Local reaction of living tissues to injury or illness, including burns, pneumonia, leprosy, tuberculosis, and rheumatoid arthritis. Its major signs are heat, redness, swelling, and pain. The process begins with brief contraction of nearby arterioles (see arteries). Dilation follows, flushing the capillaries with blood, from which fluid, plasma proteins, and leukocytes pass into the injured tissues, causing swelling as they attack the cause of injury. Initial acute inflammation can have any of four outcomes: resolution (return to normal), organization (new tissue buildup; see scar), suppuration (pus formation; see abscess), or chronic inflammation. Sometimes treatment—including antibiotics for bacteria, or surgical removal of an irritating foreign body—can eliminate the cause. If not, anti-inflammatory drugs (e.g., cortisone or aspirin) may be given, or simple remedies (e.g., hot or cold compresses) may be applied.
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Inflammation (Latin, inflamatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
|Causative agent||Pathogens, injured tissues||Persistent acute inflammation due to non-degradable pathogens, persistent foreign bodies, or autoimmune reactions|
|Major cells involved||Neutrophils, mononuclear cells (monocytes, macrophages)||Mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts|
|Primary mediators||Vasoactive amines, eicosanoids||IFN-γ and other cytokines, growth factors, reactive oxygen species, hydrolytic enzymes|
|Duration||Few days||Up to many months, or years|
|Outcomes||Healing, abscess formation, chronic inflammation||Tissue destruction, fibrosis|
|Loss of function||Functio laesa**|
|All the above signs may be observed in specific instances, but no single sign must, as a matter of course, be present.
These are the original, so called, "cardinal signs" of inflammation.*|
Functio laesa is a bit of an apocryphal notion, as it is not really unique to inflammation and is a characteristic of many disease states.**
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Virchow in the 19th century (1870).
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened colour and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, tobacco smoke, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).
|Bradykinin||Kinin system||A vasoactive protein which is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.|
|C3||Complement system||Cleaves to produce C3a and C3b. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an opsonin, which marks the invader as a target for phagocytosis.|
|C5a||Complement system||Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as a chemoattractant to direct cells via chemotaxis to the site of inflammation.|
|Factor XII (Hageman Factor)||Liver||A protein which circulates inactively, until activated by collagen, platelets, or exposed basement membranes via conformational change. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.|
|Membrane attack complex||Complement system||A complex of the complement proteins C5b, C6, C7, C8, and multiple units of C9. The combination and activation of this range of complement proteins forms the membrane attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing death.|
|Plasmin||Fibrinolysis system||Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.|
|Thrombin||Coagulation system||Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, which aggregates to form a blood clot. Thrombin can also bind to cells via the PAR1 receptor to trigger several other inflammatory responses, such as production of chemokines and nitric oxide.|
Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
|Lysosome granules||Enzymes||Granulocytes||These cells contain a large variety of enzymes which perform a number of functions. Granules can be classified as either specific or azurophilic depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins which allow these enzymes to act as inflammatory mediators.|
|Histamine||Vasoactive amine||Mast cells, basophils, platelets||Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation and increased venous permeability.|
|IFN-γ||Cytokine||T-cells, NK cells||Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.|
|IL-8||Chemokine||Primarily macrophages||Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.|
|Leukotriene B4||Eicosanoid||Leukocytes||Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosome enzymes by these cells.|
|Nitric oxide||Soluble gas||Macrophages, endothelial cells, some neurons||Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.|
|Prostaglandins||Eicosanoid||Mast cells||A group of lipids which can cause vasodilation, fever, and pain.|
|TNF-α and IL-1||Cytokines||Primarily macrophages||Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation of fibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate.|
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.
Active mechanisms which serve to terminate inflammation include:
Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-Β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics.|30px|30px|Charles Serhan
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF-α are associated with obesity. During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet. The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense research.
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation: