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INFLAMACIÓN

•Inflammation is a defense reaction caused by tissue damage or injury •Characterized by redness, heat, swelling, and pain. •The primary objective of inflammation is to localize and eradicate the irritant and repair the surrounding tissue. •For the survival of the host, inflammation is a necessary and beneficial process. •The inflammatory response involves three major stages: first, dilation of capillaries to increase blood flow; second, microvascular structural changes and escape of plasma proteins

from

the

bloodstream;

and

third,

leukocyte

transmigration through endothelium and accumulation at the site of injury.

•The leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with extravasation of the leukocyte. •At least five steps of the adhesion cascade are capture, rolling. slow rolling, firm adhesion, and transmigration. •Each of these five steps appears to be necessary for effective leukocyte recruitment, because blocking any of the five can severely reduce leukocyte accumulation in the tissue. •These steps are not phases of inflammation, but represent the sequence of events from the perspective of each leukocyte. •At any given moment, capture, rolling, slow rolling, firm adhesion and transmigration all happen in parallel, involving different leukocytes in the same microvessels.

Endothelium

•The endothelium is located at the interface between the blood and the vessel wall. •The cells are in close contact and form a slick layer that prevents blood cell interaction with the vessel wall as blood moves through the vessel lumen. •The endothelium consists of simple squamous epithelium that lines the lumen of all blood vessels. •It plays a critical role in the mechanics of blood flow, the regulation of coagulation, leukocyte adhesion, and vascular smooth muscle cell growth, and also serves as a barrier to the transvascular diffusion of liquids and solutes. •For years the endothelium was thought of as an inert single layer of cells that passively allowing the passage of water and other small molecules across the vessel wall. • However, this dynamic tissue performs many other active functions, such as the secretion and modification of vasoactive substances and the contraction and relaxation of vascular smooth muscle.

Leukocytes The cellular components of blood include erythrocytes (red blood cells), leukocytes (white blood cells), and platelets. Normal human blood contains 4.8 - 5.2 million erythrocytes/ml and 4000 - 10,000 leukocytes/ml. Leukocytes are divided into five classes based on morphological and tinctorial characteristics when stained. The five classes of leukocytes are: neutrophils (40% - 75%) eosinophils (1% - 6%) basophils (less than 1%) monocytes (2%-10%) lymphocytes (20%-45%) Collectively, neutrophils, eosinophils, and basophils are known as granulocytes due to the presence of granules in their cytoplasm. In addition, monocytes and lymphocytes are also known as mononuclear cells.

Neutrophils Within 12 hours of being discharged from the marrow into the bloodstream, neutrophils migrate into the extravascular tissue. Tissue neutrophils are activated by chemoattractants at the site of injury. Neutrophils ingest bacteria by phagocytosis and then release enzymes (such as lysozyme) to destroy the bacteria. Eosinophils Eosinophils migrate from the marrow through the blood into the extravascular tissue, and they survive there for weeks. Again, chemoattractants direct the movement of eosinophils, and like neutrophils, eosinophils are phagocytic. They do not ingest organisms, but they do exert cytotoxic effects on them. Basophils Basophils are morphologically similar to mast cells, and along with other granulocytes, basophils are motile cells with phagocytic properties. They may migrate into extravascular tissues where they may be stimulated by complexes of antigens that are bound to IgE.

Monocytes Monocytes are larger than other leukocytes, and they mature into macrophages once they are released into the bloodstream. Monocytes then migrate to tissues, particularly the liver, lymph nodes, and lungs, where they may stay for days or years. Here, the monocytes are actively phagocytic, and they ingest particulate matter. Monocytes are also important to the immune response. They ingest and process antigens and are involved in antigen presentation, by B- and T-lymphocytes. Lymphocytes Two main types of lymphocytes are B-cells and T-cells. B-cells are characterized by the presence of immunoglobulins on their surface, and upon stimulation with antigen, they are transformed into plasma cells. Plasma cells are then able to secrete antibodies specific to the antigen. T-cells take part in cell mediated immune response, which does not depend on the presence of circulating antibodies.

