacteria where the mixture of neutrophils (viable and dead), necrotic tissue, and tissue fluid in the acute inflammatory exudate form a semi-liquid material referred to as pus , hence the term purulent inflammation (see Fig. 3.4 ). Within tissues, a circumscribed collection of semi-liquid pus is termed an abscess (see Fig. 3.12 ). The destruction of tissue may be due as much to release of neutrophil lysosomal enzymes as to tissue destruction by bacteria. Bacteria that produce purulent inflammation are described as pyogenic bacteria . They initiate massive neutrophilic infiltration with subsequent destruction of infected tissues. Pyogenic bacteria include staphylococci, some streptococci (Streptococcus pyogenes , S. pneumoniae), Escherichia coli and the neisseriae ( Neisseria meningitidis, N. gonorrhoeae ).

    Fig. 3.4, Acute inflammatory exudate. (A) Neutrophilic exudate (HP); (B) highly fibrinous exudate (HP); (C) fibrinous inflammation: acute pericarditis (LP).

  • Fibrinous inflammation refers to a pattern of acute inflammation where the acute inflammatory exudate has a high plasma protein content (see Fig. 3.4 ). Fibrinogen, derived from plasma, is converted to fibrin, which is deposited in tissues. This pattern is particularly associated with membrane-lined cavities such as the pleura, pericardium and peritoneum, where the fibrin strands form a mat-like sheet causing adhesion between adjacent surfaces.

  • Serous inflammation describes a pattern of acute inflammation where the main tissue response is an accumulation of fluid with a low plasma protein and cell content. This is often called a transudate , which by definition has a specific gravity of <1.012 or protein content of <25 g/L in contrast to an exudate, with a specific gravity of >1.020 and protein content of >25 g/L. This pattern of response is most commonly seen in the skin in response to a burn.

Clinical features and nomenclature of acute inflammatory processes

The vascular and exudative phenomena of acute inflammation are responsible for the clinical features and were described by Celsus in the first century AD. The cardinal signs of Celsus are:

  • redness (rubor) caused by hyperaemia

  • swelling (tumor) caused by fluid exudation and hyperaemia

  • heat (calor) caused by hyperaemia

  • pain (dolor) resulting from release of bradykinin and PGE 2 .

  • Virchow later added:

  • loss of function (functio laesa) caused by the combined effects of the above.

Clinically, patients who have significant acute inflammation feel unwell and have a fever. This is mediated by cytokines released into the blood (interleukins 1 and 6 (IL-1 and IL-6 respectively), tumour necrosis factor (TNF) and prostaglandins), acting on the hypothalamus. Laboratory investigations commonly reveal a raised neutrophil count in the blood (neutrophil leukocytosis).

The nomenclature used to describe inflammation in different tissues employs the tissue name (or its Greek or Latin equivalent) and the suffix ‘-itis’. For example, inflammation of the appendix is referred to as appendicitis , inflammation of the Fallopian tube is termed salpingitis and inflammation of the pericardium is termed pericarditis . Notable exceptions to this rule include pleurisy , for inflammation of the pleura and acute cellulitis for inflammation of subcutaneous tissues. Many examples of acute inflammatory diseases are presented in the systematic pathology chapters, which form the second half of this book. Common examples are outlined in Table 3.1 .

Key to Figure

Ex exudate F fibrin Fa pericardial fat N neutrophils P pericardium

Table 3.1
Nomenclature and aetiology of common types of inflammation.
Tissue Acute inflammation Typical causes
Meninges Meningitis Bacterial and viral infections
Brain Encephalitis Viral infections
Lung Pneumonia Bacterial infections
Pleura Pleurisy Bacterial and viral infections
Pericardium Pericarditis Bacterial and viral infections, myocardial infarction
Oesophagus Oesophagitis Gastric acid reflux, fungal infection ( Candida albicans )
Stomach Gastritis Helicobacter pylori infection, reflux/chemical gastritis
Colon Colitis Bacterial infections, inflammatory bowel disease
Rectum Proctitis Infections, ulcerative colitis
Appendix Appendicitis Faecal obstruction
Liver Hepatitis Alcohol abuse, viral infections
Gallbladder Cholecystitis Bacterial infections, chemical irritation
Pancreas Pancreatitis Obstructed pancreatic duct, alcoholism, shock
Urinary bladder Cystitis Bacterial infections
Bone Osteomyelitis Bacterial infections
Subcutaneous tissues Cellulitis Bacterial infections
Joints Arthritis Infections, autoimmune diseases
Arteries Arteritis Immune complex deposition
Kidney Pyelonephritis Bacterial infections
Peritoneum Peritonitis Spread from intra-abdominal inflammation, e.g. appendicitis, salpingitis
Ruptured viscus, e.g. perforated peptic ulcer

