The Inflammatory Response
The Inflammatory Response
Inflammation is triggered in response to the detection of foreign antigens within the body that may cause harm or damage. This activates an immune cascade, with the aim to control and eradicate the pathogen before any significant harm can occur.
Inflammation can be stimulated by a number of factors such as microorganisms, chemicals and physical agents, which can generate symptoms such as redness, heat, swelling and pain. Although uncomfortable at the time these physical symptoms indicate the inflammatory response is at work. Inflammation that lasts a short period of time is known as acute inflammation, however if this continues over an extended period of time it is know as chronic inflammation. This often requires treatment as the body is unable to handle the infection and significant tissue damage may occur. When the immune system is unable to regulate the inflammatory response this can be seen as allergic or hypersensitivity reaction, where by an environmental agent that should pose no threat to the human body is seen as an allergen. In addition to this an autoimmune reaction is where the body sees its own tissues as foreign and a reaction is triggered in response to this.
When a cell becomes damaged through injury or invasion chemical mediators such as histamine, prostaglandins and cytokines are released into the surrounding area. These cause the blood vessels to dilate increasing blood flow to the site of infection. Following this the blood vessel walls also become more permeable allowing proteins such as clotting factors, antibodies and lymphocytes to reach the area. This movement can be seen as swelling. whilst redness develops from the blood vessels dilating.
With the arrival of lymphocytes to the infected area the pathogen may be broken down and digested by phagocytosis. Neutrophils, a type of granulocyte are often the first to the site of infection, arriving within an hour of injury. Their movement is recognised to be influenced by the release of chemicals at the site of infection, producing a concentration gradient. Neutrophils migrate along this gradient in a process called chemotaxis. Within 24-48 hours monocytes may arrive at the site of infection where they mature into macrophages. Macrophages are the largest type of immune cell, which, following phagocytosis display part of the antigen on their cell surface. This acts as a flag to prompt the arrival of other immune cells to the site of infection.
Chemicals released during an inflammation play an crucial role in the initiation and propagation of the response. Some of the most well known mediator systems include:
- Vasoactive amines, histamine, serotonin
- Plasma protein system, Kinin, Clotting/Fibrinolytic System, Complement System
- Prostaglandins, Leukotrienes (Eicosinoids)
- Phagocyte Products
- Nitric Oxide
Stored within the granules of mast cells histamine is released following trauma of damaged cells, presence of complement components or IgE complexes. It may also be secreted with serotonin by platelets, exposed to PAF and collagen. Both of these chemicals are recognised to induce vasodilation and increase permeability of the blood vessels. Histamine remains in the circulation for about an hour where it is then broken down by histiminase.
Following increased permeability of the blood vessels plasma proteins may move into the site of infection with ease. As Hageman factor (factor XII) moves from the basement membrane and interstitial matrix it becomes activated to factor XIIa from contact with collagen. This is a crucial process as factor XIIa may then go on to activate both the kinin, complement and clotting system.
1. Kinin System,
The product of the kinin system is Bradykinin, which exerts its effects through smooth muscle contraction, arteriole dilation, increased permeability of the venules and pain.
2. Clotting system,
Unless severe damage is present clotting does not usually occur until later on. Early clotting is inhibited by the presence of heparin, a natural anticoagulant released from the mast cells, whilst fibrinogen, an important clotting factor, may not reach the site of infection due to its larger MW. Plasmin can be considered the most important clotting factor because of its involvement in the complement system, activating C3 and C5. Other factors include thrombin, which converts fibrinogen to fibrin and fibrinopeptides. Fibrinopeptides which increase vascular permeability and act as a chemotactic for leukocytes.
3. Complement system,
Refers to a series of over 20 proteins that become activated in an enzyme cascade when components of a pathogen are recognised. The activation of one protein enzymatically cleaves and activates the next protein in the cascade, following in a sequential manner. The end product for this system is C5-9 which is known as the membrane attack complex MAC. This is able to insert into the plasma membrane of certain pathogens inducing cell lysis and death. Activated C3 can trigger this lytic pathway from its cleavage into C3b and C3a.
- C3b the larger fragment is considered the crucial step as it binds to C5 convertase, part of the lytic pathway. It may also bind to cell membranes and act as an opsonin for neutrophils and macrophages.
- C3a is recognised to promote inflammation cause mast cell degranulation.
- C5a produced by C5 convertase acts as a chemotaxic for macrophages, neutrophils and mast cells.
Prostaglandins and Leukotrienes
Collectively known as eicosinoids, they are considered local hormones due to their effect on cells close to their site of formation and rapid degradation. They are produced from arachidonic acid, which is formed from the hydrolysis of phospholipids in the cell membrane by phopholipase A2. following this the eicosinoids can be synthesised by two main pathways.
- COX, cyclooxygenase pathway, which produces thromboxane A2, prostacyclin (PGI2), PGD2, PGE2 and PGF2
- 5-lipoxygenase pathway, which produces leukotrienes (LTB4, LTC4, LTD4 and LTE4)
Different cells have slightly different enzyme systems which causes certain cells to produce particular eicosinoids. For instance Mast cells, leukocytes and platelets produce leukotrienes. Platelets can also produce thromboxane A2. Mast cells produce PGD2 and vascular endothelia produce prostacyclin.
The physiological effects produced by eicosinoids include:
PGE2- vasodilation, enhances effect of bradykinin.
PGI2- vasodilation, inhibits aggregation of platelets.