Selectins

Selectins are a family of transmembrane molecules, expressed on the surface of leukocytes and activated endothelial cells. Selectins contain an N-terminal extracellular domain with structural homology to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor, and two to nine consensus repeats (CR) similiar to sequences found in complement regulatory proteins. Each of these adhesion receptors is inserted via a hydrophobic transmembrane domain and possesses a short cytoplasmic tail. The initial attachment of leukocytes, during inflammation, from the blood stream is afforded by the selectin family, and causes a slow downstream movement of leukocytes along the endothelium via transient, reversible, adhesive interactions called leukocyte rolling. Each of the three selectins can mediate leukocyte rolling given the appropriate conditions. L-selectin is the smallest of the vascular selectins, and can be found on most leukocytes. P-selectin, the largest selectin, is expressed on activated platelets and endothelial cells primarily. E-selectin is expressed on activated endothelium with chemically or cytokine-induced inflammation.

L-Selectin

P-Selectin

E-Selectin

Slow Rolling •After induction of inflammation by injection of a pro-inflammatory cytokine like TNF- , leukocyte rolling velocity drops dramatically to an average between 5 and 10 µm/s •This rolling requires the expression of E-selectin on endothelial cells and CD18 integrins on the rolling leukocytes and has been termed "slow rolling" to distinguish it from the much faster rolling without cytokine stimulation. •Slow rolling can be reproduced in vitro on substrates of E-selectin and, at equivalent site densities, P-selectin. •This suggests that slow rolling is not based on a unique property of E-selectin, but the expression of E-selectin and/or its ligands appears to be sufficiently high in vivo to support slow rolling..

This slide shows the muscle coats and peritoneum of a normal appendix. The peritoneal surface runs diagonally across the upper right hand corner. It is covered by a layer of mesothelial cells (not apparent in this picture) underlying which is a layer of pale staining fibrous tissue in which are a few small blood vessels. The outer longitudinal and inner circular muscle coats consist of smooth muscle with a few small blood vessels.

This slide shows the same area in an acutely inflamed appendix. The changes are striking. The peritoneum is widened by an increase in tissue fluid (oedema) and by many inflammatory cells. In addition, the blood vessels are dilated. The muscle coat also shows oedema which has caused separation of the muscle fibres. There are numerous inflammatory cells between the muscle fibres.

Tipos de Inflamación Serous inflammation In serous inflammation, there is abundant protein-rich fluid exudate with a relatively low cellular content. Examples include inflammation of the serous cavities, such as peritonitis, and inflammation of a synovial joint, acute synovitis. Vascular dilatation may be apparent to the naked eye, the serous surfaces appearing injected, i.e. having dilated, blood-laden vessels on the surface, (like the appearance of the conjunctiva in 'blood- shot' eyes). Catarrhal inflammation When mucus hypersecretion accompanies acute inflammation of a mucous membrane, the appearance is described as catarrhal. The common cold is a good example. Fibrinous inflammation When the inflammatory exudate contains plentiful fibrinogen, this polymerises into a thick fibrin coating. This is often seen in acute pericarditis and gives the parietal and visceral pericardium a 'bread and butter' appearance.

Haemorrhagic inflammation Haemorrhagic inflammation indicates severe vascular injury or depletion of coagulation factors. This occurs in acute pancreatitis due to proteolytic destruction of vascular walls, and in meningococcal septicaemia due to disseminated intravascular coagulation.

Suppurative (purulent) inflammation The terms 'suppurative' and 'purulent' denote the production of pus, which consists of dying and degenerate neutrophils, infecting organisms and liquefied tissues. The pus may become walled-off by granulation tissue or fibrous tissue to produce an abscess (a localised collection of pus in a tissue) . If a hollow viscus fills with pus, this is called an empyema, for example, empyema of the gall bladder or of the appendix.

Membranous inflammation In acute membranous inflammation, an epithelium becomes coated by fibrin, desquamated epithelial cells and inflammatory cells. An example is the grey membrane seen in pharyngitis or laryngitis due to Corynebaeterium diphtheriae. Pseudomembranous inflammation The term 'pseudomembranous' describes superficial mucosal ulceration with an overlying slough of disrupted mucosa, fibrin, mucus and inflammatory cells. This is seen in pseudomembranous colitis due to Clostridium difficile colonisation of the bowel, usually following broad-spectrum antibiotic treatment.

Necrotising (gangrenous) inflammation High tissue pressure due to oedema may lead to vascular occlusion and thrombosis, which may result in widespread septic necrosis of the organ. The combination of necrosis and bacterial putrefaction is gangrene. Gangrenous appendicitis is a good example.

