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Overview of Inflammation

Inflammation gets rid of damaged or necrotic tissues and foreign invaders such as microbes. This is a fundamentally protective response.

It rids the organism of:

  • the initial cause of cell injury (e.g. microbes, toxins)
  • the consequences of such injury (e.g. necrotic cells and tissues).

Without inflammation, infections would go unchecked, wounds would never heal and injured tissues would remain permanent festering sores.

Inflammation can sometimes be inappropriately triggered or poorly controlled. This causes tissue injury in many disorders.

It is a complex reaction in tissues and results in mainly responses of blood and leucocytes. The main defenders are:

  • plasma proteins
  • circulating leucocytes
  • tissue phagocytes (originating from the circulating leucocytes) ).

The circulatory system gives proteins and leucocytes omnipotence. Invaders (microbes, necrotic cells) are typically in the tissues. So our defenders (above) must be recruited to extravascular sites. The inflammatory response achieves this (by coordinating responses in vessels, leucocytes and plasma proteins).

Soluble mediators produced by cells or derived from plasma proteins trigger the vascular and cellular reactions in inflammation. They are generated/activated in response to the inflammatory stimulus. They determine the pattern, severity and clinical and pathological manifestations of inflammation.

Inflammatory stimuli that trigger these mediators include:

  • microbes
  • necrotic cells (irrespective of cause of cell death)
  • hypoxia.

Inflammation can be acute or chronic, based on the nature of the stimulus and the effectiveness of the initial reaction in eliminating the stimulus.

Acute inflammation has a rapid onset (~minutes) and short duration (hours to days).

Characteristics

  • exudation of fluid and plasma proteins (oedema)
  • emigration of leucocytes (mainly neutrophils aka PMNs).

Possible Outcomes

  • success in eliminating the offenders; the reaction subsides.
  • failure in eliminating the offenders; progression to chronic phase.


Chronic inflammation may follow acute inflammation or be insidious in onset.

It is of longer duration than acute inflammation.

It is characterised by:

  • the presence of lymphocytes and macrophages
  • the proliferation of blood vessels (angiogenesis)
  • fibrosis
  • tissue destruction

Our bodies “mop up” the inflammatory response. Inflammation is terminated when the offending agent is eliminated. The reaction resolves rapidly. The mediators are broken down/dissipated and the leucocytes have short life spans in tissues. Anti-inflammatory mechanisms are activated that control the response and prevent it from causing damage to the host.

Inflammation is associated with repair. While inflammation destroys, dilutes and walls off the injurious agent, it initiates the healing process. Repair begins during inflammation. Repair usually completes after the injurious influence has been neutralised.

Repair involves fixing the injured tissue, either by regeneration of the parenchymal cells, filling the defect with fibrous tissue (scarring) or, most commonly both.

Inflammation can be harmful in some situations. When inflammation is not correctly controlled or is directed at self tissues (“friendly fire”), the result is injury/disease. E.g. rheumatoid arthritis, atherosclerosis, lung fibrosis and allergic reactions. Hence anti-inflammatory drugs.

Inflammation may contribute to a variety of diseases that are not thought to be primarily due to abnormal host responses. E.g. atherosclerosis, type 2 diabetes, Alzheimer disease and cancer.

Cardinal signs of inflammation

  1. Redness
  2. Swelling
  3. Heat
  4. Pain
  5. Loss of function.

Acute inflammation

Acute inflammation is a rapid host response that delivers leucocytes and plasma proteins (e.g. antibodies) to sites of infection or tissue injury. The whole point is to bring leucocytes and proteins to the site of injury.

Three major components:

  1. alterations in vascular calibre that cause an increase in bloodflow
  2. structural changes in the microvasculature that permit plasma proteins and leucocytes to leave the circulation
  3. emigration of leucocytes from the microcirculation, their accumulation in the focus of injury and their activation to eliminate the offending agent.

In summary, we have:

  • wider vessels
  • leaky vessels
  • leucocyte chemotaxis and phagocytosis.