Outcomes of acute inflammation

The process of acute inflammation is designed to neutralise injurious agents and to restore the tissue to useful function. There are four main outcomes of acute inflammation (if the patient survives): resolution , healing by fibrosis , abscess formation and progression to chronic inflammation . Three factors determine which of these outcomes occurs:

  • the severity of tissue damage

  • the capacity of stem cells within the damaged tissue to divide and replace the specialised cells required, a process termed regeneration

  • the type of agent that has caused the tissue damage.

Resolution involves complete restitution of normal tissue architecture and function. This can only occur if the connective framework of the tissue is intact and the tissue involved has the capacity to replace any specialised cells that have been lost (regeneration). Neutrophils and damaged/dead tissue are removed by phagocytosis by macrophages ( E-Fig. 3.5 ), which leave the tissue via the lymphatics. Regeneration of tissues plays an important part in resolution, for example re-growth of alveolar lining cells following pneumonia: this regrowth is dependent on the intrinsic ability of resident stem cells to divide and differentiate into mature tissue cells. Examples of resolution are recovery from sunburn (acute inflammatory response in the skin as a result of ultraviolet radiation exposure) and the restitution of normal lung structure and function following lobar pneumonia (see Figs 3.3 and 3.7 ).

Healing by fibrosis (scar formation) occurs when there is substantial damage to the connective tissue framework and/or the tissue lacks the ability to regenerate specialised cells. In these instances, dead tissues and acute inflammatory exudate are first removed from the damaged area by macrophages (see Fig. 3.6 ), and the defect becomes filled by ingrowth of a specialised vascular connective tissue called granulation tissue (see Fig. 3.8 ). This is called organisation . The granulation tissue gradually produces collagen to form a fibrous (collagenous) scar , constituting the process of repair (see Figs 3.8 and 3.9 ). Despite the loss of some specialised cells and some architectural distortion caused by the fibrous scar, structural integrity is re-established. Any impairment of function is dependent on the extent of loss of specialised cells. Modified forms of fibrous repair occur in bone after a fracture when new bone is created (see Fig. 3.11 ), and in brain with the formation of an astrocytic scar (see Fig. 23.2).

Abscess formation takes place when the acute inflammatory reaction fails to destroy/remove the cause of tissue damage and continues, usually with a component of chronic inflammation. This is most common in the case of infection by pyogenic bacteria. As the acute inflammation progresses, there is liquefaction of the tissue to form pus. At the periphery of this acute abscess, a chronic inflammatory component surrounds the area and fibrous tissue is laid down, walling off the suppuration (see Fig. 3.12 ).

Table 3.2
Chapter review.
Concept Definition/main features Figure
Three major components of the acute inflammatory response
  • 1.

    Oedema due to increased fluid in tissue

  • 2.

    Dilated vessels

  • 3.

    Infiltration by inflammatory cells: mainly neutrophils in the early stages and macrophages later

3.1, 3.2, 3.3, 3.4
Five cardinal signs of acute inflammation
  • 1.


  • 2.


  • 3.


  • 4.


  • 5.

    Loss of function

Mediators of acute inflammation
  • 1.

    Vasodilatation: histamine, prostaglandins, nitric oxide

  • 2.

    Increased vascular permeability: serotonin (5-HT), histamine, C5a, C3a and leukotrienes

  • 3.

    Leukocyte activation and chemotaxis: C5a, leukotriene B4, various chemokines and bacterial products

3.1, 3.2
Outcomes of acute inflammation
  • 1.

    Complete resolution

  • 2.

    Healing by fibrosis (scar)

  • 3.

    Abscess formation

  • 4.

    Progression to chronic inflammation

  • 5.

    Loss of self-tolerance leading to autoimmune disease

3.5, 3.6, 3.7, 3.8, 3.12 and clinical box (Inflammation out of control).
Wound healing
  • May be by primary or secondary intention

  • Results in fibrous scar formation

  • Process differs in specialised tissues such as bone

3.9, 3.10, 3.11

Chronic inflammation may result following acute inflammation when an injurious agent persists over a prolonged period, causing concomitant tissue destruction, inflammation, organisation and repair. Some injurious agents elicit a chronic inflammatory type of response from the outset. Chronic inflammation is discussed fully in Ch. 4 .

