Inflammation is a protective immunovascular response that involves immune cells, blood vessels, and molecular mediators. The purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.
The classical signs of acute inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen.
Inflammation is tightly regulated by the body. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (eg. bacteria) and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is therefore 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 and leukocytes (especially granulocytes) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory defensive response - the two components are considered together when discussing an infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be. But because of how often the two are correlated, words ending in the suffix -itis (which refers to inflammation) are sometimes informally described as referring to infection. For example, the word urethritis strictly means only "urethral inflammation", but clinical health care providers usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis.
On the other hand, It is useful to differentiate inflammation and infection as there are many pathological situations where inflammation is not driven by microbial invasion - for example, atherosclerosis, type III hypersensitivity, trauma, ischaemia. There are also pathological situations where microbial invasion does not result in classic inflammatory response - for example, parasitosis, eosinophilia.
- 1 Causes
- 2 Types
- 3 Vascular component
- 4 Cellular component
- 5 Morphologic patterns
- 6 Inflammatory disorders
- 7 Systemic effects
- 8 Outcomes
- 9 Examples
- 10 Exercise and inflammation
- 11 Diet and chronic inflammation
- 12 See also
- 13 References
- 14 External links
- Physical injury, blunt or penetrating
- Foreign bodies, including splinters, dirt and debris
- Ionizing radiation
|Causative agent||Bacterial pathogens, injured tissues||Persistent acute inflammation due to non-degradable pathogens, viral infection, persistent foreign bodies, or autoimmune reactions|
|Major cells involved||neutrophils (primarily), basophils (inflammatory response), and eosinophils (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|
|Duration||Few days||Up to many months, or years|
|Outcomes||Resolution, abscess formation, chronic inflammation||Tissue destruction, fibrosis, necrosis|
|Loss of function||Functio laesa**|
|All the above signs may be observed in specific instances, but no single sign must, as a matter of course, be present.
These are the original, 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.**
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:
The first four (classical signs) were described by Celsus (ca. 30 BC–38 AD), while loss of function was added later by Galen even though the attribution is disputed and the origination of the fifth sign has also been ascribed to Thomas Sydenham 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 is due to the release of chemicals such as bradykinin or histamine 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 happens only where the appropriate sensory nerve endings exist in the inflamed area—e.g., acute inflammation of the lung (pneumonia) does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings.
Process of acute inflammation
The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mastocytes. These cells present on their surfaces certain receptors named pattern recognition receptors (PRRs), which recognise generic molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (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 proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). Some of the released mediators such as bradykinin increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, 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 activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis, 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.
Vasodilation and Increased Permeability
As defined, acute inflammation is an immunovascular response to an inflammatory stimulus. This means acute inflammation can be broader divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid granulocytes in the acute setting). The vascular component of acute inflammation involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue.
Upon contact with PAMPs, tissue macrophages and mastocytes release vasoactive amines such as histamine and serotonin, as well as eicosanoids such as prostaglandin E2 and leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release nitric oxide. These mediators vasodilate and permeabilise the blood vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (edema). This exuded tissue fluid contain various antimicrobial mediators from the plasma such as complement, lysozyme, antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded platelets, coagulants, plasmin and kinins can clot the wounded area and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a fibrin lattice - as would construction scaffolding at a construction site - for the purpose of aiding phagocytic debridement and wound repair later on. Some of the exuded tissue fluid is also funneled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.
Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary 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 into the tissues, with resultant stasis 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, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
Plasma cascade systems
- The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, 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.
* non-exhaustive list
|Bradykinin||Kinin system||A vasoactive protein that is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.|
|C3||Complement system||Cleaves to produce C3a and C3b. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an opsonin, which marks the invader as a target for phagocytosis.|
|C5a||Complement system||Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as a chemoattractant to direct cells via chemotaxis to the site of inflammation.|
|Factor XII (Hageman Factor)||Liver||A protein that circulates inactively, until activated by collagen, platelets, or exposed basement membranes via conformational change. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.|
|Membrane attack complex||Complement system||A complex of the complement proteins C5b, C6, C7, C8, and multiple units of C9. The combination and activation of this range of complement proteins forms the membrane attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing death.|
|Plasmin||Fibrinolysis system||Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.|
|Thrombin||Coagulation system||Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, which aggregates to form a blood clot. Thrombin can also bind to cells via the PAR1 receptor to trigger several other inflammatory responses, such as production of chemokines and nitric oxide.|
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 phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by granulocytes, whereas chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
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:
- Leukocyte margination and endothelial adhesion: Activated tissue macrophages release cytokines such as IL-1 and TNFα, which bind to their respective G protein-coupled receptors on the endothelial wall. Signal transduction induces the immediate expression of P-selectin 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 on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of immunoglobulin ligands such as ICAM-1 and VCAM-1 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 immunoglobulin ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
- 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.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue. Phagocytes express cell-surface endocytic pattern recognition receptors (PRRs) that have affinity and efficacy against non-specific microbe-associated molecular patterns (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate phagocytosis are cell wall components, including complex carbohydrates such as mannans and β-glucans, lipopolysaccharides (LPS), peptidoglycans, and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with C-type lectin receptors binding to mannans and β-glucans, and scavenger receptors binding to LPS.
Upon endocytic PRR binding, actin-myosin cytoskeletal rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe. Phosphatidylinositol and Vps34-Vps15-Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular lysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. The reactive oxygen species, superoxides and hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte.
Phagocytic efficacy can be enhanced by opsonisation. Plasma derived complement C3b and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express opsonin receptors Fc receptor and complement receptor 1 (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the lysosomal elimination of the infective agent.
