Inflammation

Inflammation

Discussion
Ask a question about 'Inflammation'
Start a new discussion about 'Inflammation'
Answer questions from other users
Full Discussion Forum
 
Encyclopedia
Inflammation is part of the complex biological response of vascular
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 tissues to harmful stimuli, such as pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Inflammation is not a synonym for infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

, even in cases where inflammation is caused by infection. Although infection is caused by a microorganism, inflammation is one of the responses of the organism to the pathogen. However, inflammation is a stereotyped response, and therefore it is considered as a mechanism of innate immunity
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...

, as compared to adaptive immunity
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...

, which is specific for each pathogen.

Without inflammation, wounds and infections would never heal. Similarly, progressive destruction of the tissue would compromise the survival of the organism. However, chronic inflammation can also lead to a host of diseases, such as hay fever
Hay Fever
Hay Fever is a comic play written by Noël Coward in 1924 and first produced in 1925 with Marie Tempest as the first Judith Bliss. Laura Hope Crews played the role in New York...

, periodontitis, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, and even cancer (e.g., gallbladder carcinoma). It is for that reason that inflammation is normally closely 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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 and leukocytes (especially granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...

s ) 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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing
Healing
Physiological healing is the restoration of damaged living tissue, organs and biological system to normal function. It is the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area....

 of the tissue from the inflammatory process.

Causes

  • Burns
    Burn (injury)
    A burn is a type of injury to flesh caused by heat, electricity, chemicals, light, radiation or friction. Most burns affect only the skin . Rarely, deeper tissues, such as muscle, bone, and blood vessels can also be injured...

  • Chemical irritants
    Irritation
    Irritation or exacerbation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant...

  • Frostbite
    Frostbite
    Frostbite is the medical condition where localized damage is caused to skin and other tissues due to extreme cold. Frostbite is most likely to happen in body parts farthest from the heart and those with large exposed areas...

  • Toxin
    Toxin
    A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

    s
  • Infection
    Infection
    An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

     by pathogen
    Pathogen
    A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

    s
  • Physical injury, blunt or penetrating
  • Immune reactions due to hypersensitivity
    Hypersensitivity
    Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

  • Ionizing radiation
    Ionizing radiation
    Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...

  • Foreign bodies, including splinters, dirt and debris
  • Trauma

Types

Comparison between acute and chronic inflammation:
Acute Chronic
Causative agent Pathogens, injured tissues Persistent acute inflammation due to non-degradable pathogens, persistent foreign bodies, or autoimmune reactions
Major cells involved neutrophils (primarily), eosinophils and basophils (response to helminth worms and parasites), 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
Onset Immediate Delayed
Duration Few days Up to many months, or years
Outcomes Resolution, abscess formation, chronic inflammation Tissue destruction, fibrosis, necrosis

Cardinal signs


The classic signs and symptoms of acute inflammation:
English Latin
p style="font-family:arial;color:red;font-size:20px;">

Redness
Rubor*
Swelling Oedema*
Heat Calor
Heat
In physics and thermodynamics, heat is energy transferred from one body, region, or thermodynamic system to another due to thermal contact or thermal radiation when the systems are at different temperatures. It is often described as one of the fundamental processes of energy transfer between...

*
Pain Dolor
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

*
Loss of function Functio laesa
Functio laesa
Functio laesa is a term used in medicine to refer to a loss of function or a disturbance of function.It was identified as the fifth sign of acute inflammation by Galen, who added it to the four signs identified by Celsus ....

**
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, or "cardinal signs" of inflammation.*

Functio laesa is an apocryphal notion, as it is not unique to inflammation and is a characteristic of many disease states.
**


Acute inflammation is a short-term process, usually appearing within a few minutes or hours and ceasing upon the removal of the injurious stimulus. It is characterized by five cardinal signs:

The acronym that may be used for this is "PRISH" for Pain, Redness, Immobility (loss of function), Swelling and Heat.

The traditional names for signs of inflammation come from Latin:
  • Dolor
    Pain
    Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

     (pain
    Pain
    Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

    )
  • Calor
    Calor
    Calor Gas is a brand of bottled butane and propane which is available in Britain and Ireland. It comes in cylinders, which have a special gas regulator.Calor was formed in 1935. Calor is the UK's leading supplier of Liquefied petroleum gas...

     (heat
    Heat
    In physics and thermodynamics, heat is energy transferred from one body, region, or thermodynamic system to another due to thermal contact or thermal radiation when the systems are at different temperatures. It is often described as one of the fundamental processes of energy transfer between...

    )
  • Rubor (redness)
  • Oedema (swelling
    Swelling (medical)
    In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....

    )
  • Functio laesa
    Functio laesa
    Functio laesa is a term used in medicine to refer to a loss of function or a disturbance of function.It was identified as the fifth sign of acute inflammation by Galen, who added it to the four signs identified by Celsus ....

     (loss of function)


The first four (classical signs) were described by Celsus
Aulus Cornelius Celsus
Aulus Cornelius Celsus was a Roman encyclopedist, known for his extant medical work, De Medicina, which is believed to be the only surviving section of a much larger encyclopedia. The De Medicina is a primary source on diet, pharmacy, surgery and related fields, and it is one of the best sources...

 (ca 30 BC–38 AD), while loss of function was added later by Galen
Galen
Aelius Galenus or Claudius Galenus , better known as Galen of Pergamon , was a prominent Roman physician, surgeon and philosopher...

 even though the attribution is disputed and the origination of the fifth sign has also been ascribed to Thomas Sydenham
Thomas Sydenham
Thomas Sydenham was an English physician. He was born at Wynford Eagle in Dorset, where his father was a gentleman of property. His brother was Colonel William Sydenham. Thomas fought for the Parliament throughout the English Civil War, and, at its end, resumed his medical studies at Oxford...

 and Virchow.

Redness and heat are due to increased blood flow at body core temperature to the inflamed site; swelling is caused by accumulation of fluid; pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

 is due to release of chemicals that stimulate nerve endings. Loss of function has multiple causes.

These five signs appear when acute inflammation occurs on the body's surface, whereas acute inflammation of internal organs may not result in the full set. Pain only happens where the appropriate sensory nerve endings exist in the inflamed area—e.g., acute inflammation of the lung (pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

) does not cause pain unless the inflammation involves the parietal pleura
Parietal pleura
The portion of the pleura external to the pulmonary pleura lines the inner surface of the chest wall, covers the diaphragm, and is reflected over the structures occupying the middle of the thorax; this portion is termed the parietal pleura....

, which does have pain-sensitive nerve endings
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...

.

Process of acute inflammation



The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mastocytes.
These cells present on their surfaces certain receptors named pattern recognition receptor
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...

s
(PRRs), which recognize molecules that are broadly shared by pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s but distinguishable from host molecules, collectively referred to as pathogen-associated molecular pattern
Pathogen-associated molecular pattern
Pathogen-associated molecular patterns, or PAMPs, are molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes...

s (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRRs recognize a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation (leakage) of plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 proteins and fluid into the tissue (edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

), which manifests itself as swelling (tumor). Some of the released mediators such as bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

 increase the sensitivity to pain (hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...

, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils, outside of the blood vessels (extravasation) into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function (functio laesa) is probably the result of a neurological reflex in response to pain.

In addition to cell-derived mediators, several acellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

 activated by bacteria, and the coagulation and fibrinolysis systems activated by necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

, e.g. a burn or a trauma.

The acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators have short half lives and are quickly degraded in the tissue. Hence, acute inflammation ceases once the stimulus has been removed.

Exudative component


The exudative component involves the movement of plasma fluid, containing important protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s such as fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

 and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically induced dilation and increased permeability of blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s, which results in a net loss of blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

. The increased collection of fluid into the tissue causes it to swell (edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

). This extravasated fluid is funneled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...

 system.

Vascular changes


Acute inflammation is characterised by marked vascular changes, including vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

, increased permeability and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...

 level, progressing to the capillary
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...

 level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 into the tissues, with resultant stasis
Stasis (medicine)
In medicine, stasis is the state in which the normal flow of a body liquid stops, for example the flow of blood through vessels or of intestinal contents through the digestive tract....

due to the increase in the concentration of the cells within blood - a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate (move) along the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force
Shear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...

 along the periphery of the vessels moves cells in the blood into the middle of the vessel.

Plasma cascade systems

  • The complement system
    Complement system
    The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

    , when activated, creates a cascade of chemical reactions that promotes opsinization
    Opsin
    Opsins are a group of light-sensitive 35–55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical...

    , chemotaxis
    Chemotaxis
    Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

    , and agglomeration
    Agglomeration
    In the study of human settlements, an urban agglomeration is an extended city or town area comprising the built-up area of a central place and any suburbs linked by continuous urban area. In France, INSEE the French Statistical Institute, translate it as "Unité urbaine" which means continuous...

    , and produces the MAC.
  • The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
  • The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury.
  • The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.

Plasma derived mediators


* non-exhaustive list
Name Produced by Description
Bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

Kinin system A vasoactive protein which is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.
C3
C3 (complement)
Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.-Function:...

Complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

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
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

, which marks the invader as a target for phagocytosis.
C5a
C5a
C5a is a protein fragment released from complement component C5. In humans, the polypeptide contains 74 amino acids. NMR spectroscopy proved that the molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present. The longest helix...

Complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

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
Factor XII
Coagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...

(Hageman Factor)
Liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

A protein which circulates inactively, until activated by collagen, platelets, or exposed basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...

s via conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a 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
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

A complex of the complement proteins C5b, C6
Complement component 6
Complement component 6 is a protein that in humans is encoded by the C6 gene.Complement component 6 is a protein involved in the complement system. It is part of the membrane attack complex which can insert into the cell membrane and cause cell to lyse....

, C7
Complement component 7
Complement component 7 is a protein involved in the complement system....

, C8
C8 complex
Complement component 8 is a protein involved in the complement system. A hereditary deficiency of C8 can result in increased susceptibility to Neisseria infections, such as meningitis and gonorrhea.-References:...

, and multiple units of C9
Complement component 9
Complement component 9 is a protein involved in the complement system....

. 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
Plasmin
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...

Fibrinolysis system Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.
Thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...

Coagulation system Cleaves the soluble plasma protein fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...

 to produce insoluble fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

, which aggregates to form a blood clot. Thrombin can also bind to cells via the PAR1
Protease-activated receptor
Protease-activated receptors are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, but also on endothelial cells, myocytes and neurons....

 receptor to trigger several other inflammatory responses, such as production of chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

s and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

.

Cellular component


The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...

s, ingesting bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, viruses, and cellular debris. Others release enzymatic granules
Granule (cell biology)
In cell biology, a granule is a small particle. It can be any structure barely visible by light microscopy. The term is most often used to describe a secretory vesicle.-Leukocytes:...

 which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...

s, while chronic inflammation is mediated by mononuclear cells such as monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s and lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s.

Leukocyte extravasation




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:
  1. Leukocyte localisation and recruitment to the endothelium local to the site of inflammation – involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine
    Histamine
    Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

    , promote the immediate expression of P-selectin
    P-selectin
    P-selectin is a cell adhesion molecule on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets...

     on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin
    E-selectin
    E-selectin, also known as CD62 antigen-like family member E , endothelial-leukocyte adhesion molecule 1 , or leukocyte-endothelial cell adhesion molecule 2 , is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in...

     on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin
    Integrin
    Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....

     ligands on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
  2. Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.
  3. Movement of leukocytes within the tissue via chemotaxis
    Chemotaxis
    Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

    :
    Leukocytes reaching the tissue interstitium bind to extracellular matrix
    Extracellular matrix
    In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

     proteins via expressed integrins and CD44
    CD44
    The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...

     to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.

Cell derived mediators


* non-exhaustive list
Name Type Source Description
Lysosome granules
Granule (cell biology)
In cell biology, a granule is a small particle. It can be any structure barely visible by light microscopy. The term is most often used to describe a secretory vesicle.-Leukocytes:...

Enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s
Granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...

s
These cells contain a large variety of enzymes which perform a number of functions. Granules can be classified as either specific
Specific granules
Specific granules are secretory vesicles found exclusively in cells of the immune system called granulocytes. They are also known as secondary granules....

or azurophil
Azurophil
An azurophil is an object readily stained with an azure dye. Azurophils include certain cytoplasmic granules in white blood cells and hyperchromatin, imparting a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils loaded with a wide variety of...

ic
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
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

Vasoactive amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

Mast cells, basophils, platelets Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...

 dilation and increased venous permeability.
IFN-γ Cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

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
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...

Chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

Primarily macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s
Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.
Leukotriene B4
Leukotriene B4
Leukotriene B4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammatory mediators and is able to induce the adhesion and activation of leukocytes on the endothelium, allowing them to bind to and cross it into the tissue...

Eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....

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
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

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.
Prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s
Eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....

Mast cells A group of lipids which can cause vasodilation, fever, and pain.
TNF-α and IL-1 Cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s
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 fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate.

Morphologic patterns


Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
  • Granulomatous inflammation: Characterised by the formation of granuloma
    Granuloma
    Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

    s, they are the result of a limited but diverse number of diseases, which include among others tuberculosis
    Tuberculosis
    Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

    , leprosy
    Leprosy
    Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...

    , sarcoidosis
    Sarcoidosis
    Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

    , and syphilis
    Syphilis
    Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

    .
  • Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrin
    Fibrin
    Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

     to pass through the blood vessels. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities
    Serous membrane
    In anatomy, serous membrane is a smooth membrane consisting of a thin layer of cells which secrete serous fluid. Serous membranes line and enclose several body cavities, known as serous cavities, where they secrete a lubricating fluid which reduces friction from muscle movement...

    , where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
  • Purulent inflammation: Inflammation resulting in large amount of pus
    Pus
    Pus is a viscous exudate, typically whitish-yellow, yellow, or yellow-brown, formed at the site of inflammatory during infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection of pus within or beneath the epidermis is known as a pustule or...

    , which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscess
    Abscess
    An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...

    es.
  • Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membrane
    Serous membrane
    In anatomy, serous membrane is a smooth membrane consisting of a thin layer of cells which secrete serous fluid. Serous membranes line and enclose several body cavities, known as serous cavities, where they secrete a lubricating fluid which reduces friction from muscle movement...

    s, but may be derived from blood plasma. Skin blister
    Blister
    A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...

    s exemplify this pattern of inflammation.
  • Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.

Inflammatory disorders


Inflammatory abnormalities are a large group of disorders which underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with etiological origins in inflammatory processes include cancer, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

, and ischaemic heart disease
Ischaemic heart disease
Ischaemic or ischemic heart disease , or myocardial ischaemia, is a disease characterized by ischaemia of the heart muscle, usually due to coronary artery disease...

.

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:

Atherosclerosis



Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance. Clinical Cardiology: New Frontiers (Inflammation and Atherosclerosis)

Allergies


An allergic reaction, formally known as type 1 hypersensitivity
Type I hypersensitivity
Type I hypersensitivity is an allergic reaction provoked by reexposure to a specific type of antigen referred to as an allergen, or to a nonimmunologic stimulus like cold weather or exercise...

, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever
Hay Fever
Hay Fever is a comic play written by Noël Coward in 1924 and first produced in 1925 with Marie Tempest as the first Judith Bliss. Laura Hope Crews played the role in New York...

, which is caused by a hypersensitive response by skin mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s to allergen
Allergen
An allergen is any substance that can cause an allergy. In technical terms, an allergen is a non-parasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals....

s. Pre-sensitised mast cells respond by degranulating
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...

, releasing vasoactive
Vasoactive
A vasoactive is a pharmaceutical agent that has the effect of either increasing or decreasing blood pressure and/or heart rate. Typically used in a setting where a patient has the blood pressure and heart rate monitored constantly, vasoactive drug therapy is typically "titrated" to achieve a...

 chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...

.

Other hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

 reactions (type 2
Type II hypersensitivity
In type II hypersensitivity the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces...

and type 3
Type III hypersensitivity
Type III hypersensitivity occurs when antigens and antibodies are present in roughly equal amounts, causing extensive cross-linking.-Presentation:...

) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.

Myopathies


Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis
Dermatomyositis
Dermatomyositis is a connective-tissue disease related to polymyositis and Bramaticosis that is characterized by inflammation of the muscles and the skin.- Causes :...

, polymyositis
Polymyositis
Polymyositis is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis.-Signs and symptoms:...

, and inclusion body myositis
Inclusion body myositis
Inclusion body myositis is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs...

.

Leukocyte defects


Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome
Chédiak-Higashi syndrome
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy...

), or produce microbicide
Microbicide
Microbicides for sexually transmitted diseases, are pharmacologic agents and chemical substances that are capable of killing or destroying certain microorganisms that commonly cause human infection, for example the human immunodeficiency virus....

s (chronic granulomatous disease
Chronic granulomatous disease
Chronic granulomatous disease is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens...

). Additionally, diseases affecting the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

 may result in abnormal or few leukocytes.

Pharmacological


Certain drugs or exogenic chemical compounds are known to affect inflammation. Vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...

 deficiency causes an increase in inflammatory responses, and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 drugs work specifically by inhibiting normal inflammatory components. Certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. NF-κB).

Cancer


Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology
Cancer immunology
Cancer immunology is the study of interactions between the immune system and cancer cells . It is also a growing field of research that aims to discover innovative cancer immunotherapies to treat and retard progression of this disease...

, suppressing cancer.

Resolution of inflammation


The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues.
Mechanisms which serve to terminate inflammation include:
  • Short half-life
    Half-life
    Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

     of inflammatory mediators in vivo.
  • Production and release of Transforming growth factor (TGF) beta from macrophages
  • Production and release of Interleukin 10
    Interleukin 10
    Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....

     (IL-10)
  • Production of anti-inflammatory lipoxin
    Lipoxin
    Lipoxins are a series of anti-inflammatory mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation....

    s
  • Downregulation of pro-inflammatory molecules, such as leukotrienes
  • Upregulation of anti-inflammatory molecules such as the Interleukin 1 receptor antagonist
    Interleukin 1 receptor antagonist
    The interleukin-1 receptor antagonist is a protein that in humans is encoded by the IL1RN gene.IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories. IL-1RA, is an agent that binds non-productively to the cell surface interleukin-1...

      or the soluble tumor necrosis factor receptor
    Tumor necrosis factor receptor
    A tumor necrosis factor receptor , or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors . The receptor cooperates with an adaptor protein , which is important in determining the outcome of the response A tumor necrosis factor receptor (TNFR), or death receptor, is a...

     (TNFR)
  • Apoptosis
    Apoptosis
    Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

     of pro-inflammatory cells
  • Desensitization of receptors
  • Increased survival of cells in regions of inflammation due to their interaction with the extracellular matrix
    Extracellular matrix
    In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

     (ECM)
  • Downregulation of receptor activity by high concentrations of ligands
  • Cleavage of chemokine
    Chemokine
    Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

    s by matrix metalloproteinases (MMPs) might lead to production of anti-inflammatory factors.

Systemic effects


An infectious organism can escape the confines of the immediate tissue via the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

 or lymphatic system
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...

, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessel
Lymph vessel
In anatomy, lymph vessels are thin walled, valved structures that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vessels are lined by endothelial cells, and deep to that have a thin layer of smooth muscles, and adventitia that bind...

s. An infection of the lymph vessels is known as lymphangitis
Lymphangitis
Lymphangitis is an inflammation of the lymphatic channels that occurs as a result of infection at a site distal to the channel. The most common cause of lymphangitis in humans is Streptococcus pyogenes...

, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.

When inflammation overwhelms the host, systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...

 is diagnosed. When it is due to infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

, the term sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

 is applied, with the terms bacteremia
Bacteremia
Bacteremia is the presence of bacteria in the blood. The blood is normally a sterile environment, so the detection of bacteria in the blood is always abnormal....

 being applied specifically for bacterial sepsis and viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...

 specifically to viral sepsis. Vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

 and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...

 and death.

Acute-phase proteins


Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...

. These proteins include C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

, serum amyloid A
Serum amyloid A
Serum amyloid A proteins are a family of apolipoproteins associated with high-density lipoprotein in plasma. Different isoforms of SAA are expressed constitutively at different levels or in response to inflammatory stimuli . These proteins are produced predominantly by the liver...

, and serum amyloid P, which cause a range of systemic effects including:

Leukocyte numbers


Inflammation often affects the numbers of leukocytes present in the body:
  • Leukocytosis
    Leukocytosis
    Leukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...

     is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per microliter, but extreme cases can see it approach 100 000 cells per microliter. Bacterial infection usually results in an increase of neutrophils, creating neutrophilia
    Neutrophilia
    Neutrophilia is a condition where a person has a high number of neutrophil granulocytes in their blood.-Causes:...

    , whereas diseases such as asthma
    Asthma
    Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

    , hay fever
    Hay Fever
    Hay Fever is a comic play written by Noël Coward in 1924 and first produced in 1925 with Marie Tempest as the first Judith Bliss. Laura Hope Crews played the role in New York...

    , and parasite infestation result in an increase in eosinophils, creating eosinophilia
    Eosinophilia
    Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...

    .
  • Leukopenia
    Leukopenia
    Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

     can be induced by certain infections and diseases, including viral infection, Rickettsia
    Rickettsia
    Rickettsia is a genus of non-motile, Gram-negative, non-sporeforming, highly pleomorphic bacteria that can present as cocci , rods or thread-like . Being obligate intracellular parasites, the Rickettsia survival depends on entry, growth, and replication within the cytoplasm of eukaryotic host cells...

    infection, some protozoa
    Protozoa
    Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...

    , tuberculosis
    Tuberculosis
    Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

    , and some cancer
    Cancer
    Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

    s.

Systemic inflammation and obesity


With the discovery of interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...

s (IL), the concept of systemic inflammation
Systemic inflammation
Chronic systemic inflammation is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system.It can contribute to the development or progression of certain conditions....

 developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 and other organ systems.

Chronic inflammation is widely observed in obesity. The obese commonly have many elevated markers of inflammation, including:
  • IL-6 (Interleukin-6)
  • IL-8 (Interleukin-8)
  • IL-18 (Interleukin-18)
  • TNF-α (Tumor necrosis factor-alpha)
  • CRP (C-reactive protein)
    C-reactive protein
    C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

  • Insulin
    Insulin
    Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

  • Blood glucose
    Blood sugar
    The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

  • Leptin
    Leptin
    Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...



Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP. Waist circumference correlates significantly with systemic inflammatory response. A predominant factor in this correlation is due to the autoimmune response triggered by adiposity, whereby immune cells may mistake fatty deposits for intruders. The body attacks fat similar to bacteria and fungi. When expanded fat cells leak or break open, macrophages mobilize to clean up and embed into the adipose tissue. Then macrophages release inflammatory chemicals, including TNF-α and (IL-6). TNF's primary role is to regulate the immune cells and induce inflammation. White blood cells then assist by releasing more cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s. This link between adiposity and inflammation has been shown to produce 10-35% of IL-6 in a resting individual, and this production increases with increasing adiposity.

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
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 and atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

 is the subject of intense
research.

Inflammation and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

-specific genes are unregulated in white adipose tissue (WAT). There were also signs of dramatic increase in circulating insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 level, adipocyte lipolysis and formation of multinucleate giant cell
Giant cell
A giant cell is a mass formed by the union of several distinct cells . It can arise in response to an infection or foreign body.Types include:* foreign-body giant cell* Langhans giant cell* Touton giant cells...

s. The fat-derived protein called angiopoietin
Angiopoietin
The angiopoietins are protein growth factors that promote angiogenesis, the formation of blood vessels from pre-existing blood vessels. There are now four identified angiopoietins:...

-like protein 2 (Angptl2) elevates in fat tissues. Higher than normal Angptl2 level in fat tissues develop inflammation as well as insulin and leptin resistance. Stored fat secretes Leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...

 to signal satiety. Leptin resistance plays a role in the process where appetite overrules the message of satiety. Angptl2 then starts an inflammatory cascade causing blood vessels to remodel and attract macrophages. Angptl2 is an adipocyte-derived inflammatory mediator linking obesity to systemic insulin resistance. It is possible that, as an inflammatory marker, leptin responds specifically to adipose-derived inflammatory cytokines.

C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

 (CRP) is generated at a higher level in obese people. It raises when there is inflammation throughout the body. Mild elevation in CRP increase risk of heart attacks, strokes, high blood pressure, muscle weakness and fragility.

Systemic inflammation and overeating


Hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...

 induces IL-6 production from endothelial cells and macrophages. Meals high in saturated fat
Saturated fat
Saturated fat is fat that consists of triglycerides containing only saturated fatty acids. Saturated fatty acids have no double bonds between the individual carbon atoms of the fatty acid chain. That is, the chain of carbon atoms is fully "saturated" with hydrogen atoms...

, as well as meals high in calories have been associated with increases in inflammatory markers. While the inflammatory responses are acute and arise in response to overeating
Overeating
Overeating generally refers to the long-term consumption of excess food in relation to the energy that an organism expends , leading to weight gainingand often obesity. It may be regarded as an eating disorder....

, the response may become chronic if the overeating is chronic.

Outcomes



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. Here are the possible outcomes to inflammation:
  1. Resolution
    The complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchyma
    Parenchyma
    Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...

    l cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.
  2. Fibrosis
    Large amounts of tissue destruction, or damage in tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen
    Collagen
    Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

    . The scar will not contain any specialized structures, such as parenchyma
    Parenchyma
    Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...

    l cells, hence functional impairment may occur.
  3. Abscess Formation
    A cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
  4. Chronic inflammation
    In acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound
    Chronic wound
    A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic....

    . Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxin
    Toxin
    A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

    s they release (including reactive oxygen species
    Reactive oxygen species
    Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

    ) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.

Examples


Inflammation is usually indicated by adding the suffix "-itis", as shown below. However, some conditions such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

 and pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

 do not follow this convention. More examples are available at list of types of inflammation.

Exercise-induced acute inflammation


Acute inflammation of the muscle cells, as understood in exercise physiology, can result after induced
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...

 eccentric and concentric muscle training. Participation in eccentric training and conditioning, including resistance training and activities that emphasize eccentric lengthening of the muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

 including downhill running on a moderate to high incline can result in considerable soreness within 24 to 48 hours, even though blood lactate levels, previously thought to cause muscle soreness, were much higher with level running. This delayed onset muscle soreness
Delayed onset muscle soreness
Delayed onset muscle soreness , also called muscle fever, is the pain and stiffness felt in muscles several hours to days after unaccustomed or strenuous exercise. The soreness is felt most strongly 24 to 72 hours after the exercise. It is caused by eccentric exercise...

 (DOMS) results from structural damage to the contractile filaments and z-disks, which has been noted especially in marathon runners whose muscle fibers revealed remarkable damage to the muscle fibers after both training and marathon competition. The onset and timing of this gradient damage
Resistance training
Resistance training has two different meanings. A broader meaning that refers to any training that uses a resistance to the force of muscular contraction , and elastic or hydraulic resistance, which refers to a specific type of strength training that uses elastic or hydraulic tension to provide...

 to the muscle parallels the degree of muscle soreness experienced by the runners.

Z-disks are the point of contact for the contractile proteins. They provide structural support for the transmission of force when the muscle fibers are activated to shorten. However, in marathon runners and those who prescribe to the overload principle to enhance their muscles, show moderate Z-disk streaming and major disruption of the thick and thin filaments in parallel groups of sarcomeres as a result of the force of eccentric actions or stretching of the tightened muscle fibers.

This disruption of the muscle fibers triggers white blood cells to increase following the induced muscle soreness, leading to the inflammatory response observation from the induced muscle soreness. Elevations in plasma enzymes, myoglobinemia, and abnormal muscle histology and ultrastructure are concluded to be associated with the inflammatory response in DOMS. High tension in the contractile-elastic system of muscle results in structural damage to the muscle fiber and plasmalemma and its epimysium, perimysium, and/or endomysium. The mysium damage disrupts calcium homeostasis in the injured fiber and fiber bundles, resulting in necrosis that peaks about 48 hours after exercise. The products of the macrophage activity and intracellular contents (such as histamines, kinins, and K+) accumulate outside the cells. These substances then stimulate the free nerve endings in the muscle; a process that appears accentuated by eccentric exercise, in which large forces are distributed over relatively small cross-sectional area of the muscle.

Post-inflammatory muscle growth and repair


There is a known relationship between inflammation and muscle growth. For instance, high doses of anti-inflammatory medicines (e.g., NSAIDs) are able to blunt muscle growth.

It has been further theorized that the acute localized inflammatory responses to muscular contraction during exercise, as described above, are a necessary precursor to muscle growth. As a response to muscular contractions, the acute inflammatory response initiates the breakdown and removal of damaged muscle tissue. Muscles can synthesize cytokines in response to contractions, such that the cytokines Interleukin-1 beta (IL-1β)
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...

, TNF-α, and IL-6 are expressed in skeletal muscle up to 5 days after exercise.

In particular, the increase in levels of IL-6 can reach up to one hundred times that of resting levels. Depending on volume, intensity, and other training factors, the IL-6 increase associated with
training initiates about 4 hours after resistance training and remains elevated for up to 24 hours.

These acute increases in cytokines, as a response to muscle contractions, help initiate the process of muscle repair and growth by activating satellite cells within the inflamed muscle. Satellite cells are crucial for skeletal muscle adaption to exercise. They contribute to hypertrophy by providing new myonuclei and repair damaged segments of mature myofibers for successful regeneration following injury- or exercise-induced muscle damage; high-level powerlifters
Powerlifting
Powerlifting is a strength sport. It resembles the sport of Olympic weightlifting, as both disciplines involve lifting weights in three attempts. Powerlifting evolved from a sport known as 'odd lifts' which followed the same three attempt format but used a wide variety of events akin to Strongman...

 can have up to 100% more satellite cells than untrained controls.

A rapid and transient localization of the IL-6 receptor and increased IL-6 expression occurs in satellite cells following contractions. IL-6 has been shown to mediate
hypertrophic muscle growth both in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. Unaccustomed exercise can increase IL-6 by up to sixfold at 5 hours post-exercise and threefold 8 days after exercise. Also telling is the fact that NSAIDs can decrease satellite cell response to exercise, thereby reducing exercise-induced protein synthesis.

The increase in cytokines after resistance exercise coincides with the decrease in levels of myostatin
Myostatin
Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...

, a protein that inhibits muscle differentiation and growth. The cytokine response to resistance exercise and moderate-intensity running occur differently, with the latter causing a more prolonged response, especially at the 12-24 hour mark.

Chronic inflammation and muscle loss


Both chronic and extreme inflammation are associated with disruptions of anabolic signals initiating muscle growth. Chronic inflammation has been implicated as part of the cause of the muscle loss that occurs with aging
Sarcopenia
Sarcopenia is the degenerative loss of skeletal muscle mass and strength associated with aging...

. Increased protein levels of myostatin have been described in patients with diseases characterized by chronic low-grade inflammation. Increased levels of TNF-α can suppress the AKT/mTOR pathway, a crucial pathway for regulating skeletal muscle hypertrophy, thereby increasing muscle catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...

. Cytokines may antagonize
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 the anabolic effects of Insulin-like growth factor 1 (IGF-1)
Insulin-like growth factor 1
Insulin-like growth factor 1 also known as somatomedin C is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" in the 1970s.IGF-1 is a hormone similar in molecular...

. In the case of sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

, an extreme whole body inflammatory state, the synthesis of both myofibrillar and sarcoplasmic proteins are inhibited, with the inhibition taking place preferentially in fast-twitch muscle fibers
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

. Sepsis is also able to prevent leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...

 from stimulating muscle protein synthesis. In animal models, when inflammation is created, mTOR loses its ability to be stimulated by muscle growth.

Exercise as a treatment for inflammation


Regular physical activity is reported to decrease markers of inflammation, although the correlation is imperfect and seems to reveal differing results contingent upon training intensity. For instance, while baseline measurements of circulating inflammatory markers do not seem to differ greatly between healthy trained and untrained adults, long-term chronic training may help reduce chronic low-grade inflammation. On the other hand, levels of inflammatory markers (IL-6) remained elevated longer into the recovery period following an acute bout of exercise in patients with inflammatory diseases, relative to the recovery of healthy controls. It may well be that low-intensity training can reduce resting pro-inflammatory markers (CRP, IL-6), while moderate-intensity training has milder and less-established anti-inflammatory benefits. There is a strong relationship between exhaustive exercise and chronic low-grade inflammation. Marathon running may enhance IL-6 levels as much as 100 times over normal and increases total leuckocyte count and neturophil mobilization. As such, individuals pursuing exercise as a means to treat the other factors behind chronic inflammation may wish to balance their exercise protocol with bouts of low-intensity training, while striving to avoid chronic over-exertion.

Signal-to-noise theory


Given that localized acute inflammation is a necessary component for muscle growth, and that chronic low-grade inflammation is associated with a disruption of anabolic signals initiating muscle growth, it has been theorized that a signal-to-noise model may best describe the relationship between inflammation and muscle growth. By keeping the "noise" of chronic inflammation to a minimum, the localized acute inflammatory response signals a stronger anabolic response than could be achieved with higher levels of chronic inflammation.

See also


  • Anaphylatoxin
    Anaphylatoxin
    Anaphylatoxins, or anaphylotoxins, are fragments that are produced as part of the activation of the complement system.. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense...

  • Anti-inflammatories
    Anti-inflammatory
    Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

  • Essential fatty acid interactions
    Essential fatty acid interactions
    The actions of the ω-3 and ω-6 essential fatty acids are best characterized by their interactions; they cannot be understood separately.Arachidonic acid is a 20-carbon ω-6 conditionally essential fatty acid...

  • Healing
    Healing
    Physiological healing is the restoration of damaged living tissue, organs and biological system to normal function. It is the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area....

  • Interleukin
    Interleukin
    Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...

  • Lipoxin
    Lipoxin
    Lipoxins are a series of anti-inflammatory mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation....

  • Substance P
    Substance P
    In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...


External links