Inflammation Out of Control

Inflammation can do harm as well as good. In most people, inflammation is activated appropriately in response to some kind of adverse stimulus and terminated promptly when the infective organisms have been eliminated and tissue damage repaired. In some individuals, control of the inflammatory process is lost; this is called autoimmune disease .

One of the major stimuli of acute inflammation is a type of adaptive immune response where specific antibodies recruit components of the acute inflammatory response as effector mechanisms, thereby directing the non-specific components of the acute inflammatory system at specific targets ( E-Fig. 3.6 ).

Normally, the immune system is programmed to ignore antigenic stimuli within the individual’s own body, a process known as self-tolerance . When this self-tolerance is lost for one or more antigens, autoimmune disease results. These may be organ-specific antigens as in the organ-specific autoimmune disease Hashimoto’s thyroiditis (see Fig. 20.3 ) or, at the other end of the spectrum, the antigens triggering the response may be widespread in many tissues, as in systemic lupus erythematosus (SLE) , where the body reacts to double-stranded DNA as well as many other cellular antigens, causing systemic disease.

In many autoimmune disorders, inflammation and pain may cause major morbidity. Also, the misdirection of the immune response causes local tissue damage such as pain and swelling in the joints in rheumatoid arthritis (see Fig. 22.11 ) or renal failure due to renal damage in SLE. Many anti-inflammatory drugs are available but side effects are common and can be potentially serious. Recently, immunomodulating therapies have been used to treat some inflammatory conditions, e.g. anti-TNF antibodies in rheumatoid arthritis and inflammatory bowel disease. These therapies can have side effects, including an increased propensity to some infective organisms such as Mycobacterium tuberculosis, highlighting the complex immunomodulating role of biological therapies.

Delayed Wound Healing

Many factors can delay or stop healing. A common factor is continuing inflammation where the initial stimulus to inflammation persists: a good example of this would be an infected wound or persistent peptic ulceration due to Helicobacter pylori infection (see Ch. 13 ). The presence of dead tissue or a foreign body in a wound can delay healing, as well as host factors such as poor nutrition, poor circulation, pre-existing diabetes mellitus or medications such as steroids.

Key to Figures

C capillary F fibroblasts M macrophage My myocardial remnant P proteinaceous debris


Keloid is the name given to excessive formation of scar tissue. Some individuals have a tendency to form excessive amounts of collagen. When this occurs but does not extend beyond the bounds of the pre-existing wound, it is called a hypertrophic scar . However, when is extends beyond the pre-existing scar, it is called keloid and can give rise to a very unsightly appearance. Unfortunately, attempts to remove the excessive scar tissue surgically can give rise to even more keloid formation and a poor cosmetic outcome.

Key to Figures

C capillaries D dermis F fibroblasts S scar

Fig. 3.5
Outcomes of acute inflammation.
The flow chart in Fig. 3.5 summarises the main outcomes following acute inflammation. If the tissue damage is minimal, as in mild acute inflammation then resolution is possible, but complete resolution is uncommon. Acute inflammation usually leads to tissue damage.
If the inflammation then resolves, the inflamed area heals with formation of a fibrous scar. If the inflammation persists and there is ongoing tissue damage, chronic inflammation ensues (see Ch. 4 ).

Fig. 3.6
Early outcome of acute inflammation: macrophage accumulation (HP).
As early as the second or third day of the acute inflammatory response, macrophages accumulate in increasing numbers. These enter the tissue in a similar fashion to neutrophils in response to chemotactic factors. Macrophages phagocytose cell debris, dead neutrophils and fibrin. At the same time, lymphocytes begin to enter the damaged area, reflecting an immune response to any introduced antigens.
Fig. 3.6 shows an area of cardiac muscle that has undergone necrosis following blockage of its arterial supply (myocardial infarction) . The acute inflammatory response has almost run its course, and the neutrophils and fibrin predominant in the earlier stages have been removed by macrophages. All that remains is a soft, loose tissue containing a few necrotic myocardial remnants (My) , one of which is shown here being engulfed by macrophages (M) . The macrophages can be identified under these circumstances by the foamy appearance of their cytoplasm, which also often contains brownish pigment granules. These brown granules are iron-containing pigments (haemosiderin) derived from haemoglobin. Further details of the events following myocardial infarction are shown in Fig. 10.2.