The local manifestations of acute inflammation are:

  • vascular dilation and increased blood flow (causing redness [erythema] and warmth)
  • leakage of plasma proteins (causing oedema)
  • neutrophil emigration

Stimuli for acute inflammation

Acute inflammation can be caused by any cause of cellular injury in a vascularised tissue. This includes:

  • Chemical
  • Hypoxia
  • Infectious (bacterial, viral, fungal, parasitic). Microbial toxins. Toll-like receptors (TLRs) and cytoplasmic receptors can detect the presence of microbes, triggering signalling pathways that stimulate the production of mediators.
  • Nutritional
  • Physical
  • Immunological. The immune system may damage the individual’s own tissues (autoimmunity or allergic reactions due to hypersensitivity). Autoimmune diseases are persistent, difficult to cure and likely to progress to chronicity because the stimuli (self tissues) cannot be removed. The inflammation is induced by cytokines produced by leucocytes (hence “immune-mediated inflammatory disease”).
  • Genetic

and:

Tissue necrosis from any cause (CHINPIG) releases chemicals (uric acid, ATP, a DNA-binding protein called HMGB-1 and DNA). This response is mediated largely by a protein called HIF-1 alpha (hypoxia-induced factor – 1 alpha), which is produced by cells deprived of oxygen and activates the transcription of many genes involved in inflammation (including vascular endothelial growth factor – VEGF. This increases vascular permeability). Foreign bodies (splinters, dirt, sutures) usually cause inflammation because they cause traumatic tissue injury or carry microbes.

All inflammatory reactions share the same basic features, though different stimuli may induce reactions with some distinctive characteristics.

Reactions of blood vessels in acute inflammation

Changes to blood vessels in inflammation allow for maximal movement of plasma proteins and leucocytes out of circulation and into the tissue of infection/injury.


Hallmarks of inflammation include vasodilation of microvasculature (i.e. capillaries, arterioles, venules) and increased permeability (allows exudate and leucocytes to enter inflamed tissue).

Exudation is the escape of fluid, proteins and blood cells from the vascular system into the interstitial fluid.

Benefits of exudation:

  1. Dilution of irritant
  2. Extravasation of plasma proteins
    • Immunoglobulins (= antibodies)
    • Complement (part of the innate immune system)
    • Coagulation proteins including fibrinogen. When exuded, fibrinogen gets converted to fibrin by cascade. Fibrin (a sticky, high-molecular weight protein) walls off irritants, preventing dissemination.
  3. Nutrition for tissue cells and leucocytes (there is glucose etc in exudate)

Deleterious effects of exudate:

  1. Swelling of tissues
    • Pain due to stretching of tissue
    • Glottis – compromises airway
    • Bone – fixed compartment – exudation leads to high tissue pressure and subsequent ischaemia (by compression of blood vessels)
    • Meninges – fixed cranial compartment – exudation leads to raised intracranial pressure. Meningitis = inflammation of the meninges. Fatal consequences e.g. herniating brain through base of the skull.
  2. Microbe may be spread by exudate (surfing on exudate)
  3. Stasis and endothelial injury may lead to thrombosis and ischaemia. [impaired bloodflow]

Exudate is an extravascular fluid that has high protein concentration, contains cellular debris and has a high specific gravity. Its presence implies inflammation (as there is an increase in the normal permeability of small blood vessels in an area of injury).

Different types of exudate: Morphology (appearance) of exudate depends upon:

  1. Nature and dose of the irritant e.g. pyogenic (N-formylated attracts neutrophils)
  2. The organ or tissue involved e.g. pericardium = fibrinous
  3. Nature of the host response e.g. Viral = Lymphocytes. Parasite = Eosinophils. Bacteria = Neutrophils [VLPEBN]

Examples:

  • Serous (thin, watery e.g. runny nose)
  • Mucous (rich in protein)
  • Fibrinous (Pericardium has more leaky endothelium, therefore more likely to haemorrhage and to have fibrinous exudate)
  • Purulent / Suppurative (full of pus)
  • Pseudomembranous (tenacious pseudomembrane)
  • Ulcerative (lose epithelial lining)
  • Haemorrhagic (severe = necrosis of endothelium)

Transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity. It is an ultrafiltrate of blood plasma. It results from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability.

Oedema is an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate.

Pus is a purulent exudate. It is an inflammatory exudate rich in 1) leucocytes (mostly neutrophils), 2) the debris of dead cells and (often) 3) microbes.

Angiogenesis is the proliferation of blood vessels. It is prominent during repair and in chronic inflammation.