TXA2- vasoconstriction, promotes aggregation of platelets.
LTB4- chemotactic agent for neutrophils and macrophages
LTC4, LTD4, LTE4- vasoconstriction and constriction of smooth muscle, increased vascular permeability.
Platelet activating factor PAF
Synthesised by activated mast cells, phagocytes and endothelial cells, it is recognised to increase vascular permeability and act as a chemotactic agent for leukocyte aggregation/ adhesion. PAF may also stimulate target cells to synthesise eicosinoids and enhance their effects.
Are polypeptide products produced by a variety of cells such as lymphocytes, monocytes and endothelial cells. Interleukins such as IL-1, IL-6 and IL-8 are recognised to be pro-inflammatory, whilst interleukin IL-4, IL-10 and IL-13 are anti inflammatory. TNF (TNF-alpha and TNF-beta) is another cytokine, with TNF-alpha and IL-1 sharing similar pro-inflammatory properties. Both can induce fever, the production of collagenase and PGE2, thought to contribute to joint damage in conditions such as rheumatoid arthritis, and stimulating the release of IL-6. Generally cytokines exhibit their effects locally with synergistic and antagonistic properties depending upon the various target cells. However TNF-a, TNF-b, IL-1 and IL-6 can also have major systemic effects if chronic infection is present. For instance in bacterial sepsis following the release of endotoxins. Overall cytokines are recognised to activate immune cells and further stimulate the release of chemical mediators propagating the inflammatory response. The immune cells effected are based upon the specific cytokine released.
Lysosomal enzymes involved in phagocytosis can sometimes leak out following digestion, stimulating inflammation. Cationic proteins found within the granules of neutrophils can activate mast cells when unintentionally released. They also act as a chemotactic agent for monocytes and inhibit their movement. Another type are neutral proteases found in monocytes and neutrophils. These hydrolyse a variety of proteins such as collagen, elastin, cartilage and the basement membrane causing tissue damage and the subsequent release of fibrin, plasminogen and kininogen. Reactive oxygen species may also be present further escalating tissue damage.
Synthesised by macrophages, vascular endothelia and some neuronal cells, nitric oxide predominantly causes vasodilation, reduced platelet aggregation and reduced platelet adhesion. NO has a localised effect with it rapidly degraded. It may also have a cytotoxic effect on some cells and tissues.
Ending the inflammatory response
Once infection has been eliminated inflammation should decrease, the trigger for this is thought to be apoptosis. Apoptosis is a form of programmed cell death that causes the cell to self destruct. Certain signals are thought to regulate this process with cells receiving messages to stay alive or die. During inflammation Helper T cells are recognised to emit a stay alive signal, which is released for as long as foreign antigens are recognised. This helps to prolong the response and fight the infection. Once no further antigens are detected the helper T cell stops signalling to stay alive, this is turn causes the other immune cells to begin apoptosis. Cells will only begin to self destruct if already primed for apoptosis and once the stay alive signal is stopped. If foreign antigens are continued to be recognised chronic inflammation may develop.
Healing and repair
Apotosis clears the way for immune cells no longer required, it also rids the body of damaged cells to enable reparation. How well cells are able to regenerate and undergo proliferation depends on the cell type and the tissue structure. Liver cells do not usually undergo proliferation but if damage occurs they can be stimulated to do so. The structure of the tissue also influences how well regeneration can take place, for instance the skin which can be seen as a flat uncomplicated structure is fairly easy to rebuild. Glands however are much harder to rebuild due to the more complex shape and different cell types. Cirrhosis of the liver is an example of when the body is unable to sufficiently repair the tissue leading to abnormal structures and scarring, this in turn can prevent the tissue from being able to function normally. In addition diseases such as this can lead to haemorrhaging and death if not recognised.
Scar tissue is formed from fibrous connective tissue forming a loose framework over the damaged area. This provides structure and support to the area holding the tissue in place. Endothelial cells may then develop new blood vessels in the area, supplying oxygen and nutrients essential for growth. Fibroblasts may also move into the area which are able to synthesise collagen a well as supply carbohydrates and water. Collagen is essential for this process as it provides mechanical strength and rebuilds lost tissue producing a scar. Often the scar tissue takes up less volume than the tissue it is replacing, this can cause the tissue to become distorted and contract which is often seen in cases of severe trauma or burns. Scars will also often lack glands, melanin and hairs.
Chronic inflammation may progress from acute inflammation if the infection is not taken under control and persists in the tissue for an extended period of time. It may also occur from repeated cycles of acute inflammation. In some cases however chronic inflammation is an independent response. Examples of this include:
- Rheumatoid arthritis
- Chronic lung disease
Chronic inflammation can be caused when the infectious pathogen or foreign material is able to resist the the hosts natural defences. This can prevent the body from being able to remove the agent by phagocytosis, for instance substances such as plastic, metal or wood splinters. Some microorganisms such as bacteria, fungi, protozoa, and metazoal parasites are also able to resist phagocytosis with insufficient enzymes to induce degradation.
Macrophages are recognised to be the main contributor to chronic inflammation, with their effects influencing the progression of tissue damage and impairment. Because macrophages have a longer life span than other leukocytes they can remain at the site of infection for longer periods, this means they can continue releasing inflammatory mediators, they may also continue to phagocytose material even if they do not have enough room to engulf and digest the material. Lymphocytes also have a role in chronic inflammation by activating the macrophages.