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Acute Inflammation


Acute inflammation is the immediate response to an inflammatory agent (such as a pathogen or foreign material) or necrotic cells/tissue caused by cell injury and death. It undergoes many vascular changes in order to increase the amount of antibodies and leukocytes at the site of inflammation. The major contributing factors are:

  1. Alterations in the vascular flow and calibre – increasing blood flow
  2. Structural changes of the microvasculature (capillaries, arterioles and venules) – Resulting in the leakage of plasma proteins (e.g. fibrin) and the evasion of leukocytes
  3. Emigration of leukocytes from the microcirculation – Resulting in the accumulation of leukocytes in the area of injury


Mechanisms of the Vascular Changes

Changes in Vascular Flow and Calibre

These vascular changes occur very early on in acute inflammation, they develop at varying rates dependent on the severity of the injury.

  • In the first few seconds vasoconstriction of arterioles will occur, this is a momentary effect
  • Next vasodilation will occur, increasing arteriole diameter and opening new capillary beds. This results in an increase of blood flow
  • After vasodilation, the circulation of the blood will begin to slow down. This occurs in a matter of minutes (<30mins). This is known as stasis. It is due to a number of factors such as:
    • Increased microvasculature permeability
    • Loss of fluid
    • Increased blood viscosity (High concentrations of red blood cells in small vessels)
    • Movement of protein rich fluid into the extravascular tissues
    • The development of stasis brings around the onset of cellular events involved with acute inflammation. This includes; leukocyte margination (the movement of leukocytes out of the circulatory system towards the site of injury or infection), rolling (transient sticking of leukocytes to endothelium, followed by an avid binding of leukocytes to endothelium) and migration of leukocytes through the vascular wall into the interstitial tissue

Increased Vascular Permeability

The causes of increased vascular permeability are:

  • The leakage of protein across venules. This decreases intravascular osmotic pressure and increases interstitial pressure.
  • Increased hydrostatic pressure in the capillary bed, this is due to vasodilation. Fluid outflow occurs, allowing fluids to build up in interstitial tissues. This results in an oedema.
  • Endothelium-mediated Vascular Leakage – There are 4 mechanisms by which vascular leakage occurs, the basic principal behind all of them is a change in shape of the endothelium, which can occur in a multitude of manners as described below:
    • Endothelial Contraction – The endothelial cells of venules are forced to contract by chemical mediators (e.g. histamine, leukotrienes), forming a gap between the cells, thus increasing permeability.
    • Cytoskeletal Reorganisation – Endothelial cells of venules and capillaries can reorganise their cytoskeleton by cytokine stimuli (such as IL-1 or TNF), this causes endothelial retraction, creating gaps between the cells as before.
    • Direct Injury – This can affect arterioles, capillaries and venules and is any direct damage caused to the endothelial cells resulting in the formation of gaps (increasing permeability). This could be as a result of toxins, burns, chemicals or bacterial infection. In severe cases you may get necrosis or detachment of the endothelial cells.
    • Leukocyte dependent Injury – This is the activation of adhered leukocytes, which then release toxic oxygen (such as free radicals) and proteolytic enzymes resulting in endothelial injury. Again resulting in the formation of gaps.

Mechanisms of Cellular Events (Extravasation)


The main goal of inflammation is to get leukocytes to the point of injury. Leukocytes ingest the inflammatory causing agents, kill bacteria and other microbes and degrade necrotic tissue/ foreign antigens. However, they can also prolong inflammation by inducing tissue damage; they release enzymes, chemical mediators and toxic oxygen radicals to do this.

In order to recruit leukocytes to the site of inflammation, a series of interactions between adhesion molecules on the endothelium and specific receptors on the surface of leukocytes occurs. This is explained by the 5 stages of extravasation. This process is mediated by the adhesion molecules, which include selectins, immunoglobulin family and integrins.


