The inflammatory response

By Alexander Rice,2014-04-20 19:33
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The inflammatory response

The inflammatory response

    Inflammation is a non-specific immune response to trauma, endogenous antigens, chemical agents and microbial pathogens. The inflammatory response occurs immediately after trauma and prevents pathogenic proliferation, minimises further damage to cells and tissue and finally enhances repair and healing. Inflammation manifests itself by redness, swelling, heat and pain, together with alteration of

    function. The processes involved in inflammation may be summarised as:

     mobilisation of resident macrophages

     localised vasodilation

     increase in vascular permeability

     infiltration of area by leukocytes

     damage repair -clotting process

    Principle events in the inflammatory response are shown schematically in Fig. 01

     mast cell epidermis


     resident macrophage macrophage endothelial (mature monocyte) cells of capillary

    monocyte capillary


    Fig 01. Principal events in the inflammatory response.

    Tissue damage and invading bacteria result in the release of histamine by

    mast cells. Localised vasodilation brings more blood to the area. An increase

    in vascular permeability results in plasma leaking into the interstitial area and infiltration of area by leukocytes.

    The redness and heat observed in inflammation are caused by vasodilation bringing blood to the area of injury. Swelling is oedema resulting from increased vascular

    permeability, allowing plasma into the interstitial area. Swelling may also result in pain due to localised pressure stimulating pain receptors.

    Mast cells are found in connective tissue adjacent to blood vessels. In response to trauma, chemical agents or triggering by the immune system, they release mediators (locally acting chemicals). These can be preformed in granules and released very quickly in a process termed degranulation. Alternatively, they can be synthesised de-novo by the mast cell and released over a longer period, Figure 02.

     granules nucleus

    products of products of

     synthesis degranulation leukotrienes histamine

    leukocyte prostaglandins

     chemotactic factors

Fig. 02. The role of the mast cell in inflammation

    The mast cell releases mediators in response to injury or stimulation by the immune system, IgE antibodies and complement proteins.

    Products of degranulation include histamine which causes vasodilation and increased permeability of blood vessels. Chemotactic factors are also released in degranulation which attract neutrophils (early response leucocytes) and monocytes (late response leukocytes) both of which mature into phagocytes.

Vascular permeability

    Under the influence of mediators such as histamine, small blood vessels dilate and become more permeable. Plasma is exuded from the blood into the interstitial area and resulting in oedema. This process is an important immune mechanism - rather than just incidental to damage.

    Plasma contains many circulating proteins that would not normally be found outside blood vessels. These proteins include four major enzyme cascades:

     coagulation cascade

     fibrinolytic cascade

     complement cascade

     kinin cascade

    The coagulation cascade is partly responsible for haemostasis, the arrest of blood from damaged vessels. It is a complex series of events, triggered by tissue damage, that results in the conversion of the soluble plasma protein fibrinogen into insoluble fibrin.

    The fibrinolytic cascade will eventually remove the fibrin clot in wound resolution. It consists primarily of the plasma protein plasminogen that is eventually converted to plasmin, an enzyme that digests fibrin. As the clot forms, plasminogen is incorporated into the fibrin strands to be activated during resolution when blood loss has been stabilised.

    The complement cascade consists primarily of nine plasma borne proteins that are activated by pathogens or antibodies. Vascular permeability allows complement proteins to come into contact with microorganisms that may have gained access to the site of injury. At the end of the cascade, complement forms itself into a structure called a membrane attack complex that is inserted into the cell wall of bacteria causing them to lyse and die. Complement also stimulates mast cells to release mediators and acts as a chemoattractant for leukocytes, Fig 03.

     blood vessel

    C3a stimulates

    mast cells to

    release histamine

    C5a attracts


     leukocytes destroy complement proteins bacteria C5, C6, C7, C8 & C9

     combine to destroy



Fig. 03 The role of the complement system in inflammation

    Interstitial fluid forms in the tissue beds and is drained by the lymphatic system, eventually feeding into the circulatory system. On its path to the circulatory system, lymph passes through lymph nodes containing T cells and B cells. In inflammation, vascular permeability increases interstitial pressure so additional fluid is drained from the area. This lymph carries bacteria or bacterial antigens that may be present in the inflamed area, stimulating, the immune cells in the lymph nodes to produce antibodies, specific to the bacterial antigen. These antibodies, released into the lymph, enter the circulatory system and thus are carried to the site of inflammation where they assist in the destruction of bacterial pathogens, Fig. 04.

     blood vessel


Fig. 04. Activation of antibodies in inflammation

    Bacterial antigens are carried to the lymph nodes where antibodies specific to those antigens are formed. These are carried in the blood to the site of inflammation where they assist in the destruction of pathogens.