Beneficial effects Both the fluid and cellular exudates may have useful effects. Beneficial effects of the fluid exudate are as follows: •Dilution of toxins. Dilution of toxins, such as those produced by bacteria, allows them to be carried away in Iymphatics. •Entry of antibodies. Increased vascular permeability allows antibodies to enter the extravascular space, where they may lead either to Iysis of microorganisms, through the participation of complement, or to their phagocytosis by opsonisation. Antibodies are also important in neutralisation of toxins. •Drug transport. The fluid carries with it therapeutic drugs such as antibiotics to the site where bacteria are multiplying. •Fibrin formation. Fibrin formation from exuded fibrinogen may impede the movement of micro-organisms, trapping them and so facilitating phagocytosis. •Delivery of nutrients and oxygen. Delivery of nutrients and oxygen, essential for cells such as neutrophils which have high metabolic activity, is aided by increased fluid flow through the area. •Stimulation of immune response. The drainage of this fluid exudate into the Iymphatics allows particulate and soluble antigens to reach the local Iymph nodes where they may stimulate the immune response.

Harmful effects The release of Iysosomal enzymes by inflammatory cells may also have harmful effects: •Digestion of normal tissues. Enzymes such as collagenases and proteases may digest normal tissues, resulting in their destruction. This may result particularly in vascular damage, for example in type III hypersensitivity reactions and in some types of glomerulonephritis. •Swelling. The swelling of acutely inflamed tissues may be harmful: for example, the swelling of the epiglottis in acute epiglottitis in children due to Haemophilus influenzae infection may obstruct the airway, resulting in death. Inflammatory swelling is especially serious when it occurs in an enclosed space such as the cranial cavity. Thus, acute meningitis or a cerebral abscess may raise intracranial pressure to the point where blood flow into the brain is impaired, resulting is ischaemic damage, or may force the cerebral hemispheres against the tentorial orifice and the cerebellum into the foramen magnum (pressure coning). •Inappropriate inflammatory response. Sometimes, acute inflammatory responses appear inappropriate, such as those which occur in type I hypersensitivity reactions (e.g. hay fever) where the provoking environmental antigen (e.g. pollen) otherwise poses no threat to the individual. Such allergic inflammatory responses may be life-threatening, for example extrinsic asthma.

Features of the Fluid Exudate The increased vascular permeability means that large molecules, such as proteins, can escape from vessels. Hence, the exudate fluid has a high protein content of up to 50 g/l. The proteins present include immunoglobulins, which may be important in the destruction of invading micro-organisms, and coagulation factors, including fibrinogen, which result in fibrin deposition on contact with the extravascular tissues. Hence, acutely inflamed organ surfaces are commonly covered by fibrin: the fibrinous exudate. There is a considerable turnover of the inflammatory exudate it is constantly drained away by local Iymphatic channels to be replaced by new exudate. This slide shows the peritoneal surface of an acutely inflamed appendix. The pink layer on the peritoneal surface consists of fibrin in which cells are enmeshed.

This slide shows pink staining threads of fibrin with leucocytes in alveoli.

Formation of the Cellular Exudate The accumulation of neutrophil polymorphs within the extracellular space is the diagnostic histological feature of acute inflammation.

High-magnification of pus in the lumen of the appendix. Pus consists of living and degenerate neutrophil polymorphs together with liquefied tissue debris. The neutrophil is the main cell to mediate the effects of acute inflammation. If tissue damage is slight, an adequate supply is derived from normal numbers circulating in blood. If tissue damage is extensive, stores of neutrophils, including some immature forms, are released from bone marrow to increase the absolute count of neutrophils in the blood. To maintain the supply of neutrophils, growth factors derived from the inflammatory process stimulate division of myeloid precursors in the bone marrow, thereby increasing the number of developing neutrophils.