  1. Changes in vascular flow and calibre
    • Vasodilation of arterioles, followed by opening of new capillary beds in the area. Results in increased blood flow, causing heat and redness (erythema). Vasodilation is induced by several mediators (notably histamine and NO) on vascular smooth muscle.
    • Increased permeability of the microvasculature quickly follows vasodilation. This occurs primarily in the venules (histamine receptors lie only on venules), as a result of histamine-induced contraction by endothelial cells, opening the gaps in between them. It results in protein-rich fluid (proteinaceous exudate) leaking into the vascular tissues (see below). With severe irritants (e.g. burns), endothelial cells may be directly injured (apoptosis, necrosis). This results in very large proteins leaving, or possibly even rbcs (haemorrhage).
    • Slower blood flow caused by the loss of fluid and increased vessel diameter. There is also concentration of red cells in small vessels and increased viscosity of the blood. This causes stasis: small vessels be packed with slowly-moving red blood cells. Vascular congestion produces localised redness.
    • Blood leucocytes (mainly neutrophils) accumulate along the vascular endothelium as stasis develops. Mediators produced at the site of infection stimulate endothelial cells to express increased levels of adhesion molecules (they become sticky). Leucocytes then stick to the endothelium and soon afterward migrate through the vascular wall and into the interstitial tissue.
  2. Increased vascular permeability (vascular leakage)
    • Escape of proteinaceous exudate into the extravascular tissue, causing oedema.
    • Contraction of endothelial cells resulting in increased endothelial spaces is the most common mechanism of vascular leakage. Caused by histamine, bradykinin, leucotrienes, the neuropeptide substance P, and other chemical mediators. Called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15-30 minutes).

      Delayed prolonged leakage is caused by mild injury (burns, x- or uv-radiation, exposure to some bacterial toxins), and vascular leakage begins after a delay of 2 to 12 hours and lasts for hours to days. May be caused by contraction of endothelial cells or mild endothelial damage.

    • Endothelial injury, resulting in endothelial cell necrosis and detachment. Severe injuries (eg burns or microbes that target endothelium) cause direct damage to endothelial cells. (Neutrophils that adhere to endothelium during inflammation may also injure the endothelial cells and amplify the reaction). Leakage starts immediately after injury and continues for several hours until the damaged vessels are thrombosed or repaired.
    • Transcytosis. This is increased transport of fluid and proteins through the endothelial cell. This may involve channels consisting of the vesiculo-vacuolar organelle (interconnected, uncoated vesicles located close to intercellular junctions). VEGF promotes vascular leakage by increasing the number and size of these channels.

      In summary, mechanisms for increased vascular permeability include:

    • Retraction of endothelial cells
      • Occurs mainly in venules
      • Induced by histamine, NO, other mediators
      • Rapid and short-lived (minutes)
    • Endothelial injury
      • Occurs in arterioles, capillaries, venules
      • Caused by burns, some microbial toxins
      • Rapid; may be long-lived (hours to days)
    • Leucocyte-mediated vascular injury
      • Occurs in venules, pulmonary capillaries
      • Associated with late stages of inflammation
      • Long-lived (hours)
    • Increased transcytosis
      • Occurs in venules
      • Induced by VEGF
  3. Responses of lymphatic vessels:
    • Lymphatics and lymph nodes filter and police extravascular fluids.
    • Lymphatics normally drain the small amount of extravascular fluid that seeps out of capillaries.
    • Inflammation increases lymph flow to drain oedema fluid that accumulates due to increased vascular permeability.
    • Lymphatic vessels proliferate in inflammation to handle the load.
    • The lymph vessels are thin and delicate. Fibrils tether lymph vessels to surrounding tissue, maintaining patency (keeping them open). #*They have discontinuous epithelium to allow free passage of leucocytes. When the tissues inflame, there is more tension on fibrin proteins, opening the lymph vessels. They drain away:
      • Fluid
      • Plasma proteins
      • Necrotic debris
      • Leucocytes (that may return antigens to the lymph nodes, allowing the production of a specific response)
      • Bacteria (a downside – may spread microbes)
    • By draining inflammatory exudate etc from tissues, they return it to tissues.
    • Lymph fluid may contain leucocytes, cell debris and microbes.
    • Lymphangitis is when the lymph vessels become secondarily inflamed.
    • Lymphadenitis is when the draining lymph nodes become secondarily inflamed. Inflamed lymph nodes are often enlarged due to hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This is called reactive or inflammatory, lymphadenitis.
    • Red streaks near a skin wound indicate that it is infected. The streaks follow the lymph vessels indicating lymphangitis. Accompanying painful enlargement of the draining lymph nodes indicates lymphadenitis.