The kinin cascade starts with the oedematous seepage of plasma proteins,

    containing kinin precursors, into the inflamed area. Inflammatory processes convert these precursors into bradykinin, a vasodilator and cause of vascular permeability. Bradykinin is also a potent pain-producing agent, stimulating nociceptors in the inflamed area and this effect is stimulated by prostaglandins, Fig. 05.


Fig 05. The kinin cascade

Bradykinin, activated in the inflammatory response, stimulates nociceptive neurons.

    This action is potentiated by the presence of prostaglandins

    Neutrophils and the longer-lived macrophages have similar functions in inflammation, they clear the inflamed area of bacteria and dead cells by phagocytosis. They are attracted to the site of inflammation by chemotactic chemicals release by the mast cells. As the endothelial cells of the small blood vessels have been made more permeable by the action of histamine and prostaglandins, the neutrophils and macrophages are able to squeeze through the wall of the blood vessels and into the

    area of inflammation. As the process of phagocytosis takes place, there is a gradual accumulation of toxins and eventually the cells die and add to the purulent exudate or pus that eventually leaves the body through the lymphatic system or epithelium.

The Eicosanoids in inflammation

    Eicosanoid is the term that covers mediators synthesised from arachidonic acid and includes the prostanoids (prostaglandins and thromboxanes) and leukotrienes. These mediators are synthesised in most cells, including mast cells, platelets and neutrophils. The synthesis pathway is complex but generally involves an oxygenase enzyme, acting on arachidonic acid, Fig. 05.


     5-lipoxygenase cyclo-oxygenase (COX)

     PGI PGF PGD PGE 2222;

various actions - vasodilation, platelet aggregation increased vascular

    hyperalgesia etc. vasoconstriction permeability

     * 5-hydroperoxyeicosatetraeonic acid

    Fig. 05 Eicosanoid mediators derived from phospholipase and arachidonic acid

    The actions of prostaglandins are extremely complex and this complexity extends to their role in inflammation. Generally, they produce vasodilation and act synergistically with histamine and bradykinin, increasing vascular permeability and stimulating nociceptors.

    It is important to note that prostaglandins, produced constitutively, have a major role in normal cell homoeostasis. Prostaglandins, especially PGE, also have a anti-2

    inflammatory role, modulating the action of mast cells and macrophages.

    Leukotrienes appear in the later stages of inflammation, they cause smooth muscle contraction, increase the permeability of blood vessels and attract macrophages to the site. There is some evidence that they play a significant role in the inflammatory response in asthma.

    Thromboxanes are derived mainly from platelets and cause vasoconstriction as well as increasing platelet aggregation (via the upregulation of GP IIb/IIIa receptors).

Other Inflammatory Mediators

    Platelet activating factor (PAF) is released from mast cells, platelets, macrophages and neutrophils and is believed to play a significant role in chronic anaphylactic and inflammatory conditions such as asthma. Its precise actions have yet to be fully characterised but it is known to cause vasodilation, an increase in vascular permeability and the chemoattraction of neutrophils and monocytes to the inflamed area.

    Nitric oxide (NO), as with some prostaglandins, has both a pro and anti-inflammatory role. An isoenzyme of Nitric oxide synthase (NOS) is induced by certain inflammatory processes. NO is known to cause vasodilation, increase vascular permeability and stimulate the production of prostaglandins.

    Complex though the actions of the mediators mentioned above might seem, there are many more players. Interferons, interleukins, cytokines and chemokines are all involved and new research is constantly shedding more light on their roles in the fascinating but complex process that is inflammation.

?Roger McFadden @ University of Central England 2003

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