* non-exhaustive list
|Lysosome granules||Enzymes||Granulocytes||These cells contain a large variety of enzymes that perform a number of functions. Granules can be classified as either specific or azurophilic depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins that allow these enzymes to act as inflammatory mediators.|
|Histamine||Vasoactive amine||Mast cells, basophils, platelets||Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation and increased venous permeability.|
|IFN-γ||Cytokine||T-cells, NK cells||Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.|
|IL-8||Chemokine||Primarily macrophages||Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.|
|Leukotriene B4||Eicosanoid||Leukocytes||Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosome enzymes by these cells.|
|Nitric oxide||Soluble gas||Macrophages, endothelial cells, some neurons||Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.|
|Prostaglandins||Eicosanoid||Mast cells||A group of lipids that can cause vasodilation, fever, and pain.|
|TNF-α and IL-1||Cytokines||Primarily macrophages||Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation of fibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF-α inhibits osteoblast differentiation.|
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 granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, sarcoidosis, and syphilis.
- Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrin 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, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine (Pseudomembranous colitis), pseudomembranous tubes can be formed.
- Purulent inflammation: Inflammation resulting in large amount of pus, 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 abscesses.
- Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters 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 abnormalities are a large group of disorders that 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, and ischaemic heart 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:
- Acne vulgaris
- Autoimmune diseases
- Autoinflammatory diseases
- Celiac disease
- Chronic prostatitis
- Inflammatory bowel diseases
- Pelvic inflammatory disease
- Reperfusion injury
- Rheumatoid arthritis
- Transplant rejection
- Interstitial cystitis
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.
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive 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.
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, polymyositis, and inclusion body myositis.
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), or produce microbicides (chronic granulomatous disease). In addition, diseases affecting the bone marrow may result in abnormal or few leukocytes.
Certain drugs or exogenic chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses, and anti-inflammatory 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).
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, suppressing cancer. Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as NF-κB, may mediate some of the most critical effects of inflammatory stimuli on cancer cells. This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells, is very likely to affect carcinogenesis on the one hand; on the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.
According to a review of 2009, recent data suggests that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.
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 that serve to terminate inflammation include:
- Short half-life of inflammatory mediators in vivo.
- Production and release of Transforming growth factor (TGF) beta from macrophages
- Production and release of Interleukin 10 (IL-10)
- Production of anti-inflammatory lipoxins
- Downregulation of pro-inflammatory molecules, such as leukotrienes.
- Upregulation of anti-inflammatory molecules such as the Interleukin 1 receptor antagonist or the soluble tumor necrosis factor receptor (TNFR)
- Apoptosis of pro-inflammatory cells
- Desensitization of receptors.
- Increased survival of cells in regions of inflammation due to their interaction with the extracellular matrix (ECM)
- Downregulation of receptor activity by high concentrations of ligands
- Cleavage of chemokines by matrix metalloproteinases (MMPs) might lead to production of anti-inflammatory factors.
- Production of resolvins, protectins or maresins.
|“||Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics.||”|
Connection to depression
There is evidence for a link between inflammation and depression. Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.[dubious ] In addition there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode". Classical symptoms of being physically sick like lethargy show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during depressive episodes in manics and drop off during remission. Furthermore it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment. Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.
An infectious organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, 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 vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
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. These proteins include C-reactive protein, serum amyloid A, and serum amyloid P, which cause a range of systemic effects including:
Inflammation often affects the numbers of leukocytes present in the body:
- Leukocytosis 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, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.
- Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.
Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
- IL-6 (Interleukin-6)
- IL-8 (Interleukin-8)
- IL-18 (Interleukin-18)
- TNF-α (Tumor necrosis factor-alpha)
- CRP (C-reactive protein)
- Blood glucose
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 cytokines. 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 and atherosclerosis is the subject of intense research.
In the obese mouse models, inflammation and macrophage-specific genes are upregulated in white adipose tissue (WAT). There were also signs of dramatic increase in circulating insulin level, adipocyte lipolysis and formation of multinucleate giant cells. The fat-derived protein called angiopoietin-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 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 (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 induces IL-6 production from endothelial cells and macrophages. Meals high in saturated fat, 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, the response may become chronic if the overeating is chronic.
Bente Klarlund Pedersen wrote in 2013 that interstitial abdominal adiposity (also referred to as accumulated intra-abdominal fat) is a major and possibly primary factor in increasing systemic risk for multiple inflammatory diseases. However, she indicates that this is mediated via TNF-α, rather than Interleukin 6, which she identified as a myokine in 2003. Dr. Pedersen concludes: "Until the beginning of this millennium, it was commonly thought that the increase in IL-6 during exercise was a consequence of an immune response due to local damage in the working muscles and it was hypothesized that macrophages were responsible for this increase. However, an early study demonstrated that IL-6 mRNA in monocytes did not increase as a result of exercise. Further work confirmed this finding at the protein level. In addition, the liver clears, rather than secretes, IL-6 during exercise. The finding that the nuclear transcription rate for IL-6 and the IL-6mRNA levels were rapidly and markedly increased after the onset of exercise suggested that a factor associated with contraction was responsible for the increase in IL-6 transcriptional rate within the nuclei from myocytes.... We recently reported that insulin-resistant individuals demonstrated IL-6 resistance. Accordingly, we suspect that muscle disuse may lead to IL-6 resistance. The elevated circulating levels of IL-6 that accompany obesity and physical inactivity may represent a compensatory mechanism. This would be in line with the well-known facts that insulin resistance is accompanied by hyperinsulinemia and that chronic high circulating levels of leptin may reflect leptin resistance."