Reactions of leucocytes to inflammation

The main point of inflammation is to bring leucocytes to the site of injury to destroy the infective agent. Neutrophils and macrophages are the most important leucocytes in (typical) inflammation as they are capable of phagocytosis.

Benefits of leucocyte activity: They ingest and kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. Leucocytes also produce growth factors that aid in repair.

Deleterious aspects of leucocyte activity: When strongly activated, they may induce tissue damage and prolong inflammation. (Their products can also injure host tissues).

Processes involving leucocytes in inflammation:

  1. Recruitment of leucocytes to sites of infection and injury. Extravasation is the movement of leukocytes out of the circulatory system, towards the site of tissue damage or infection. Steps in extravasation include:
    • In the lumen:
      • Margination. In normal flowing blood in venules, rbcs and leucocytes are confined to a central axial column. Surrounding the central axial column is a sheath of flowing plasma. Early in inflammation, the venule dilates and the walls become leaky, so the exudate leaves and slows blood flow (stasis). Wall shear stress decreases, so leucocytes move to the periphery of the vessel. This leucocyte redistribution is called margination. Rbcs stack up on top of each other (rouleax formation).
      • Rolling. More and more leucocytes move to the periphery. They adhere transiently to the endothelium, detach and bind again. (Weakly adherent).
      • Adhesion to endothelium. In inflammation, the endothelium is activated and can bind leucocytes to help them exit the blood vessels.The leucocytes eventually com to rest at some point where they adhere firmly.
      • Migration across the endothelium and vessel wall.
      • Migration in the tissues (up a chemical gradient) toward a chemotactic stimulus.
    • Cytokine considerations:

      There are complementary adhesion types on the leucocyte and the endothelial cells (of the venule wall). Their adhesiveness is governed by cytokines, secreted by cells in tissues in response to inflammatory stimuli, ensuring that leucocytes are recruited to the injured area.

      • Selectins mediate the initial rolling interactions. There are three types of selectins: E-selectin on endothelium; L-selectin on leucocytes; and P-selectin on platelets and endothelium.

        The ligands for selectins are sialylated oligosaccharides bound to mucin-like glycoprotein backbones. The expression of selectins and their ligands is mediated by cytokines produced due to inflammatory stimuli. The relevant cytokines are TNF (tumour necrosis factor), IL-1 (interleukin-1) and chemokines (chemoattractant cytokines). These are secreted by tissue macrophages, mast cells and endothelial cells in the presence of microbes or necrotic tissue.

        TNF and IL-1 stimulate endothelial cells of venules near the infection. In 1-2 hours the endothelial cells express E-selectin and the ligand for L-selectin. Histamine, thrombin and PAF (platelet activating factor) stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (Weibel-Palade bodies) to the cell surface.

        Leucocytes express L-selectin at the tips of their microvilli and also express ligands for E- and P-selectins. Thus the leucocyte clings like Velcro.

        These are low-affinity interactions, easily disrupted by flowing blood. The leucocytes bind, detach, bind, detach etc and start to roll and slow down.

      • Integrins: Firm adhesion is mediated by Integrins. TNF and IL-1 cause endothelial cells to express ligands for integrins: VCAM-1 (vascular cell adhesion molecule 1, the ligand for the VLA-4 integrin) and ICAM-1 (intercellular adhesion molecule-1, the ligand for the LFA-1 and Mac-1 integrins). Leucocytes normally express integrins in a low-affinity state. Chemokines from the injury site enter the blood vessel and bind to the endothelial surface. They bind to the rolling leucocyte and convert VLA-4 and LFA-1 to high-affinity forms.

        Thus the integrins bind with their ligands and the leucocytes come to a halt. Their cytoskeletons reorganise and they spread out on the endothelial surface.