The Stages of Extravasation

The main processes can be grouped into 5 stages:

  1. Rolling of leukocytes along the endothelium
  2. The activation of leukocytes
  3. A stable adherence of the leukocytes onto the endothelium
  4. Transmigration of leukocytes through the vessel wall (This is known as diapedesis or extravasation)
  5. Leukocyte migration into the interstitial tissue towards a chemotactic stimulus


Stage 1 – Rolling

During normal blood flow there is no interaction between leukocytes and endothelial cells (Leukocyte integrin is in a low affinity state which will not bind to integrin ligands on the endothelial surface.)

Early in inflammation endothelial cells become activated by cytokines (cytokine-induced activation) which results in a loose adherence of leukocytes to the endothelial cells. (Selectin ligands on the leukocyte bind to selectin on the endothelial cells). There is only a small amount of contact between the membranes

Slowing of blood flow (stasis) many more leukocytes are now attached and rolling slowly to the endothelial lining of the vessel. They are not disrupted and removed from the lining as they would be in normal blood flow due to the much slower speed (decreased pressure) of the blood. Neutrophils already attached to the endothelial cells may attach to further neutrophils increasing total numbers.

Stage 2 – Leukocyte Activation

The rolling leukocytes become activated by chemokines displayed on the endothelial cells (bound by proteoglycans). This causes a rearrangement of the leukocyte skeleton, allowing the leukocytes to become flattened against the endothelial lining (This allows the integrin displayed on the leukocytes to engage the ligands on the endothelial cells resulting in a much stronger link than selectin binding alone).

Stage 3 – Stable Adherence

Leukocytes are now bound firmly to the endothelial cell surfaces by high-affinity integrins. The leukocytes are no longer rolling and are fixed in place. The leukocyte shape becomes even more flattened.

Stage 4 – Transmigration

At the inter-endothelial junctions, leukocytes are able to squeeze through into the interstitial tissue by changing shape to less than 0.1µm in diameter. A hole in the vascular basal lamina is produced by dissolution via enzymes secreted by the leukocyte.

Stage 5 – Migration into Interstitial Tissue

In the interstitial tissue, leukocytes can utilise the integrin displayed on their surface to move through the tissue. They ‘crawl’ along the fibrin or fibronectin scaffold of the tissue, formed by extravasated plasma proteins. The leukocytes migrated towards sources of chemokines along chemical gradients (Chemotaxis).

Extravasation Kinetics

The type of emerging leukocyte from the microvasculature depends on the age of the inflammation site and the type of inflammatory stimulus. In general, with most types of inflammation; after 6-24 hours neutrophils are predominant in the infiltrate. After 24-48 hours the neutrophils are replaced by macrophages. This is due to the different patterns of adhesion molecules and chemokines which are expressed over time. It is also due to the fact that neutrophils are very short lived, undergoing apoptosis within 24-48 hours.

In Pseudomonas (gram-negative infectious bacteria) infections, neutrophils remain predominant for 2-4 days.

In viral infections, lymphocytes are often the first type of inflammatory cells.

In hypersensitivity reactions eosinophils are often the main leukocyte type.

When lymphocytes and macrophages begin to appear at an inflammatory site, we begin to consider the inflammation as chronic. One of the main characteristic of acute inflammation is the abundance of neutrophils.


Chemotaxis is the movement of cells (taxis) towards a chemical (chemo) gradient. The chemo- attractants (the material which is causing the attraction of the cells) can be either:

  • Exogenous (Components not from the body)
    • Bacterial products (Peptides, lipids)
    • Exogenous chemoattractants are more effective at attracting leukocytes than the endogenous chemoattractants
    • Endogenous (Components formed by the body)
      • Components of the complement system (particularly C5a)
      • Products of the lipoxygenase pathway
      • Cytokines (predominantly chemokines)

How do chemoattractants induce cell movement?