Fig. 3.7
Resolution of acute inflammation: lobar pneumonia (MP).
Occasionally, a damaging stimulus might excite a strong acute inflammatory response with minimal tissue damage. In such circumstances, resolution of the exudate might occur without any need for organisation and repair, thereby leaving no residual tissue scarring.
This phenomenon occurs in lobar pneumonia ( Fig. 3.7 ), in which the acute inflammatory response is due to infection by a bacterium, commonly the pneumococcus (see Fig. 3.3 ). The alveoli of one or more lobes of the lung are filled with acute inflammatory exudate and the loss of respiratory function may be so great as to cause fatal hypoxia . In the pre-antibiotic era, this was a common cause of death in previously fit young people.
Bacteria are engulfed by neutrophils and fibrin strands are broken down by fibrinolysins derived from plasma and neutrophil lysosomes. Macrophages (M) are recruited and phagocytose apoptotic neutrophils, extravasated red cells and other cell debris. Fluid and degraded proteinaceous material (P) , together with the macrophages, are then resorbed into the circulation via alveolar wall vessels and interstitial lymphatics or may be coughed up as brown-coloured sputum. Alveolar spaces are thus cleared of exudate and can participate in gas exchange. Regeneration of alveolar lining cells completes the return to normal structure and function.

Fig. 3.8
Granulation tissue. (A) Vascular granulation tissue (HP); (B) fibrous granulation tissue (MP).
Where there is significant damage to the connective tissue framework, the first phase of the healing process is the formation of granulation tissue , a mixture of proliferating capillaries, fibroblasts and inflammatory cells. Formation of a network of new capillaries (C) (angiogenesis) occurs by a combination of budding from vessels at the periphery of the damaged area and from endothelial precursor cells. This is stimulated by growth factors such as vascular endothelial growth factor (VEGF) . In this early form, called vascular granulation tissue ( Fig. 3.8A ), the spaces between the capillaries are occupied by macrophages, lymphocytes, proliferating fibroblasts and loose oedematous extracellular matrix. The capillaries are thin-walled and relatively leaky, leading to extravasation of erythrocytes and fluid into the tissue. Students often confuse granulation tissue with granulomas (see Ch. 4 ) but the two are quite different.
Over time, most of the vessels regress, collagen is laid down, and the inflammatory cells return to the circulation. The effect of this progression is seen in Fig. 3.8B , where numerous plump activated fibroblasts (F) can be seen with a few residual lymphocytes and relatively inconspicuous capillaries (C) . This is called fibrous granulation tissue in recognition of the presence of mature collagenous fibrous tissue. Collagen, laid down by the fibroblasts, becomes remodelled in an orderly pattern (upper left area of micrograph) and the fibrous granulation tissue takes on the characteristics of an early fibrous scar (see Fig. 3.10 ).
Granulation tissue is also involved in healing of wounds, whatever the cause and site of the tissue defect. In the case of a simple skin incision, where the wound edges are in close apposition and the actual defect is minimal, healing occurs quickly with a small amount of granulation tissue and is termed healing by primary intention . In other situations, the tissue defect will be large and filled with blood clot and a variable amount of tissue debris. In this case, described as healing by secondary intention , organisation and filling of the defect by granulation tissue take considerably longer ( Fig. 3.9 ).

Fig. 3.9
The processes involved in wound healing. The left column shows the process of wound healing by primary intention. This process would occur in incised, somewhat shallow wounds. The right column shows healing by secondary intention, a process that usually occurs in ragged, deeper wounds or wounds that are infected.

Fig. 3.10
Fibrous scar. (A) Fibrous scar tissue (HP); (B) skin scar (LP).
The deposition of collagen within fibrous granulation tissue occurs over a period of many weeks. Collagen is remodelled in an appropriate orientation to withstand the tensile stresses placed on the area of repair. With time, the previously plump and metabolically active fibroblasts regress and become relatively inconspicuous, as shown in Fig. 3.10A , a micrograph of a typical area of early fibrous scar. Note the condensed nuclei of inactive fibroblasts (F ). Some capillaries (C) persist, accounting for the red appearance of recent scars.
The micrograph in Fig. 3.10B illustrates, at low magnification, a recent area of scarring in the skin after healing of a simple incision for biopsy of a skin tumour. Immature collagenous tissue forms a pale scar (S) , which interrupts the normal pink collagen of the dermis (D) on either side. There are no skin appendages in a skin scar. During the ensuing months and years, the cellularity of the scar diminishes, there is progressive loss of capillary vessels and the scar contracts so that after many years, a skin scar may be virtually undetectable with the naked eye. Note that healing of skin of mucous membrane involves epithelialisation of the surface by proliferation of epithelium at the edges of the defect (i.e. epithelial regeneration).

Key to Figures

B bone C provisional callus Ca capillaries F fibrin G granulation tissue N neutrophils O osteoblasts Os osteoid

Non-Union of Fractures

While most fractures heal completely and well with modern management, in some individuals, there is delay in complete healing of a fracture; in others there may be cessation of the healing process without restitution of functional bone, known as non-union . A wide range of factors may contribute to delayed or failed healing, the most important of which are poor immobilisation, poor blood supply, poor nutrition (lack of protein, vitamin C, etc.), the presence of infection and foreign bodies or fragments of necrotic bone in the fracture. Old age, drugs such as steroids and non-steroidal anti-inflammatory drugs (NSAIDs), diabetes mellitus, burns and irradiation may also delay or stop healing.

Types of Fracture

Fractures are described as complete or incomplete depending on whether the entire thickness of the bone is fractured. In closed fractures the overlying skin is intact, while compound fractures include disruption of the overlying skin. A comminuted fracture has multiple separate bone fragments. Pathological fractures occur in bone with pre-existing disease, such as osteoporosis or metastatic tumour. Greenstick fracture is an incomplete fracture where there is initial bending with partial fracture of the side under tension: it typically occurs in children.

Fig. 3.11
Specialised healing in bone. (A) LP; (B) HP.
In most tissues, fibrous scar forms a functionally adequate, albeit unspecialised, replacement for damaged tissues. In bone, the replacement of damaged tissue by fibrous scar is inadequate for restoration of function (e.g. weight bearing) and therefore in bone healing the processes that form bone during embryonic development are reactivated. This leads to new bone formation, a process of regeneration rather than repair . As in other forms of wound healing, the process is carefully controlled and orchestrated by an array of mediators, including platelet-derived growth factor (PDGF), transforming growth factor β (TGFβ), fibroblast growth factors (FGF) and bone morphogenetic proteins (BMPs).
Immediately following fracture, there is bleeding in and around the fracture site resulting in a mass of coagulated blood, a haematoma . An initial acute inflammatory response is rapidly followed by organisation of the haematoma with formation of granulation tissue as described in Fig. 3.8 . In the case of bone fracture, this granulation tissue is termed provisional or soft tissue callus (C) and forms around the broken ends of the bone (B) , loosely uniting them; this is seen at low magnification in Fig. 3.11A . Mesenchymal stem cells found in the cambium layer of the periosteum are activated and divide and differentiate into chondrocytes and osteoblasts to produce cartilaginous matrix and osteoid, the organic matrix of bone, respectively. This is seen in Fig. 3.11B where typical granulation tissue (G) at the top of the field gives way to osteoblasts (O) , which surround pink-staining, newly formed osteoid (Os) . Osteoid then becomes mineralised to form the bony callus between the two fractured ends. This initial bone is haphazardly arranged (known as woven bone ) and, over the next few months, undergoes extensive remodelling by osteoclasts and osteoblasts to form lamellar bone with trabecular architecture, best suited to resist local stresses. The end result is normal bony architecture and function.

Fig. 3.12
Abscess formation. (A) LP; (B) HP.
An abscess is a localised collection of pus, which usually develops following extensive tissue damage by one of the pyogenic bacteria, such as Staphylococcus aureus . Such organisms excite an inflammatory exudate in which neutrophils predominate. In these circumstances, large numbers of neutrophils die, releasing their lysosomal enzymes and undergoing autolysis; the resulting viscous fluid, pus , contains dead and dying neutrophils, necrotic tissue debris and the fluid component of the acute inflammatory exudate with a little fibrin. Pyogenic bacteria often remain viable within the abscess cavity and may cause enlargement of the lesion, which is described as an acute abscess . At an early stage, expansion of the lesion is limited by the processes of organisation and repair at the margins of the abscess. Thus, the abscess may become walled off, isolating the bacteria- containing pus and preventing further spread; an abscess encapsulated by granulation and fibrous tissue is termed a chronic abscess . On the other hand, if the bacteria are highly virulent and present in large numbers, such attempts at organisation and repair may be overwhelmed and expansion of the abscess ensues with destruction of surrounding tissue. The coexistence of active tissue damage and attempts at repair are typical of chronic inflammation (see Ch. 4 ).
Fig. 3.12A shows an abscess in the wall of the colon. The centre consists of a collection of pus (P) . At its margin is a pink-staining zone of fibrin (F) . As yet, there is little evidence of organisation at the margins of the abscess; this therefore represents an acute abscess. Fig. 3.12B shows the wall and lumen of a chronic abscess at high power, illustrating the neutrophils (N) and tissue debris in the cavity of the abscess and the capillaries (Ca) in the inflamed granulation tissue of the wall.

E-Fig. 3.1 H
Mast cells. (A) H&E (HP); (B) toluidine blue (HP); (C) EM ×12,000.
Mast cells are found in all supporting tissues but are particularly prevalent in the skin, gastrointestinal lining, the serosal lining of the peritoneal and pleural cavities and around blood vessels. Their major constituents and functions are very similar to those of basophils, to which they are related. Mast cells are long-lived with the ability to proliferate in the tissues. Mast cell degranulation results in the release of histamine and other vasoactive mediators which induce the immediate hypersensitivity (anaphylactoid) response characteristic of urticaria, allergic rhinitis, asthma and anaphylactic shock. Mast cells may be inconspicuous in routine histological sections due to the water solubility of their densely basophilic granules, which tend to be lost during preparation. Special techniques of fixation, embedding and staining may be employed. With suitable preparation, micrograph (A) , however, the characteristic feature of mast cells is an extensive cytoplasm packed with large granules; these are smaller in size, though more numerous, than those of basophils. When stained with certain blue basic dyes such as toluidine blue , the granules bind to the dye, changing its colour. This property of staining a different colour to the dye is known as metachromasia , micrograph (B) . In the electron micrograph (C) , mast cell granules G are seen to be membrane bound and to contain a dense amorphous material. The granules are liberated from the cell by exocytosis when stimulated during an inflammatory or allergic response. The cytoplasm contains a few rounded mitochondria Mi and a little rough endoplasmic reticulum. The non-segmented nucleus Nu has less condensed chromatin than that of basophils. Other differences from basophils include a more uniform distribution of their thin surface processes, a greater number of cytoplasmic filaments and a lack of glycogen granules.

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.

E-Fig. 3.2 H
Endothelial cell EM×68,000.
Endothelial cells are flat polygonal cells which are connected to each other by junctional complexes. They have numerous pinocytotic vesicles V and specialised membrane-bound organelles called Weibel-Palade bodies WP which store von Willebrand factor. Endothelial cells have a range of metabolic functions, many concerned with the fine control of blood coagulation and thrombosis, as well as regulating local control of blood vessel constriction/dilatation and changes in vessel wall permeability. Endothelial cell damage may lead to pathological thrombosis or haemorrhage, or exudation of some components of blood into the extravascular tissues.

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.

E-Fig. 3.3 H
Neutrophils. (A) Giemsa (HP); (B) H&E (HP); (C) H&E (MP); (D) Giemsa (HP).
Neutrophils account for 40% to 60% of the leucocytes in the circulating blood, with 1.0 to 5.0 × 10 9 /L. They are 12 to 14 µm in diameter. The lifespan of a neutrophil is a few days and they are rarely found in normal tissue. Neutrophils exhibit progressive segmentation of their nucleus, with a young cell having 2 lobes, the average cell 3 to 4 lobes and older cells 5 lobes. They have a lightly stippled granular pink cytoplasmic appearance due to numerous small membrane-bound granules (0.2 to 0.8 µm in diameter), micrograph (A) . These granules include the azurophilic primary granules (purple) and the specific secondary granules (pink/lilac), tertiary granules and secretory granules . In H&E stains, they have pink or pale red cytoplasm, micrograph (B) . Neutrophils leave the vascular space in response to chemotactic signals generated by inflammation. They are highly motile, phagocytose bacteria and kill them by fusing the phagosome with neutrophil primary granules and producing activated oxygen derivatives. Under certain conditions, they degranulate, releasing granule contents including inflammatory mediators, antibacterial enzymes and tissue matrix breakdown enzymes. Massed neutrophils and their debris in tissue are visually recognised as pus, micrograph (C) . Neutrophils do not re-enter the blood stream from tissue but undergo lysis or apoptosis in tissues. As an incidental finding the inactivated X chromosome in females is seen as a small drumstick-shaped appendage D in a few (3%) percent of neutrophils, micrograph (D) .

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.

E-Fig. 3.4 H
Neutrophil EM ×10,000.
With electron microscopy, neutrophils have three distinguishing features. Firstly, multiple nuclear lobes N with condensed chromatin; these lobes are seen as separate in the thin EM sections. Secondly, the cytoplasm contains many membrane-bound granules. The primary granules P are large, spheroidal and electron-dense. The secondary or specific granules S are more numerous, small and often rod-like and are of variable density and shape. Tertiary and secretory granules cannot be readily distinguished from other membrane-bound vesicles on ultrastructure. The third feature is that other cytoplasmic organelles are scarce. Additionally, the cytoplasm is particularly rich in dispersed glycogen. The mature neutrophil has few organelles for protein synthesis and has a limited capacity to regenerate secreted proteins; it tends to degenerate after a single burst of activity. The paucity of mitochondria and the abundance of glycogen in neutrophils reflect the importance of the anaerobic mode of metabolism. Energy production via glycolysis permits neutrophils to function in the poorly oxygenated environment of damaged tissues. Neutrophils are highly motile cells, moving through the extracellular spaces in a crawling fashion with an undulating pseudopodium typically thrust out in the line of advance. Motility and endocytotic (phagocytic) activity are reflected in a large content of the contractile proteins, actin and myosin, as well as tubulin and microtubule-associated proteins.

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.

E-Fig. 3.5 H
Monocytes. (A–C) Giemsa (HP); (D) EM×20,000.
Monopoiesis, the formation of monocytes, is described as having three morphological stages. The first is the monoblast, micrograph (A) . These mature with development of cytoplasmic granules and the start of a ‘frosted glass’ character to the cytoplasm; they are then called promonocytes , micrograph (B). These proliferate and mature into monocytes, micrograph (C) . A typical promonocyte will undertake two serial cell divisions to produce 4 monocytes in a process taking about 60 hours. Monocytes are the largest of the white cells (up to 20 µm in diameter) and constitute from 2% to 10% of leucocytes in peripheral blood. They circulate for 3 to 4 days on average before migrating into tissues. These cells are motile, highly phagocytic and may mature in tissues into tissue resident macrophages of varying kinds with extended lifespans. Monocytes, micrograph (C) , are characterised by a large, eccentrically placed nucleus which stains less intensely with more open chromatin than other leucocytes. Nuclear shape is variable but often with a deep indentation in the nucleus near to the centre of the cell, giving a horseshoe shape. Two or more nucleoli may be visible. Cytoplasm is abundant and stains pale greyish-blue with Romanowsky methods. There are numerous small, purple-stained lysosomal granules and cytoplasmic vacuoles which confer a ‘frosted-glass’ appearance.With the electron microscope, micrograph (D) , the cytoplasm is seen to contain a variable number of ribosomes, polyribosomes and little rough endoplasmic reticulum. The Golgi apparatus G is well developed and is located with the centrosome in the vicinity of the nuclear indentation. Small elongated mitochondria M are prolific. Small pseudopodia P extend from the cell, reflecting phagocytic ability and amoeboid movement. The cytoplasmic granules Gr of monocytes are electron-dense and homogeneous. Half resemble primary (azurophilic) granules of neutrophils and these contain myeloperoxidase, acid phosphatase, elastase and cathepsin G. The other half are secretory granules containing plasma proteins, membrane adhesion proteins and tumour necrosis factor alpha (TNF-α). Monocytes are capable of continuous lysosomal activity and regeneration and utilise aerobic and anaerobic metabolic pathways, depending on the availability of oxygen in the tissues.

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.

E-Fig. 3.6
The basics of the immune response . This diagram outlines the key steps in the adaptive immune response, i.e. recognition of antigen, activation of the response, generation of effector mechanism and destruction or inactivation of the antigen.
Recognition of antigen
T and B cells carry antigen receptors on their surface, the T cell receptor ( TCR ) and B cell receptor ( BCR ). The BRC consists of surface immunoglobulin plus certain accessory molecules. Random rearrangement of the genes for the variable region of the receptor molecules gives rise to receptors with a truly staggering range of antigen binding sites. Each individual T or B cell has specificity for only one antigen, but the entire population is very varied.
Activation of the immune system
Initiation of an immune response first requires contact between antigen Ag and surface receptors on mature lymphocytes. There are several mechanisms of activation:

  • 1.