    • Leucocyte migration through endothelium. Diapedesis (or transmigration) is the process of migration of leucocytes through the endothelium. It occurs mainly in post-capillary venules. Chemokines stimulate the leucocytes stuck to the endothelial wall to migrate through the spaces between the endothelial cells and follow the chemical concentration gradient. Molecules in the intercellular junctions between endothelial cells are involved. These include PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 and others. After going through the endothelium, leucocytes pierce the basement membrane, probably by secreting collagenases, and enter extravascular tissue. Leucocytes then migrate toward the chemotactic gradient and accumulate in the extravascular site. Integrins and CD44 bind to matrix proteins in the connective tissue so leucocytes adhere to the extracellular matrix. Thus the leucocytes remain at the site where they’re needed.
    • Chemotaxis of leucocytes. After exiting the circulation, leucocytes emigrate in tissues to the injury site by chemotaxis (locomotion oriented along a chemical gradient). Common exogenous chemoattractants include bacterial products, including peptides that possess an N-formylmethionine terminal amino acid, and some lipids. Common endogenous chemoattractants:
      • cytokines e.g. IL-8,
      • components of the complement system (particularly C5a)
      • arachidonic acid (AA) metabolites, mainly leucotriene B4 (LTB4).
      • lysosomal enzymes from neutrophils
    • Mechanism of chemotaxis:
      • These chemoattractants bind to specific seven-transmembrane G protein-coupled receptors on the surface of leucocytes. Signals initiated from these receptors activate messengers that increase cytosolic calcium and activate guanosine triphosphatases of the Rac/Rho/cdc42 family and kinases. This stimulates actin polymerisation, so more actin is at the leading edge of the cell and myosin localises at the back. The leucocyte extends filopodia that pull the back of the cell in the direction of extension. Hence leucocytes move to chemoattractant stimulus (and to the site of injury).
    • Neutrophils dominate in the inflammatory infiltrate during the first 6-24 hours in acute inflammation, and monocytes dominate between 24-48 hours.
      • Reasons:
        • neutrophils are more numerous in the blood
        • they respond more rapidly to chemokines
        • they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells (eg P and E selectins)
        • after entering tissues, neutrophils are short lived (apoptosis after 24-48 hours)
        • monocytes survive longer
        • monocytes proliferate in the tissues so become the dominant population in chronic inflammation
      • Exceptions:
        • Pseudomonas bacteria – neutrophils are continuously recruited for several days
        • Viral infections – lymphocytes may arrive first
        • Hypersensitivity reactions – eusoinophils may arrive first
    • Blockers of TNF (major leucocyte recruitment cytokine) successful therapeutics for chronic inflammatory disease. Antagonists of integrins (eg VLA-4), selectins and chemokines are good against inflammatory diseases. Ideally: don’t block physiological benefit of inflammation.
  2. Recognition of microbes and necrotic tissues
    • Once leucocytes are at the site of injury, they need to perform their function: recognition of the offending agents, which deliver signals that then activate the leucocytes to ingest and destroy the offending agents and amplify the inflammatory reaction.
      • Leucocytes have several receptors that recognise external stimuli and deliver activating signals:
        • Receptors for microbial products: Toll-like receptors (TLRs). Recognise components of different types of microbes. On cell surface and in endosomal vesicles of leucocytes (and other cell types) so are able to sense products of extracellular and ingested microbes. They stimulate the production of microbial substances and cytokines by leucocytes.
        • G protein-coupled receptors: found on neutrophils, macrophages and most other leucocytes. Recognise bacterial peptides containing N-formylmethionyl residues (few mammalian proteins are initiated by N-formylmethionine).
        • Other G protein-coupled receptors recognise things produced in response to microbes and cell injury. E.g. chemokines, breakdown products of C5a, platelet activating factor (PAF), prostaglandins and leucotrienes. These bind to receptors on leucocytes ==> migration of cells from blood and production of microbial substances.
        • Receptors for opsonins. Opsonisation is the process of coating an antigen (e.g. a microbe) to target it for ingestion (phagocytosis). Opsonins form this coating. Examples of opsonins are antibodies, components of the complement system (C3b, C4b, iC3b) and lectins.
        • Receptors for cytokines. Leucocytes have receptors for cytokines that are produced in response to microbes (e.g. IFN-gamma, which activates macrophages. Secreted by NKT cells and activated T cells).
  3. Removal of the offending agent
    • Leucocyte activation is a series of responses (mentioned above) to recognition of microbes and necrotic tissue.
    • Various biochemical changes (details p53) result in:
      • Phagocytosis:
        • Recognition and attachment, particularly of particles coated in opsonins (which make it more 'tasty' to leucocytes). The particle is bound to phagocyte receptors.
        • Engulfment into a phagosome (pinched off cell membrane around the particle). The phagosome then fuses with lysosomes that digest it.
        • Killing and degradation
        • Microbial killing is accomplished largely by reactive oxygen species (ROS), reactive nitrogen species (mainly from NO) and enzymes. Ingested material is broken down in the phagolysosome.