  • The chemoattractant binds to receptors on the cell
  • This initiates an activation pathway
  • Calcium is mobilised from intracellular stores causing an influx of extracellular calcium into the cell
  • The increased cytosolic calcium triggers the assembly of contractile elements
  • This results in movement of the cell


Chemokines are small proteins capable of being produced by nearly all bodily cells. Their effects are:

  • Chemotactic effect on leukocytes
  • Angiogenesis (The formation of new blood cells)
  • Collagen production
  • Proliferation of haematopoietic precursors
  • Act as viral co-receptors
  • They can bind to extracellular matrix components
  • They can interact with specific receptors on leukocytes for example

Leukocyte Movement

By extending a pseudopod (an extension) from the leukocyte, it is able to pull the rest of the cell in the direction of the pseudopod extension.

Their movement is therefore a step-by-step process, where after each movement the leukocyte determines the direction of the strongest source of the chemoattractant and moves in that direction.

Phagocytosis and Enzyme Release

Phagocytosis is a process whereby phagocytes (macrophages and neutrophils) engulf large particles typically >0.5µm in diameter. The phagocytotic process can be split into three main stages:

  1. Recognition and attachment of the particle to be phagocytosed
  2. The engulfing of the particle
  3. The killing or degradation of the particle

Stage 1 – Recognition and Attachment

Recognition of micro-organisms is usually only possible when coated in opsonins (a material which makes the micro-organism more ‘appealing’ to phagocytes). Major opsonins include:

  • The Fc fragment of IgG (antibody) which binds to an Fc receptor on the phagocyte
  • C3b the ‘opsonic fragment’ of C3, a component of the complement system. Which binds to C3 receptors on the phagocyte
  • Lectins in the serum, which bind to bacterial cell walls. These bind to the C1q receptor on phagocytes.




Stage 2 – Engulfing

Engulfment of the particle occurs when an opsonised particle with the Fc fragment binds to the Fc receptor on the phagocyte.

Pseudopods (Like those used for movement) form around the particle, this causes the particle to become enclosed within a phagosome (A vesicle within the phagocyte). The phagosome fuses with lysosomes within the cytoplasm to form a phagolysosome. An increase in the cytosolic calcium causes the lysosomes to degranulate, releasing their destructive enzymes into the phagolysosome.

Stage 3 – Killing and Degradation

Phagocytosis activates the enzyme NADPH oxidase in the phagosomal membrane. This causes a cascade of reactions:

  • Oxidation of NADPH means a reduction of oxygen, forming H2O2
  • Myeloperoxidase (MPO) in neutrophilic azurophilic granules, forms OCL from H2O2
  • This results in the halogenation of bacteria and the oxidation of proteins and lipids

There is also an oxygen-independent method of degradation:

  • Bacterial permeability increasing (BPI) protein increases the permeability of micro-organism outer membranes.
  • Lysozymes affect the glycoprotein coat of bacteria
  • Lactoferrin a globular multifunctional protein with antimicrobial activity is released
  • Major basic protein is also released which is cytotoxic to many parasites (Found predominantly in eosinophils, hence their association with parasitic infections)
  • Another component which is released is defensin, these are peptides which are cytotoxic to microbes

After the bacteria has been killed, acid hydrolases in azurophilic granules degrade the bacteria at a relatively low pH for cells/tissue of 4-5

Leukocyte-Induced Tissue Injury

Both oxygen independent and dependent methods of killing bacteria can be potentially harmful if the leukocyte products are released into the extracellular space. This could occur when:

  • Fusion of the phagosome with the lysosome to form a phagolysosome occurs whilst the phagosome is still open on the cell surface (This is referred to as regurgitation during feeding)
  • Frustrated phagocytosis occurs, when the phagocyte for some reason cannot engulf the particle and so releases its lysosomes onto the particle
  • Surface phagocytosis occurs, meaning that a material is trapped on a surface, so the phagocyte again is unable to engulf the particle, releasing its lysosomes directly
  • Exocytosis occurs, meaning the phagocyte directly releases its granules

In concern with tissue injury, the most important factors are lysosomal enzymes, oxygen-derived active metabolites and products of arachidonic acid metabolism. If endothelial injury occurs, this may lead to chronic inflammation.

Chemical Mediators of Inflammation

Chemical mediators may be either plasma derived or cell derived.

