|
|
|
|
|
|
||
|
|
|
|
|
|
||
When you hit your thumb with a hammer or cut yourself with the kitchen knife, you notice the area surrounding the injury becomes red, warm, swollen and painful - this is inflammation. You might think that what you are observing is the random consequence of the tissue damage but this is not the case. Inflammation is a carefully programmed, non-specific immune response to trauma, endogenous antigens, chemical agents and microbial pathogens. The inflammatory response occurs immediately after trauma or infection and prevents the spread of pathogens, minimises further damage to cells and tissue and finally enhances repair and healing.
Inflammation manifests itself by the following symptoms...
• Redness
• Heat
• Swelling
• Pain
• Alteration of functionThe inflammatory response involves three key processes…
1. Vasodilation resulting in increased blood flow to the damaged area
2. Increase vascular permeability – plasma leaks from blood vessels into the damaged area
3. Emigration of neutrophils (white blood cells) from blood into the damaged areaSome of these processes can explain the symptoms of inflammation listed above, for example, redness and heat. Inflammation results in vasodilation so more blood flows to the damaged area and blood makes the area red and warm - Figure 01.
Figure 01 - Vasodilation of small blood vessels makes the inflamed area red and warm
Inflammation results in swelling, pain and alteration of function due to plasma leaking from the small blood vessels into the area of damage or infection Figure 02.
Figure 02 - Plasma leaking from the small blood vessels results in swelling (oedema)
The increase in fluid in the area of inflammation causes swelling (oedema) and pressure on pain neurons that results in the dull ache, familiar in inflammation. Swelling can also impede muscle and joint movement and cause loss of function. Chemicals released in inflammation can add to the sensation of pain and these are discussed later.
The processes of inflammation are shown in Figure 03 below.
Fig 03. 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 the area by neutrophils. These mature in the inflamed area and phagocytose (eat) invading bacteria.The cellular basis of inflammation
Mast CellsMast cells (granulocytes) are found in connective tissue adjacent to blood vessels. Trauma or immune system components such as complement proteins and antibodies cause mast cells to release mediators (locally acting chemicals) - Figure 04. Some mediators are pre-formed in granules and released very quickly in a process termed degranulation. Other mediators are synthesised by mast cells and released over a longer period. Other white blood cells such as basophils and eosinophils also release these mediators
Figure 04 - Mast cells release mediators either by
degranulation or more gradually by synthesisThe early mediators in inflammation are the products of degranulation from the mast cells and include histamine and chemotactic factors. Histamine causes vasodilation and increased permeability of small blood vessels. Chemotactic factors attract neutrophils (early response leucocytes) and these mature into phagocytes.
The chemotactic factors attract circulating neutrophils which congregate on the endothelium of small blood vessels. They then squeeze through the endothelium (in a process called diapedesis) and migrate towards the area of inflammation. Once in the area of inflammation the neutrophils mature and phagocytose (eat) micro-organisms that may have caused the infection or have been introduced in
to a wound during trauma - Figure 05.
Figure 05 - A mature neutrophil phagocytoses bacteria during inflammationThe inflammatory exudate
The exudation of plasma from the small blood vessels results in the familiar oedema (swelling) observed in inflammation. the function of this is to bring plasma proteins into intimate contact with the damaged area. These proteins help heal wounds and prevent infection
Proteins in the inflammatory exudate include…
• Clotting proteins - especially fibrinogen that forms blood clots and prevents further loss of blood
• Fibrinolytic proteins – including plasminogen which will degrade the clot when the wound has healed
• Complement system – plasma proteins that stimulate immune responses and destroy bacteria
• Kinin cascade – kinins cause vasodilation, increase the permeability of blood vessels and stimulate pain receptorsClotting Proteins
Clotting proteins are brought into the inflamed area with plasma. Fibrin strands combine with platelets to form a mesh that traps red blood cells and makes a blood clot - Figure 06.
Figure 06 - Fibrin strands and platelets trap red
blood cells to form a clotFibrin circulates in the blood in the form of a soluble protein called fibrinogen. The conversion of fibrinogen into fibrin is brought about by the action of an enzyme called thrombin. Thrombin is formed from prothrombin by a chain reaction of events involving numerous clotting factors known as the clotting cascade - Figure 07.
Figure 07 - The coagulation cascade converts prothrombin into the active
enzyme thrombin and this in turn converts plasminogen into plasminFibrinolytic Proteins
When inflammation has been resolved an important part of the wound healing process is the destruction of the blood clot that initially prevented the loss of blood and protected the wound. This is done by an enzyme called plasmin that is activated towards the end of the healing process. Plasmin attacks fibrin and thus breaks down the clot.
The Complement System
The complement system is a cascade of enzymatic proteins that circulate in the blood. None of them have particularly memorable names but they play an important part in protecting us against bacterial invaders. They are called complement because they complement the immune system. Here are some of the proteins (the C stands for complement)...
• C5a and C3a increase vascular permeability, attract neutrophils and stimulate mast cells to release histamine
• C2a, C3b & C4b promote phagocytosis by bacteria (opsonisation)
• C5, C6, C7, C8 & C9 form membrane attack complexes that destroy bacteria - Figure 08.
Figure 08 - Complement proteins combine to form a membrane
attack complex that causes lysis in bacteriaThe Kinin Cascade
Kinins. released in inflammation, cause vasodilation, increase the permeability of blood vessels and stimulate pain receptors. Prostaglandins, also produced in inflammation, potentiate the action of bradykinin and increase the sensation of pain.
The Lymphatic System in InflammationLymphatic vessels drain tissue fluid and return it to the main circulatory system.
In inflammation, lymphatic vessels drain the fluid exudate that is responsible for swelling. Bacteria that have infected the inflamed are are carried in lymphatic vessels and pass through lymph nodes. B cells in the lymph nodes respond to bacteria by producing antibodies specific to those bacteria. The antibodies are release into the blood stream where they bind to bacteria, agglutinate them and mark them for destruction by macrophages - Figure 09.
Figure 09 - Antibodies bind to bacteria, agglutinate them
and mark them for destruction by neutrophilsProstaglandins
Prostaglandins are important mediators in the inflammatory process. They are members of a large family derived from arachidonic acid (a fatty acid) and are found in most tissues of the body. Prostaglandin biochemistry is complex, as are the actions of prostaglandins themselves. They belong to the eicosanoid family that includes prostaglandins, thromboxanes and leukotrienes. Prostaglandins and thromboxanes are collectively known as prostanoids - Figure 10.
Figure 10 - relationships within the eicosanoid familyProstaglandin E2 (PGE2) main prostanoid involved in inflammation. It is secreted by mast cells and macrophages. PGE2 acts synergistically with histamine and bradykinin, resulting in…
• Vasodilation
• Increased vascular permeability
• Potentiation of nociceptor stimulation by bradykinin
• Pain neuromodulation in the dorsal horn of spinal cord
• Pyresis (fever)
Prostanoids have many roles unconnected with inflammation, including the promotion of gastric mucus secretion, the inhibition of gastric acid secretion, sleep regulation and the regulation of platelet aggregation in clotting.
Prostaglandins are major targets of non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and ibuprofen.