Other Functional Responses of Activated Leucocytes:

  • Release growth factors (particularly macrophages) that drive repair. They stimulate proliferation of endothelial cells and fibroblasts and the synthesis of collagen and enzymes that remodel connective tissue.
  • Some macrophages are activated by IFN-gamma and have strong microbicidal activity
  • Other macrophages respond to IL-4 and IL-13 and are mainly involved in tissue repair and fibrosis.
  • Different stimuli activate leucocytes to secrete mediators of inflammation as well as inhibitors of the inflammatory response (hence they both amplify and control the reaction).
  • Classically activated macrophages – 1) microbicidal actions: phagocytosis and killing of bacteria and fungi 2) pathological inflammation
  • Alternatively activated macrophages – 1) Anti-inflammatory 2)Wound repair, fibrosis.


Leucocyte-mediated tissue injury

Leucocytes can cause tissue injury in several situations:

  • Chronic diseases such as tuberculosis and some viral diseases – prolonged host response causes “collateral damage” and contributes more to pathology than does the microbe itself
  • Autoimmune diseases (inflammatory response directed at self)
  • Allergic diseases – overreaction against harmless substances (e.g. asthma)

Leucocytes cause injury via the same mechanisms they use to kill microbes. Once leucocytes are activated, their effector mechanisms do not distinguish between offender and host.

Activated macrophages and neutrophils release microbicides into both the phagolysosomes and the extracellular space. These include: 1) lysosomal enzymes 2) reactive oxygen and nitrogen species. These can damage cells and vascular endothelium.

Leucocyte-dependent tissue injury underlies many acute and chronic human diseases.

If phagocytes encounter materials that they can’t ingest (eg immune complexes deposited on immovable flat surfaces), the inability of the leucocytes to surround and ingest these substances (frustrated phagocytosis) triggers them to release large amounts of lysosomal enzymes into the extracellular environment. [Phagocytosis of some substances damages membranes (e.g. urate crystals), injuring the membrane and releasing lysosome contents].

Sentinel cells are cells that are resident in tissues which serve important functions in initiating acute inflammation. Sentinel cells = {mast cells, macrophages}. They are stationed in tissues and rapidly recognise injurious stimuli and initiate the host defense reaction. Mast cells react to CHINPIG and release histamine, leukotrienes, enzymes and many cytokines that contribute to inflammation (including TNF, IL-1 and chemokines). Macrophages recognise microbial products and secrete most of the cytokines important in acute inflammation.

DISORDERS (where the host response plays a significant role in tissue injury) CELLS AND MOLECULES INVOLVED IN INJURY
Acute
Acute respiratory distress syndrome Neutrophils
Acute transplant rejection Lymphocytes; antibodies and complement
Asthma Eosinophils; IgE antibodies
Glomerulonephritis Neutrophils, monocytes; antibodies and complement
Septic shock Cytokines
Lung abscess Neutrophils (and bacteria)
Chronic
Arthritis Lymphocytes, macrophages; antibodies
Atherosclerosis Macrophages; lymphocytes
Chronic transplant rejection Lymphocytes; cytokines
Pulmonary fibrosis Macrophages, fibroblasts

Termination of the acute inflammation response

The acute inflammation response needs to be tightly controlled to minimise host tissue damage. Passive termination: Mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives and are degraded after their release. Neutrophils don’t live long in tissues – they die by apoptosis within a few hours after leaving the blood. Active termination: as inflammation develops the process triggers stop signals that actively terminate inflammation. These include:

  1. (change in the type of arachidonic acid produced) pro-inflammatory leukotrienes give way to anti-inflammatory lipoxins
  2. IL-10 and transforming growth factor-beta (TGF-beta) (anti-inflammatory cytokines) are released from macrophages and other cells
  3. Resolvins and protectins (anti-inflammatory lipid mediators derived from polyunsaturated fatty acids) are released.
  4. Neural impulses (cholinergic discharge) inhibits the production of TNF in macrophages.