  • Plasma derived
    • These are mediators which exist in the plasma but require activation
    • Cell derived
      • These are located within intracellular granules and are secreted from there
      • They are only synthesised in response to a stimulus
      • They usually bind a specific receptor
      • Have direct enzymatic activity or mediate oxidative damage
      • They have a short life span
      • They are considered to have more potential for harmful effect

Vasoactive Amines

  • Histamine
    • The main source of histamine is from mast cells, it is released when these mast cells degranulate, which may occur from a variety of stimuli
      • Physical injury
      • Immune reaction, binding of antibodies to mast cells
      • Fragments of the complement system may cause degranulation
      • Cytokines
      • Neuropeptides
  • The effects of histamine include:
    • Dilation of arterioles
    • Constriction of large arteries
    • Induction of formation of endothelial gap
    • Serotonin
      • Serotonin is pre-formed in platelets and mast cells
      • It has similar effects to histamine
      • Released when platelets aggregate

Plasma Proteases

  • The Complement System
    • Lysing of microbes occurs by the formation of a membrane attack complex (MAC) by the complement cascade
    • The lysis of the lipid membrane results in cell death
    • C3a and C5a are responsible for the vascular phenomena
    • C5a is responsible for leukocyte adhesion, chemotaxis and activation
    • C3b is responsible for opsonisation of particles
    • The Kinin System 
      • Proteases (kallikriens) generate vasoactive peptides from plasma proteins – resulting in the release of bradykinin
      • This is triggered by the activation of factor XII of the intrinsic clotting pathway.
      • Prekallikrien is synthesised into killikrien (a potent activator of factor XII), which is synthesised into bradykinin
      • Killikrien is chemotactic
      • Bradykinin is responsible for increasing vascular permeability
      • The Clotting System involves a series of plasma proteins activated by factor XII.
        • The protein thrombin is responsible for leukocyte adhesion
        • Factor X is responsible for the increase in vascular permeability by the formation of endothelial gaps.

Arachidonic Acid Metabolites

Arachidonic acid metabolites (eicosanoids) are rapidly formed, short lived, locally active hormones normally found esterified in cell membrane phospholipids. Certain stimuli can release them however. They are responsible for the mediation of nearly all steps of inflammation and are formed by two classes of enzymes:

  • Cyclooxygenases
    • Form prostaglandins and thromboxanes
    • Are an important target of anti-inflammatory drugs
    • See NSAIDs for how drugs affect this enzyme
    • Lipoxygenases
      • Form leukotrienes and lipoxins

Platelet Activating Factor (PAF)

Found in leukocytes and platelets they can be either secreted or remain cell-bound. Their effects are:

  • At low concentrations they cause vasodilation and form endothelial gaps
  • At high concentrations they initiate vasoconstriction
  • They increase leukocyte adhesion to endothelium
  • They are chemotactic
  • They increase the synthesis of eicosanoids
  • They are involved in the degranulation and oxidative bursts associated with the killing and degradation of bacteria etc. In phagocytosis

Cytokines and Chemokines

These are produced during immune and inflammatory responses, they are transient and their secretion is closely regulated. They can have both positive and negative regulatory actions and they mediate their effects by binding to specific receptors on target cells.


Nitric Oxide

Nitric oxide is a very soluble gas lasting only for a matter of seconds. It is found in endothelial cells, macrophages and neurons in the brain. It is another rapidly formed, short-lived, locally active hormone. It is produced by the enzyme nitric oxide synthase, which can be abbreviated to:

  • eNOS – Found in the endothelial cells
  • iNOS – Inducible NOS
  • nNOS – Neuronal NOS

The effects of Nitric oxide gas include

  • Vascular dilation
  • Reduction in leukocyte recruitment
  • Antimicrobial activity
  • Inhibition of mast cells
  • Reduction of platelet aggregation
  • Cell necrosis

Nitric oxide therefore inhibits the inflammation process.