Dr. Pedersen continues (in the same article): "Abdominal adiposity is associated with CVD, type 2 diabetes, dementia, colon cancer, and breast cancer, as well as all-cause mortality independently of body mass index, that is, also in people with a normal body weight. Thus, it appears that the health consequences of abdominal adiposity and physical inactivity are very similar. It is well known that both physical inactivity and abdominal adiposity are associated with persistent systemic low-grade inflammation. Models of lipodystrophy suggest that if the subcutaneous fat becomes inflamed and adipocytes undergo apoptosis/necrosis, the fat storing capacity is impaired and fat will, as a consequence, be deposited as ectopic fat. One obvious explanation to the differential outcome of accumulating fat subcutaneously or as ectopic fat could be that when fat is stored in “the wrong places,” it will stimulate an inflammatory response. Evidence exists that visceral fat is more inflamed than subcutaneous fat and constitutes an important source of systemic inflammation.... Accumulating data suggest that although TNF-α is not the pathogenetic factor, it plays a direct role in the metabolic syndrome. In short, patients with diabetes have a high protein expression of TNF-α in skeletal muscle and increased TNF-α levels in plasma, and it is likely that adipose tissue, which produces TNF-α, is the main source of the circulating TNF-α. In vitro studies demonstrate that TNF-α has direct inhibitory effects on insulin signaling. In addition, TNF-α infusion in healthy humans induces insulin resistance in skeletal muscle, without an effect on EGP. It has also been proposed that TNF-α causes insulin resistance indirectly in vivo by increasing the release of FFAs from adipose tissue. TNF-α increases lipolysis in human and 3T3-L1 adipocytes. However, TNF-α has no effect on muscle fatty acid oxidation, but increases fatty acid incorporation into diacylglycerol, which may be involved in the development of the TNF-α-induced insulin resistance in skeletal muscle. In addition, evidence suggests that TNF-α plays a direct role in linking insulin resistance to vascular disease. Moreover, in CVDs, activated immune cells also play major roles, particularly in the etiology of atherosclerosis. Importantly, also tumor initiation, promotion, and progression is stimulated by systemic elevation of proinflammatory cytokines."
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:
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 parenchymal cells regenerate. In situations where limited or short-lived inflammation has occurred this is usually the outcome.
Large amounts of tissue destruction, or damage in tissues unable to regenerate, cannot be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
- Abscess Formation
A cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
- 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 inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. As a consequence, chronic inflammation is almost always accompanied by tissue destruction.
Inflammation is usually indicated by adding the suffix "itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.
Exercise and inflammation
Exercise-induced acute inflammation
Acute inflammation of the muscle cells, as understood in exercise physiology, can result after induced eccentric and concentric muscle training. Participation in eccentric training and conditioning, including resistance training and activities that emphasize eccentric lengthening of the muscle 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 (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 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 transmission of force when muscle fibers are activated to shorten. However, in marathon runners and those who subscribe to the overload principle to enhance their muscles, show moderate Z-disk streaming and major disruption of thick and thin filaments in parallel groups of sarcomeres as a result of the force of eccentric actions or stretching of tightened muscle fibers.
This disruption of muscle fibers triggers white blood cells to increase following induced muscle soreness, leading to the inflammatory response observation from induced muscle soreness. Elevations in plasma enzymes, myoglobinemia, and abnormal muscle histology and ultrastructure are concluded to be associated with inflammatory response. 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 injured fibers and fiber bundles, resulting in necrosis that peaks about 48 hours after exercise. The products of macrophage activity and intracellular contents (such as histamines, kinins, and K+) accumulate outside cells. These substances then stimulate free nerve endings in the muscle; a process that appears accentuated by eccentric exercise, in which large forces are distributed over a relatively small cross-sectional area of the muscle.
Post-inflammatory muscle growth and repair
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), 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 (Interleukin 6), a myokine, 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 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 and in vivo. 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 (myokines) after resistance exercise coincides with the decrease in levels of myostatin, 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.
Developing research has demonstrated that many of the benefits of exercise are mediated through the role of skeletal muscle as an endocrine organ. That is, contracting muscles release multiple substances known as myokines, including but not limited to those cited in the above description, which promote the growth of new tissue, tissue repair, and various anti-inflammatory functions, which in turn reduce the risk of developing various inflammatory diseases. The new view that muscle is an endocrine organ is transforming our understanding of exercise physiology and with it, of the role of inflammation in adaptation to stress.
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. 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. Cytokines may antagonize the anabolic effects of Insulin-like growth factor 1 (IGF-1). In the case of sepsis, 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. Sepsis is also able to prevent leucine 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 training may help reduce chronic low-grade inflammation. On the other hand, levels of the anti-inflammatory myokine IL-6 (Interleukin 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.
Regarding the above, IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.
Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory.
Several studies show that markers of inflammation are reduced following longer-term behavioural changes involving both reduced energy intake and a regular program of increased physical activity, and that, in particular, IL-6 was miscast as an inflammatory marker. For example, the anti-inflammatory effects of IL-6 have been demonstrated by IL-6 stimulating the production of the classical anti-inflammatory cytokines IL-1ra and IL-10. As such, individuals pursuing exercise as a means to treat the causal factors underlying chronic inflammation are pursuing a course of action strongly supported by current research, as an inactive lifestyle is strongly associated with the development and progression of multiple inflammatory diseases. Note that cautions regarding over-exertion may apply in certain cases, as discussed above, though this concern rarely applies to the general population.