    Activation of T cells is dependent on antigen presenting cells APC . The antigen is taken up by an APC (e.g. macrophage, B lymphocyte, dendritic cell, Langerhans cell of skin) and broken down to short peptides. Processed antigen PA is then bound to a major histocompatibility complex molecule MHC , and the MHC-peptide complex is incorporated into the cell membrane so that the bound antigenic peptide is exposed to the extracellular fluid. Contact with a mature T cell bearing a T cell receptor with appropriate specificity activates the T cell. The type of response depends on whether the peptide is presented bound to MHC class I or II. Antigenic peptides bound to class II MHC molecules induce a T helper cell T H response needed to activate B cells B and cytotoxic T cells T C . B cell receptors (sIg) or T C receptor must also bind to the antigen for activation to occur. T H cells secrete a variety of interleukins IL that mediate activation, clonal expansion and maturation of the B or cytotoxic T cell response.

  • 2.

    Antigen synthesised within a body cell (e.g. tumour cell, virus-infected cell) is presented on the APC plasma membrane bound to a class I MHC protein where it is recognised by cytotoxic T cells T C . Cytotoxic T cells are able to kill the abnormal cells directly. T H activation is also required for a T C response to be mounted.

  • 3.

    B lymphocytes interact with unprocessed antigens. They recognise antigen by means of the BCR (surface immunoglobulin, sIg). In most cases, the unprocessed antigen is presented to the B cell on the surface of an APC such as a follicular dendritic cell in a lymphoid follicle. The majority of antigens can only activate a B cell if there is ‘help’ from an activated T helper cell T H . Activation without T cell help will occur if sIg binds to a protein or polysaccharide antigen with a repeating chemical structure (e.g. the polysaccharide coat of the bacterium Pneumococcus ). Such antigens are often known as T cell–independent antigens . Few naturally occurring antigens are of this type (not illustrated).

Generation of effector mechanisms

  • 1.

    Production of antibodies by plasma cells. Mechanisms of antibody-mediated antigen elimination are as follows:

    • Antibody blocks the entry of organisms (such as viruses) into cells by binding to viral surface antigens.

    • Antigen-antibody complexes ( immune complexes ) activate complement to produce (among other factors) the membrane attack complex MAC , which punctures the outer membrane of the attacking organism.

    • Bound antibody with or without complement opsonises organisms and facilitates phagocytosis by neutrophils and macrophages .

    • Antibody is essential for antibody-dependent cell cytotoxicity ( ADCC ) (see below).

    • Antibody bound to toxins inactivates them and facilitates their removal by phagocytic cells.

  • 2.

    Cell-mediated cytotoxicity is the destruction by apoptosis of abnormal cells by cytotoxic T cells, natural killer (NK) cells or antibody dependent cytotoxic cells. Certain types of organism, such as Mycobacterium tuberculosis , the cause of tuberculosis, activate T helper cells (T H 1) to secrete cytokines that in turn activate macrophages. Activated macrophages are more effective at killing phagocytosed organisms. This is the mechanism of type IV hypersensitivity ( chronic granulomatous inflammation ) (not illustrated).

Termination of the immune response
There are a number of mechanisms for switching off the immune response when the need for it has been removed. These include removal of antigen, the short life span of plasma cells, the activities of regulatory T cells and a variety of other mechanisms that downregulate the activity of T and B cells. It is vital that the immune response is terminated when no longer needed to prevent damage to normal tissue from an overenthusiastic immune response. These mechanisms are also important in the prevention of autoimmunity.
Immunological memory
When activated lymphocytes undergo clonal expansion during an immune response, some of the cells so generated mature to become memory T and B cells. These lymphocytes have a similar appearance to naïve lymphocytes but are able to produce a faster and more effective response to a smaller quantity of antigen. This is known as a secondary immune response and is the basis of lifelong immunity after certain infections and of vaccination.

Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.


Chapter 3 Question 1

Which ONE of the following combination of processes is an essential component of the acute inflammatory response?


  • A)

    Vascular dilatation, endothelial activation, macrophage activation and migration.

  • B)

    Vascular dilatation, vascular smooth muscle activation, macrophage activation and migration.

  • C)

    Vascular dilatation, endothelial activation, neutrophil activation and migration.

  • D)

    Vascular dilatation, vascular smooth muscle activation, neutrophil activation and migration.

  • E)

    Vascular constriction, endothelial activation, neutrophil activation and migration.

Chapter 3 Question 2

Which ONE of the following causes vasodilatation?


  • A)


  • B)

    Leukotriene C4

  • C)

    Nitric dioxide

  • D)


  • E)

    Serotonin (5-HT)

Chapter 3 Question 3

Which ONE of the following is not one of the cardinal clinical features of acute inflammation?

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