Nomenclature of Inflammation

To name a type of inflammation, there are a number of steps which go towards building up the full title of the inflammation at hand:

  • The type of inflammation is known by the tissue affected (Using its Greek or Latin name) and then suffixing it with -itis
  • The exact nomenclature should include
    • Type of inflammation as above
    • The duration – acute (short), subacute, chronic (long)
    • The extent to which the tissue is affected – focal (small area), multifocal (multiple small areas), disseminated (large spread areas of inflammation), diffuse (entire tissue inflamed)
    • Finally the degree of severity – mild, moderate or severe
    • For example moderate chronic multifocal appendicitis, a long duration inflammation of the appendix

Morphological Patterns of Acute Inflammation

Acute inflammation is characterised as exudative inflammation (secretion of certain fluids), the type of exudative inflammation can be:

  • Serous
  • Fibrinous
  • Suppurative (purulent – containing pus)
  • Haemorrhagic
  • Necrotising

Serous Inflammation

This involves the outpouring of a ‘thin’ liquid which can arise from blood serum or secretions from mesothelial cells. This occurs mainly on the skin (in blisters) or on serosal surfaces and mucosa.

Fibrinous Inflammation

When permeability of the vascular architecture is increased it is possible for larger molecules such as fibrinogen to leave the vessels. This results in a clotting of the exudate. This can occur at mucosal and serosal surfaces as well as in the lungs and joints.

Fibrino-necrotising (diphtheroid) inflammation

A type of fibrinous inflammation, this occurs on mucosa and is the clotting of the fibrinous exudate not only on the surface (as above) but also deep within layers of necrotic epithelium and submucosal connective tissue. When removed the underlying mucosa is lost as well.

Suppurative Inflammation

The exudate is dominated by dead neutrophils (this is also known as pus). Pus is an accumulation of necrotic tissue, neutrophils and fibrin which is transformed into a yellowish mass by proteolytic and hydrolytic enzymes released from neutrophils. This type of inflammation (also referred to as purulent inflammation because of the pus) is usually induced by bacteria.

Purulent inflammation can result in the formation of pustules (accumulated pus between epithelial cells in mucosa or skin), empyema (accumulation of pus in pre-existing cavities), cellulitis (inflammation of connective tissue) or an abscess (accumulation of pus in a cavity which developed due to necrotic tissue)

Haemorrhagic Inflammation

This is when red blood cells are introduced into the exudate due to severe damage to blood vessels in the inflammation response

Necrotising Inflammation

Exudation and severe tissue necrosis, mainly seen with specific types of bacteria, this often leads to ulcers.

Outcomes of Acute Inflammation

The progression of acute inflammation can develop in a number of ways:

  1. Complete Resolution
  • The inflamed tissue returns to normal operation
  • This occurs if the injury is short lived and tissue destruction was limited. Parenchymal cells (the organs functional cells) can regenerated, mediated mainly by lymphatics and phagocytes
  • Vessels will return to normal permeability
  • Drainage of oedema fluid/proteins associated with inflammation into the lymphatic system or by pinocytosis (by macrophages)
  • Phagocytosis of any cells destroyed by apoptosis/ necrotic debris
  1. Abscess Formation
  • Pus accumulates within cavities developed due to tissue necrosis
  • Usually induced by deep rooted bacteria
  • The abscess is barricaded off by connective tissue to limit any further spread
  • The abscess may rupture to release pus, this may be dangerous in terms of ulceration (formation of ulcers) or the release of abscess contents into adjacent tissue cavities resulting in further inflammatory processes
  • Fistula may also form (Abnormal tube shaped passageways between organs/vessels which normally shouldn’t connect)
  1. Healing by Connective Tissue Replacement (Fibrosis)
  • Occurs after a substantial tissue loss/damage
  • After the inflammation stimulus is removed the tissue is repaired with excess of fibrin (partial/total loss of some cell function)
  • Collagen is also produced in an attempt to heal the injury, collagen is formed by fibroblasts
  • Tissue scarring will occur
  1. Progression to Chronic Inflammation
  • If the initial cause of the inflammation cannot be resolved, then the inflammation process progresses forming chronic inflammation
  • This may occur if the initial injurious agent persists or if the normal healing process is impaired