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.
Diet and chronic inflammation
|Please add medical references. (April 2014)|
In general pro-inflammatory foods are highly processed or refined and fall into groups of: 1. Foods from animals including meat and dairy, excepting cold water fish; 2. Foods high on the glycemic scale; 3. Foods containing little or no fiber; 4. Foods high in saturated, hydrogenated or damaged fats." Examples of anti-inflammatory diets include the Mediterranean diet.
These pro-inflammatory foods include:
- Processed oils
- Fatty meat and dairy including most beef, pork and whole milk.
- Trans fat
- Sugar, other sweeteners and foods with added sugar or syrup. (This is a long list)
- Flour containing gluten
- White rice
- omega-6 (ω-6) fatty acids (omega 3 and 9 fatty acids are anti-inflammatory)
- nightshades: potatoes, tomatoes, eggplant, peppers
- citrus fruits
|Wikimedia Commons has media related to Inflammation.|
- Essential fatty acid interactions
- Substance P
- Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE; Nielsen; Andersen; Girardin (February 2007). "Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation". Clin. Exp. Immunol. 147 (2): 061127015327006––. doi:10.1111/j.1365-2249.2006.03261.x. PMC 1810472. PMID 17223962.
- Abbas A.B.; Lichtman A.H. (2009). "Ch.2 Innate Immunity". In Saunders (Elsevier). Basic Immunology. Functions and disorders of the immune system (3rd ed.). ISBN 978-1-4160-4688-2.
- Stedman's Medical Dictionary (Twenty-fifth ed.). Williams & Wilkins. 1990.
- Rather, L. J. (1971). "Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus". Bull N Y Acad Med 47 (3): 303–322. PMC 1749862. PMID 5276838.
- Cotran; Kumar, Collins (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. ISBN 0-7216-7335-X.
- Parakrama Chandrasoma, Clive R. Taylor (c. 2005). "Part A. General Pathology, Section II. The Host Response to Injury, Chapter 3. The Acute Inflammatory Response, sub-section Cardinal Clinical Signs". Concise Pathology (3rd edition (Computer file) ed.). New York, N.Y.: McGraw-Hill. ISBN 0-8385-1499-5. OCLC 150148447. Retrieved 2008-11-05.
- A Massage Therapist Guide to Pathology Ruth Werner (2009). A massage Therapist Guide to Pathology (4th ed.). Philadelphia, PA and Baltimore, MD: Wolters Kluwer.
- Vogel, Wolfgang H.; Berke, Andreas (2009). Brief History of Vision and Ocular Medicine. Kugler Publications. p. 97. ISBN 90-6299-220-X.
- Porth, Carol (2007). Essentials of pahtophysiology: concepts of altered health states. Hagerstown, MD: Lippincott Williams & Wilkins. p. 270. ISBN 0-7817-7087-4.
- Dormandy, Thomas (2006). The worst of evils: man's fight against pain. New Haven, Conn: Yale University Press. p. 22. ISBN 0-300-11322-6.
- Libby, P (Dec 19–26, 2002). "Inflammation in atherosclerosis.". Nature 420 (6917): 868–74. doi:10.1161/hc0902.104353. PMID 12490960.
- Wiedermann U et al. (1996). "Vitamin A deficiency increases inflammatory responses". Scand J Immunol. 44 (6): 578–584. doi:10.1046/j.1365-3083.1996.d01-351.x. PMID 8972739.
- Hargrave, B. Y.; Tiangco, D. A.; Lattanzio, F. A.; Beebe, S. J. (2003). "Cocaine, not morphine, causes the generation of reactive oxygen species and activation of NF-κB in transiently cotransfected heart cells". Cardiovasc Toxicol 3 (2): 141–151. doi:10.1385/CT:3:2:141. PMID 14501032.
- Montiel-Duarte, C.; Ansorena, E.; López-Zabalza, M. J.; Cenarruzabeitia, E.; Iraburu, M. J. (2004). "Role of reactive oxygen species, glutathione and NF-κB in apoptosis induced by 3,4-methylenedioxymethamphetamine ("Ecstasy") on hepatic stellate cells". Biochem Pharmacol 67 (6): 1025–1033. doi:10.1016/j.bcp.2003.10.020. PMID 15006539.
- Hendrik Ungefroren; Susanne Sebens; Daniel Seidl; Hendrik Lehnert; Ralf Haas (2011). "Interaction of tumor cells with the microenvironment". Cell Communication and Signaling 9 (18). doi:10.1186/1478-811X-9-18.
- Coussens, L. M.; Werb, Z. (2002). "Inflammation and cancer". Nature 420 (6917): 860–867. Bibcode:2002Natur.420..860C. doi:10.1038/nature01322. PMC 2803035. PMID 12490959.
- Gunn, L; Ding, C; Liu, M; Ma, Y; Qi, C; Cai, Y; Hu, X; Aggarwal, D; Zhang, HG; Yan, J (Sep 15, 2012). "Opposing roles for complement component C5a in tumor progression and the tumor microenvironment.". Journal of immunology (Baltimore, Md. : 1950) 189 (6): 2985–94. doi:10.4049/jimmunol.1200846. PMID 22914051.
- Copland, JA; Sheffield-Moore, M; Koldzic-Zivanovic, N; Gentry, S; Lamprou, G; Tzortzatou-Stathopoulou, F; Zoumpourlis, V; Urban, RJ; Vlahopoulos, SA (Jun 2009). "Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?". BioEssays : news and reviews in molecular, cellular and developmental biology 31 (6): 629–41. doi:10.1002/bies.200800138. PMID 19382224.
- Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A; Allavena; Sica; Garlanda; Mantovani (July 2009). "Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability". Carcinogenesis (review) 30 (7): 1073–81. doi:10.1093/carcin/bgp127. PMID 19468060.
- Eming, S. A.; Krieg, T.; Davidson, J. M. (2007). "Inflammation in wound repair: molecular and cellular mechanisms". Journal of Investigative Dermatology 127 (3): 514–525. doi:10.1038/sj.jid.5700701. PMID 17299434.
- Ashcroft, G. S.; et al., Gillian S.; Yang, Xiao; Glick, Adam B.; Weinstein, Michael; Letterio, John J.; Mizel, Diane E.; Anzano, Mario; Greenwell-Wild, Teresa; Chuxia, Sharon M. (1999). "Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response". Nat Cell Biol 1 (5): 260–266. doi:10.1038/12971. PMID 10559937.
- Ashcroft, G. S. (1999). "Bidirectional regulation of macrophage function by TGF-β". Microbes Infect 1 (15): 1275–1282. doi:10.1016/S1286-4579(99)00257-9. PMID 10611755.
- Werner, F.; et al., MK; Feinberg, MW; Sibinga, NE; Pellacani, A; Wiesel, P; Chin, MT; Topper, JN et al. (2000). "Transforming growth factor-β1 inhibition of macrophage activation is mediated via Smad3". J Biol Chem 275 (47): 36653–36658. doi:10.1074/jbc.M004536200. PMID 10973958.
|last10=in Authors list (help)
- Sato, Y.; Ohshima, T.; Kondo, T. (1999). "Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing". Biochem Biophys Res Commun 265 (1): 194–199. doi:10.1006/bbrc.1999.1455. PMID 10548513.
- Serhan, C. N. (2008). "Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators". J Periodontol 79 (8 Suppl): 1520–1526. doi:10.1902/jop.2008.080231. PMID 18673006.
- Greenhalgh, D. G. (1998). "The role of apoptosis in wound healing". Int J Biochem Cell Biol 30 (9): 1019–1030. doi:10.1016/S1357-2725(98)00058-2. PMID 9785465.
- Jiang, D.; et al., Jiurong; Fan, Juan; Yu, Shuang; Chen, Suping; Luo, Yi; Prestwich, Glenn D; Mascarenhas, Marcella M et al. (2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan". Nat Med 11 (11): 1173–1179. doi:10.1038/nm1315. PMID 16244651.
|last10=in Authors list (help);
|last11=in Authors list (help);
|last12=in Authors list (help);
|last13=in Authors list (help);
|last14=in Authors list (help);
|last15=in Authors list (help);
|last16=in Authors list (help)
- Teder, P.; et al., RW; Jiang, D; Liang, J; Cohn, L; Puré, E; Henson, PM; Noble, PW (2002). "Resolution of lung inflammation by CD44". Science 296 (5565): 155–158. Bibcode:2002Sci...296..155T. doi:10.1126/science.1069659. PMID 11935029.
- McQuibban, G. A.; et al., JH; Tam, EM; McCulloch, CA; Clark-Lewis, I; Overall, CM (2000). "Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3". Science 289 (5482): 1202–1206. Bibcode:2000Sci...289.1202M. doi:10.1126/science.289.5482.1202. PMID 10947989.
- Serhan CN, Savill J; Savill (2005). "Resolution of inflammation: the beginning programs the end". Nat. Immunol. 6 (12): 1191–1197. doi:10.1038/ni1276. PMID 16369558.
- Michael Berk et al.. "So depression is an inflammatory disease, but where does the inflammation come from?" BMC Medicine 2013, 11:200. http://www.biomedcentral.com/1741-7015/11/200 accessed March 4, 2014 doi:10.1186/1741-7015-11-200
- Cox, William T. L.; Abramson, Lyn Y.; Devine, Patricia G.; Hollon, Steven D. (2012). "Stereotypes, Prejudice, and Depression: The Integrated Perspective". Perspectives on Psychological Science 7 (5): 427–449. doi:10.1177/1745691612455204.
- Kershaw, E. E.; Flier, J. S. (2004). "Adipose tissue as an endocrine organ". J Clin Endocrinol Metab 89 (6): 2548–2556. doi:10.1210/jc.2004-0395. PMID 15181022. Review.
- Bastard J et al. (2000). "Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss". J Clin Endocrinol Metab 85 (9): 3338–3342. doi:10.1210/jc.85.9.3338. PMID 10999830.
- Mohamed-Ali V et al. (2001). "beta-Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies". J Clin Endocrinol Metab 86 (12): 5864–5869. doi:10.1210/jc.86.12.5864. PMID 11739453.
- Loffreda, S.; et al., SQ; Lin, HZ; Karp, CL; Brengman, ML; Wang, DJ; Klein, AS; Bulkley, GB et al. (1998). "Leptin regulates proinflammatory immune responses". FASEB J 12 (1): 57–65. PMID 9438411.
|last10=in Authors list (help);
|last11=in Authors list (help);
|last12=in Authors list (help)
- Esposito, K.; et al., F; Marfella, R; Giugliano, G; Giugliano, F; Ciotola, M; Quagliaro, L; Ceriello, A; Giugliano, D (2002). "Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress". Circulation 106 (16): 2067–2072. doi:10.1161/01.CIR.0000034509.14906.AE. PMID 12379575.
- Petersen, A. M.; Pedersen, B. K. (2005). "The anti-inflammatory effect of exercise". J Appl Physiol 98 (4): 1154–1162. doi:10.1152/japplphysiol.00164.2004. PMID 15772055. Review.
- Rogowski, O.; et al., Itzhak; Bassat, Orit; Chundadze, Tamar; Finn, Talya; Berliner, Shlomo; Steinvil, Arie (2010). "Waist circumference as the predominant contributor to the micro-inflammatory response in the metabolic syndrome: a cross sectional study". Journal of Inflammation (London) 26 (7): 35. doi:10.1186/1476-9255-7-35. PMC 2919526. PMID 20659330.
- Mohamed-Ali, V.; et al., S; Rawesh, A; Katz, DR; Miles, JM; Yudkin, JS; Klein, S; Coppack, SW (1997). "Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo". Journal of Clinical Endocrinology & Metabolism 82 (12): 4196–4200. doi:10.1210/jc.82.12.4196. PMID 9398739.
- Clément K et al. (2004). "Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects". FASEB J 18 (14): 1657–1669. doi:10.1096/fj.04-2204com. PMID 15522911.
|last10=in Authors list (help);
|last11=in Authors list (help);
|last12=in Authors list (help);
|last13=in Authors list (help);
|last14=in Authors list (help);
|last15=in Authors list (help);
|last16=in Authors list (help);
|last17=in Authors list (help)
- M Stitzinger (2007). "Lipids, inflammation and atherosclerosis" (pdf). The digital repository of Leiden University. Retrieved 2007-11-02.
- Xu, H.; et al., Glenn T.; Yang, Qing; Tan, Guo; Yang, Daseng; Chou, Chieh J.; Sole, Jason; Nichols, Andrew et al. (2003). "Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance". J Clin Invest 112 (12): 1821–1830. doi:10.1172/JCI19451. PMC 296998. PMID 14679177.
|last10=in Authors list (help);
|last11=in Authors list (help)
- Shoelson, SE; Lee, J; Goldfine, AB (July 2006). "Inflammation and insulin resistance". The Journal of Clinical Investigation (Review) 116 (7): 1793–801. doi:10.1172/JCI29069. PMC 1483173. PMID 16823477.
- Blackburn, Patricia; Côté, Mélanie; Lamarche, Benoı̂t; Couillard, Charles; Pascot, Agnès; Tremblay, Angelo; Bergeron, Jean; Lemieux, Isabelle; Després, Jean-Pierre (1 November 2003). "Impact of postprandial variation in triglyceridemia on low-density lipoprotein particle size". Metabolism 52 (11): 1379–1386. doi:10.1016/S0026-0495(03)00315-9. PMID 14624394.
- van Dijk, S. J; Feskens, E. J.; Bos, M. B; Hoelen, D. W.; Heijligenberg, R.; Bromhaar, M. G.; de Groot, L. C.; de Vries, J. H.; Muller, M.; Afman, L. A (14 October 2009). "A saturated fatty acid-rich diet induces an obesity-linked proinflammatory gene expression profile in adipose tissue of subjects at risk of metabolic syndrome". American Journal of Clinical Nutrition 90 (6): 1656–1664. doi:10.3945/ajcn.2009.27792. PMID 19828712.
- Pedersen, BK; Steensberg, A; Fischer, C; Keller, C; Keller, P; Plomgaard, P; Febbraio, M; Saltin, B (2003). "Searching for the exercise factor: is IL-6 a candidate?". Journal of muscle research and cell motility (Review) 24 (2–3): 113–9. doi:10.1023/A:1026070911202. PMID 14609022.
- Pedersen, BK (Jul 2013). "Muscle as a secretory organ". Comprehensive Physiology 3 (3): 1337–62. doi:10.1002/cphy.c120033. ISBN 9780470650714. PMID 23897689.
- Wilmore, Jack (2008). Physiology of Sport and Exercise. Champaign, IL: Human Kinetics. pp. 26–36, 98–120, 186–250, 213–218. ISBN 978-0-7360-5583-3.
- Toth, M. J.; Matthews, DE; Tracy, RP; Previs, MJ (29 December 2004). "Age-related differences in skeletal muscle protein synthesis: relation to markers of immune activation". AJP: Endocrinology and Metabolism 288 (5): E883–E891. doi:10.1152/ajpendo.00353.2004. PMID 15613683.
- Mikkelsen, U. R.; Langberg, H.; Helmark, I. C.; Skovgaard, D.; Andersen, L. L.; Kjaer, M.; Mackey, A. L. (27 August 2009). "Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise". Journal of Applied Physiology 107 (5): 1600–1611. doi:10.1152/japplphysiol.00707.2009. PMC 3774508. PMID 19713429.
- Trappe, TA; White, F; Lambert, CP; Cesar, D; Hellerstein, M; Evans, WJ (March 2002). "Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis". American journal of physiology. Endocrinology and metabolism 282 (3): E551–6. doi:10.1152/ajpendo.00352.2001 (inactive 2015-01-14). PMID 11832356.
- Marimuthu, K.; Murton, A. J.; Greenhaff, P. L. (28 October 2010). "Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans". Journal of Applied Physiology 110 (2): 555–560. doi:10.1152/japplphysiol.00962.2010. PMID 21030670.
- Cannon, Joseph G.; St. Pierre, Barbara A. (1 January 1998). "Cytokines in exertion-induced skeletal muscle injury". Molecular and Cellular Biochemistry 179 (1/2): 159–168. doi:10.1023/A:1006828425418. PMID 9543358.
- Lang, Charles H.; Hong-Brown, Ly; Frost, Robert A. (10 November 2004). "Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance". Pediatric Nephrology 20 (3): 306–312. doi:10.1007/s00467-004-1607-9. PMID 15549417.
- Pedersen, BK; Toft, AD (August 2000). "Effects of exercise on lymphocytes and cytokines". British journal of sports medicine 34 (4): 246–51. doi:10.1136/bjsm.34.4.246. PMC 1724218. PMID 10953894.
- Bruunsgaard, H; Galbo, H; Halkjaer-Kristensen, J; Johansen, TL; MacLean, DA; Pedersen, BK (Mar 15, 1997). "Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage". The Journal of physiology 499 (Pt 3): 833–41. PMC 1159298. PMID 9130176.
- McKay, Bryon R.; De Lisio, Michael; Johnston, Adam P. W.; O'Reilly, Ciara E.; Phillips, Stuart M.; Tarnopolsky, Mark A.; Parise, Gianni; Hotchin, Neil; Johnston, Adam P. W.; O'Reilly, Ciara E.; Phillips, Stuart M.; Tarnopolsky, Mark A.; Parise, Gianni (23 June 2009). Hotchin, Neil, ed. "Association of Interleukin-6 Signalling with the Muscle Stem Cell Response Following Muscle-Lengthening Contractions in Humans". PLoS ONE 4 (6): e6027. Bibcode:2009PLoSO...4.6027M. doi:10.1371/journal.pone.0006027. PMC 2696599. PMID 19554087.
- MacIntyre, Donna L.; Sorichter, Stephan; Mair, Johannes; McKenzie, Donald C.; Berg, Aloys (11 March 2001). "Markers of inflammation and myofibrillar proteins following eccentric exercise in humans". European Journal of Applied Physiology 84 (3): 180–186. doi:10.1007/s004210170002. PMID 11320633.
- Louis, E; Raue, U; Yang, Y; Jemiolo, B; Trappe, S (Nov 2007). "Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle.". Journal of applied physiology (Bethesda, Md. : 1985) 103 (5): 1744–51. doi:10.1152/japplphysiol.00679.2007. PMID 17823296.
- Serrano, AL; Baeza-Raja, B; Perdiguero, E; Jardí, M; Muñoz-Cánoves, P (Jan 2008). "Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy.". Cell metabolism 7 (1): 33–44. doi:10.1016/j.cmet.2007.11.011. PMID 18177723.
- Grounds, MD; White, JD; Rosenthal, N; Bogoyevitch, MA (May 2002). "The role of stem cells in skeletal and cardiac muscle repair.". The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 50 (5): 589–610. doi:10.1177/002215540205000501. PMID 11967271.
- Hawke, TJ; Garry, DJ (Aug 2001). "Myogenic satellite cells: physiology to molecular biology.". Journal of applied physiology (Bethesda, Md. : 1985) 91 (2): 534–51. PMID 11457764.
- Hawke, TJ (Apr 2005). "Muscle stem cells and exercise training.". Exercise and sport sciences reviews 33 (2): 63–8. doi:10.1097/00003677-200504000-00002. PMID 15821426.
- Kadi, F; Eriksson, A; Holmner, S; Butler-Browne, GS; Thornell, LE (Mar 1999). "Cellular adaptation of the trapezius muscle in strength-trained athletes.". Histochemistry and cell biology 111 (3): 189–95. doi:10.1007/s004180050348. PMID 10094415.
- Eriksson, A; Kadi, F; Malm, C; Thornell, LE (Aug 2005). "Skeletal muscle morphology in power-lifters with and without anabolic steroids.". Histochemistry and cell biology 124 (2): 167–75. doi:10.1007/s00418-005-0029-5. PMID 16059740.
- Mikkelsen, UR; Schjerling, P; Helmark, IC; Reitelseder, S; Holm, L; Skovgaard, D; Langberg, H; Kjaer, M; Heinemeier, KM (Oct 2011). "Local NSAID infusion does not affect protein synthesis and gene expression in human muscle after eccentric exercise". Scandinavian journal of medicine & science in sports 21 (5): 630–44. doi:10.1111/j.1600-0838.2010.01170.x. PMID 20738823.
- Visser, M; Pahor, M; Taaffe, DR; Goodpaster, BH; Simonsick, EM; Newman, AB; Nevitt, M; Harris, TB (May 2002). "Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study.". The journals of gerontology. Series A, Biological sciences and medical sciences 57 (5): M326–32. doi:10.1093/gerona/57.5.M326. PMID 11983728.
- Reardon, KA; Davis, J; Kapsa, RM; Choong, P; Byrne, E (Jul 2001). "Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy.". Muscle & nerve 24 (7): 893–9. doi:10.1002/mus.1086. PMID 11410916.
- Shih, Michael. "Skeletal Muscle Hypertrophy Is Regulated via AKT/mTOR Pathway." BioCarta. Web. 21 March 2011. .
- Lang, CH; Frost, RA (Jan 2007). "Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor alpha.". Metabolism: clinical and experimental 56 (1): 49–57. doi:10.1016/j.metabol.2006.08.025. PMID 17161226.
- García-Martínez, C; López-Soriano, FJ; Argilés, JM (Aug 11, 1993). "Acute treatment with tumour necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle.". Molecular and cellular biochemistry 125 (1): 11–8. doi:10.1007/BF00926829. PMID 8264567.
- Janssen, SP; Gayan-Ramirez, G; Van den Bergh, A; Herijgers, P; Maes, K; Verbeken, E; Decramer, M (Mar 1, 2005). "Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats". Circulation 111 (8): 996–1005. doi:10.1161/01.CIR.0000156469.96135.0D. PMID 15710765.
- Lang, CH; Frost, RA; Vary, TC (Aug 2007). "Regulation of muscle protein synthesis during sepsis and inflammation.". American journal of physiology. Endocrinology and metabolism 293 (2): E453–9. doi:10.1152/ajpendo.00204.2007. PMID 17505052.
- Jurasinski, CV; Vary, TC (Nov 1995). "Insulin-like growth factor I accelerates protein synthesis in skeletal muscle during sepsis.". The American journal of physiology 269 (5 Pt 1): E977–81. PMID 7491951.
- Vary, TC; Kimball, SR (Feb 1992). "Regulation of hepatic protein synthesis in chronic inflammation and sepsis.". The American journal of physiology 262 (2 Pt 1): C445–52. PMID 1371643.
- Lang, CH; Frost, RA; Bronson, SK; Lynch, CJ; Vary, TC (Jun 2010). "Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine.". American journal of physiology. Endocrinology and metabolism 298 (6): E1283–94. doi:10.1152/ajpendo.00676.2009. PMC 2886531. PMID 20388826.
- Smith, JK; Dykes, R; Douglas, JE; Krishnaswamy, G; Berk, S (May 12, 1999). "Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease.". JAMA: the Journal of the American Medical Association 281 (18): 1722–7. doi:10.1001/jama.281.18.1722. PMID 10328073.
- McFarlin, BK; Flynn, MG; Phillips, MD; Stewart, LK; Timmerman, KL (Oct 2005). "Chronic resistance exercise training improves natural killer cell activity in older women.". The journals of gerontology. Series A, Biological sciences and medical sciences 60 (10): 1315–8. doi:10.1093/gerona/60.10.1315. PMID 16282566.
- Stewart, LK; Flynn, MG; Campbell, WW; Craig, BA; Robinson, JP; McFarlin, BK; Timmerman, KL; Coen, PM; Felker, J; Talbert, E (Sep 2005). "Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4.". Brain, behavior, and immunity 19 (5): 389–97. doi:10.1016/j.bbi.2005.04.003. PMID 15963685.
- Gleeson, M (Nov 2006). "Immune system adaptation in elite athletes.". Current opinion in clinical nutrition and metabolic care 9 (6): 659–65. doi:10.1097/01.mco.0000247476.02650.18. PMID 17053416.
- Pedersen, BK; Hoffman-Goetz, L (Jul 2000). "Exercise and the immune system: regulation, integration, and adaptation.". Physiological reviews 80 (3): 1055–81. PMID 10893431.
- Ploeger, HE; Takken, T; de Greef, MH; Timmons, BW; De Greef, M. H.; Timmons, B. W. (2009). "The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review". Exercise immunology review 15: 6–41. PMID 19957870.
- Nicklas, BJ; Hsu, FC; Brinkley, TJ; Church, T; Goodpaster, BH; Kritchevsky, SB; Pahor, M (Nov 2008). "Exercise training and plasma C-reactive protein and interleukin-6 in elderly people.". Journal of the American Geriatrics Society 56 (11): 2045–52. doi:10.1111/j.1532-5415.2008.01994.x. PMC 2683336. PMID 19016938.
- Timmerman, KL; Flynn, MG; Coen, PM; Markofski, MM; Pence, BD (Nov 2008). "Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise?". Journal of leukocyte biology 84 (5): 1271–8. doi:10.1189/jlb.0408244. PMID 18664531.
- Mackinnon LT. Chronic exercise training effects on immune function. Med Sci Sports Exerc. 2000 Jul;32 (7 Suppl):S369-76. Review.
- Suzuki, Katsuhiko; Nakaji, Shigeyuki; Yamada, Mutsuo; Liu, Qiang; Kurakake, Shigeyoshi; Okamura, Noriyoshi; Kumae, Takashi; Umeda, Takashi; Sugawara, Kazuo (February 2003). "Impact of a competitive marathon race on systemic cytokine and neutrophil responses". Medicine and science in sports and exercise 35 (2): 348–55. doi:10.1249/01.MSS.0000048861.57899.04. PMID 12569227.
- Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK; Galbo; Halkjaer-Kristensen; Johansen; MacLean; Pedersen (March 1997). "Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage". J. Physiol. (Lond.) 499 (Pt 3): 833–41. PMC 1159298. PMID 9130176.
- Pedersen BK (July 2013). "Muscle as a secretory organ". Compr Physiol 3 (3): 1337–62. doi:10.1002/cphy.c120033. ISBN 9780470650714. PMID 23897689.
- Brandt, C; Pedersen, BK (2010). "The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases.". Journal of biomedicine & biotechnology 2010: 520258. doi:10.1155/2010/520258. PMC 2836182. PMID 20224659.
- Pilon, Brad. "Inflammation Affects Your Ability to Build Muscle." Inflammation Theory | Inflammation, Chronic Inflammation, Muscle Building, Health. Web. 27 Mar. 2011. <http://www.inflammationtheory.com/#2>.
- Lisa Bryant, "What is the Anti-Inflammatory Diet and How Can it Treat Diabetes, Relieve Arthritis and Prevent Cancer?" lisabryant.hubpages.com/hub/What-is-the-Anti-Inflammatory-Diet-and-How-Can-it-Treat-Diabetes--Relieve-Arthritis-and-Prevent-Cancer referencing Zwickey, Heather, Heather Schiffke, Katie McNamee, and Patricia Elmer. "Anti-Inflammatory Diet Study." A current research project by Helfgott Research Institute. 2007.