Chemical mediators released from cells •Histamine. This is the best-known chemical mediator in acute inflammation. It causes vascular dilatation and the immediate transient phase of increased vascular permeability. It is stored in mast cells, basophil and eosinophil leukocytes, and platelets. Histamine release from those sites (for example, mast cell degranulation) is stimulated by complement components C3a and C5a, and by Iysosomal proteins released from neutrophils. •Lysosomal compounds. These are released from neutrophils and include cationic proteins, which may increase vascular permeability, and neutral proteases, which may activate complement. •Prostaglandins. These are a group of long-chain fatty acids derived from arachidonic acid and synthesised by many cell types. Some prostaglandins potentiate the increase in vascular permeability caused by other compounds. Others include platelet aggregation (prostaglandin 1. is inhibitory while prostaglandin A2 is stimulatory). Part of the anti-inflammatory activity of drugs such as aspirin and the non-steroidal antiinflammatory drugs is attributable to inhibition of one of the enzymes involved in prostaglandin synthesis. •Leukotrienes. These arc also synthesised from arachidonic acid, especially in neutrophils, and appear to have vasoactive properties. SRS-A (slow reacting substance of anaphylaxis), involved in type I hypersensitivity, is a mixture of leukotrienes. •5-hydroxytryptamine (serotonin). This is present in high concentration in mast cells and platelets. It is a potent vasoconstrictor. •Lymphokines. This family of chemical messengers released by Iymphocytes. Apart from their major role in type IV hypersensitivity, Iymphokines may also have vasoactive or chemotactic properties.

Role of the Neutrophil Polymorph

The neutrophil polymorph is the characteristic cell of the acute inflammatory infiltrate. The actions of this cell will now be considered. Movement Contraction of cytoplasmic microtubules and gel/sol changes in cytoplasmic fluidity bring about amoeboid movement. These active mechanisms are dependent upon calcium ions and are controlled by intracellular concentrations of cyclic nucleotides. The movement shows a directional response (chemotaxis) to various chemicals. Adhesion to micro-organisms Micro-organisms are opsonised (from the Greek word meaning 'to prepare for the table'), or rendered more amenable to phagocytosis, either by immunoglobulins or by complement components. Bacterial lipopolysaccharides activate complement via the alternative pathway, generating component C3b which has opsonising properties. In addition, if antibody binds to bacterial antigens, this can activate complement via the classical pathway, also generating C3b. In the immune individual, the binding of immunoglobulins to micro-organisms by their Fab components leaves the Fc component exposed. Neutrophils have surface receptors for the Fc fragment of immunoglobulins, and consequently bind to the micro-organisms prior to ingestion. Phagocytosis The process whereby cells (such as neutrophil polymorphs and macrophages) ingest solid particles is termed phagocytosis. The first step in phagocytosis is adhesion of the particle to be phagocytosed to the cell surface. This is facilitated by opsonisation. 'The phagocyte then ingests the attached particle by sending out pseudopodia around it. These meet and fuse so that the particle lies in a phagocytic vacuole (also called a phagosome) bounded by cell membrane. Lysosomes, membrane-bound packets containing the toxic compounds described below, then fuse with phagosomes to form phagolysosomes. It is within these that intracellular killing of micro-organisms occurs.

Intracellular killing of micro-organisms Neutrophil polymorphs are highly specialised cells, containing noxious microbial agents, some of which are similar to household bleach. The microbial agents may be classified as: those which are oxygen-dependent those which are oxygen-independent. Oxygen-dependent mechanisms. The neutrophils produce hydrogen peroxide which reacts with myeloperoxidase in the cytoplasmic granules in the presence of halide, such as Cl, to produce a potent microbial agent. Other products of oxygen reduction also contribute to the killing, such as peroxide anions (O2-), hydroxyl radicals (.OH) and singlet oxygen (1O2). Oxygen-independent mechanisms. These include Iysozyme (muramidase), lactoferrin which chelates iron required for bacterial growth, cationic proteins, and the low pH inside phagocytic vacuoles. Release of lysosomal products Release of Iysosomal products from the cell damages local tissues by proteolysis by enzymes such as elastase and collagenase, activates coagulation factor XII, and attracts other leukocytes into the area. Some of the compounds released increase vascular permeability, while others are pyrogens, producing systemic fever by acting on the hypothalamus.

Role of the Lymphatics Terminal Iymphatics are blind-ended, endothelium-lined tubes present in most tissues in similar numbers to capillaries. The terminal Iymphatics drain into collecting Iymphatics which have valves and so propel Iymph passively, aided by contraction of neighbouring muscles, to the Iymph nodes. The basal lamina of Iymphatic endothelium is incomplete, and the junctions between the cells are simpler and less robust than those between capillary endothelial cells. Hence, gaps tend to open up passively between the Iymphatic endothelial cells,allowing large protein molecules to enter. In acute inflammation, the Iymphatic channels become dilated as they drain away the oedema fluid of the inflammatory exudate. This drainage tends to limit the extent of oedema in the tissues. The ability of the Iymphatics to carry large molecules and some particulate matter is important in the immune response to infecting agents; antigens are carried to the regional Iymph nodes for recognition by Iymphocytes. If the lymphatic system becomes blocked either as a result of acute inflammation or in filariasis (infection by parasitic larvae), severe tissue oedema may occur, resulting in elephantiasis.

Sequelae of Acute Inflammation The sequelae of acute inflammation depend upon the type of tissue involved and the amount of tissue destruction, which depend in turn upon the nature of the injurious agent. The possible outcomes of acute inflammation are: Resolution Supporation Organisation Chronic Inflammation Resolution of Acute Inflammation The term resolution means the complete restoration of the tissues to normal after an episode of acute inflammation. The conditions which favour resolution are: •minimal cell death and tissue damage occurrence in an organ or tissue which has regenerative capacity (e.g. the liver) rather than in one which cannot regenerate (e.g. the central nervous system) •rapid destruction of the causal agent (e.g. phagocytosis of bacteria) •rapid removal of fluid and debris by good local vascular drainage. •A good example of an acute inflammatory condition which usually resolves completely is acute lobar pneumonia. The alveoli become filled with acute inflammatory exudate containing fibrin, bacteria and neutrophil polymorphs. The alveolar walls are thin and have many capillaries (for gas exchange) and Iymphatic channels. The sequence of events leading to resolution is usually: •phagocytosis of bacteria (e.g. pneumococci) by neutrophils and intracellular killing •fibrinolysis •phagocytosis of debris, especially by macrophages, and carriage through Iymphatics to the hilar Iymph nodes •disappearance of vascular dilatation. •Following this, the lung parenchyma would appear histologically normal.

Suppuration Suppuration is the formation of pus, a mixture of living, dying and dead neutrophils and bacteria, cellular debris and sometimes globules of lipid. The causative stimulus must be fairly persistent and is virtually always an infective agent, usually pyogenic bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes, Neisseria species or coliform organisms). Once pus begins to accumulate in a tissue, it becomes surrounded by a 'pyogenic membrane' consisting of sprouting capillaries, neutrophils and occasional fibroblasts. Such a collection of pus is called an abscess, and bacteria within the abscess cavity are relatively inaccessible to antibodies and to antibiotic drugs (thus, for example, acute osteomyelitis, an abscess in the bone marrow cavity, is notoriously difficult to treat). Abscess An abscess (for example, a boil) usually 'points', then bursts; the abscess cavity collapses and is obliterated by organisation and fibrosis, leaving a small scar. Sometimes, surgical incision and drainage is necessary to eliminate the abscess. If an abscess forms inside a hollow viscus (e.g. the gall bladder) the mucosal layers of the outflow tract of the viscus may become fused together by fibrin, resulting in an empyema. Such deep-seated abscesses sometimes discharge their pus along a sinus tract (an abnormal connection, lined by granulation tissue, between the abscess and the skin or a mucosal surface). If this results in an abnormal passage connecting two mucosal surfaces or one mucosal surface to the skin surface, it is referred to as a fistula. Sinuses occur particularly when foreign body materials are present, which are indigestible by macrophages and which favour continuing suppuration. The only treatment for this type of condition is surgical elimination of the foreign body material.

Organisation Organisation of tissues is their replacement by granulation tissue. The circumstances favouring this outcome are when: •Iarge amounts of fibrin are formed, which cannot be removed completely by fibrinolytic enzymes from the plasma or from neutrophil polymorphs •substantial volumes of tissue become necrotic or if the dead tissue (e.g. fibrous tissue) is not easily digested •exudate and debris cannot be removed or discharged. During organisation, •new capillaries grow into the inert material (inflammatory exudate), •macrophages migrate into the zone •fibroblasts proliferate, resulting in fibrosis. A good example of this is seen in the pleural space following acute lobar pneumonia. Resolution usually occurs in the lung parenchyma, but very extensive fibrinous exudate fills the pleural cavity. The fibrin is not easily removed and consequently capillaries grow into the fibrin, accompanied by macrophages and fibroblasts (the exudate becomes 'organised'). Eventually, fibrous adhesion occurs between the parietal and visceral pleura. Progression to Chronic Inflammation If the agent causing acute inflammation is not removed, the acute inflammation may progress to the chronic stage. In addition to organisation of the tissue just described, the character of the cellular exudate changes, with Iymphocytes, plasma cells and macrophages (sometimes including multi nucleate giant cells) replacing the neutrophil polymorphs. Often, however, chronic inflammation occurs as a primary event, there being no preceeding period of acute inflammation.

Examples of Organisms which can be Associated with Chronic Inflammatory Processes •

Mycobacterium tuberculosis. The red - stained, elongated organisms shown here are M. tuberculosis within macrophages in a tuberculous abscess. Mycobacteria have a thick, waxy cell wall that protects them against the enzymic and other mechanisms used by macrophages to inactivate organisms. They are thus able to survive for prolonged periods within macrophages and so are also protected against other cellular and humoral mechanisms for dealing with invading organisms. (Ziehl-Neelsen stain).

2. Streptococci in chronic abscess. Streptococci can survive within pus in a chronic abscess cavity where they are protected from other mechanisms for disposal of bacteria, e.g. macrophages, opsonising antibodies, complement and, of course, theraputically administered antibiotics.(Gram stain).

3. Fungi. This is an illustration of mycelial filaments of the fungus Mucor in a chronic abscess. The presence of the fungus has stimulated vigorous fibrosis and this has enabled the organism to become surrounded by dense collagenous tissue and thus protected from phagocytosis, antibodies, complement, etc.

4. Syphilis. This illustration shows the organisms Treponema pallidum in a syphilitic lesion in the brain. Such lesions are now rare, since the disease is treatable with antibiotics such as the penicillins. (Levaditi silver stain).

Chronic Inflammation Chronic inflammation is an inflammatory response of prolonged duration - weeks, months, or even indefinitely - whose extended time course is provoked by persistance of the causative stimulus to inflammation in the tissue. The inflammatory process inevitably causes tissue damage and is accompanied by simultaneous attempts at healing and repair. The exact nature, extent and time course of chronic inflammation is variable, and depends on a balance between the causative agent and the attempts of the body to remove it. Chronic inflammation may develop in the following ways: • • •

as a progression from acute inflammation if the original stimulus persists, after repeated episodes of acute inflammation, de novo if the causative agent produces only a mild acute response.

Aetiological agents producing chronic inflammation include: •

Infectious organisms that can avoid or resist host defences and so persist in the tissue for a prolonged period. Examples include Mycobacterium tuberculosis, Actinomycetes, and numerous fungi, protozoa and metazoal parasites. Such organisms are in general able to avoid phagocytosis or survive within phagocytic cells, and tend not to produce toxins causing acute tissue damage.

•

Infectious organisms that are not innately resistant but persist in damaged regions where they are protected from host defences. The common example here is of bacteria which grow in the pus within an undrained abscess cavity, where they are protected both from host immunity and from blood-borne theraputic agents, e.g. antibiotics. Some locations are particularly prone to chronic abscess formation, e.g. bone, pleural cavities.

•

Irritant non-living foreign material that cannot be removed by enzymic breakdown or phagocytosis. Examples include a wide range of materials implanted into wounds (wood splinters, grit, metals and plastics), inhaled (silica dust and other particles or fibres), or deliberately introduced (surgical prostheses, sutures, etc.). Dead tissue components that cannot be broken down may have similar effects, e.g. keratin squames from a ruptured epidermoid cyst or fragments of dead bone (sequestrum) in osteomyelitis.

•

In some cases the stimulus to chronic inflammation may be a "normal" tissue component. This occurs in inflammatory diseases where the disease process is initated and maintained because of an abnormality in the regulation of the body's immune reponse to its own tissues - the so-called autoimmune diseases.

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For many diseases characterised by a chronic inflammatory pathological process the underlying cause remains unknown. A good example here is Crohn's disease of the intestine.

Histological appearances in chronic inflammation: The microscopic appearances of chronic inflammation vary considerably according to the site involved and the causative stimulus. However, the general features are: •

A mixed inflammatory cell infiltrate containing predominantly macrophages, lymphocytes and plasma cells, with neutrophil and eosinophil polymorphs as possible minor components (compare with the predominance of neutrophils in acute inflammation). Lymphoid cells can proliferate at the site of inflammation as well as in local lymph nodes; in severe cases this can give rise to lymphoid follicles with germinal centres in the inflammatory lesion.

•

Tissue destruction (necrosis) caused both by the causative agent and by the inflammatory process itself.

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Attempts at reconstructing the damaged tissue occur simultaneously with the inflammatory process. These can be considered under the general title of healing and repair. The attempts at reconstruction may have different outcomes. If there is little tissue destruction then some organs may be able to regenerate their original structure, or mild inflammation may terminate by resolution without causing any structural damage. Commonly, however, the original structure cannot be recreated and the damaged area undergoes repair.This involves removal of the destroyed tissue by phagocytosis with proliferation of capillary blood vessels and lymphatics into the lesion together with fibroblasts and collagen production (so-called granulation tissue), ending up with a dense fibrous scar.

•

Granulomatous inflammation is a histologically distinctive form of chronic inflammation that occurs in particular circumstances in response to certain organisms or foreign material and merits description in a separate section. N.B. This term (granuloma, granulomatous inflammation) is not to be confused with granulation tissue. Look at the links explaining both processes and be sure you understand the distinction.

Types of Chronic Inflammatory Cells.

1. Lymphocytes and macrophages: This illustration shows a mixed chronic inflammatory cell infiltrate containing mainly lymphocytes and macrophages. The lymphocytes have small, round, very darkly staining nuclei and little surrounding cytoplasm; the macrophages have larger, paler, oval or bean shaped nuclei and a somewhat larger amount of cytoplasm. Plasma cells are not obvious in this field.

2. Lymphocytes around a blood vessel: Perivascular cuffingis a common pattern of lymphocytic infiltration in chronic inflammmatory reactions. Lymphocytes emerge from the circulating blood mostly through the walls of small venules and tend to aggregate around the vessels. This example is from an inflammatory disease of the brain - multiple sclerosis.

3. Macrophages in infarcted brain: Macrophages are highly phagocytic, as the name implies, and will engulf and degrade all sorts of debris in areas of damage. This example shows macrophages which have phagocytosed lipid material from broken - down myelin in an area of infarcted brain. The macrophage cell bodies are large and round, distended with pale, foamy looking lipid - filled vacuoles (lysosomes). This foamy appearance is also seen in other sites where lipid debris is being removed (fat necrosis, for example).

4. Plasma cells: These distinctive looking cells have an eccentrically placed nucleus with coarse, blotchy staining of the chromatin, said to resemble a clock face. The cytoplasm is rather blue staining (basophilic), reflecting its high content of rough endoplasmic reticulum with large numbers of ribosomes containing ribosomal RNA. There is also a prominent pale area of cytoplasm next to the nucleus - the Golgi apparatus. Plasma cells are mature, end-stage cells of the B-lymphocyte lineage, specialised for antibody production and secretion.

5.Lymphoid follicles: This is a lymphoid follicle producing lymphocytes within thyroid tissue during the chronic inflammatory process which destroys the gland in Hashimoto's Disease. The inflammation is triggered and maintained by abnormal sensitivity of the immune system against its own thyroid tissue - i.e. an auto-immune disease. The follicle is a structured aggregate of lymphoid cells, with a central region of large, pale - staining, actively proliferating precursor cells and a mantle zone of closely packed mature lymphocytes recognizable by their small, round, intensely blue/black nuclei.

Other cell types involved in the inflammatory reaction: 3. Mast cell 5. Platelet 7. Vascular endothelium

Granulomatous Inflammation: Structure of a granuloma. Granulomas are aggregates of particular types of chronic inflamatory cells which form nodules in the milimetre size range. Granulomas may be confluent, forming larger areas.The essential components of a granuloma are collections of modified macrophages, termed epithelioid cells, usually with a surrounding zone of lymphocytes. (Epithelioid cells are so named by tradition because of their histological resemblance to epithelial cells, but are not in fact epithelial; they are derived from blood monocytes, like all macrophages.) Epithelioid cells are less phagocytic than other macrophages and appear to be modified for secretory functions. The full extent of their functions is still unclear. Macrophages in granulomas are commonly further modified to form multinucleate giant cells.These arise by fusion of epithelioid macrophages without nuclear or cellular division forming huge single cells which may contain dozens of nuclei. In some circumstances the nuclei are arranged round the periphery of the cell, termed a Langhans-type giant cell (characteristically seen in tuberculosis); in other circumstances the nuclei are randomly scattered throughout the cytoplasm - for example in the foreign body type of giant cell which is formed in response to the presence of other indigestible foreign material in the tissue. Areas of granulomatous inflammation commonly undergo necrosis. The prototype example here is caseous necrosis in tuberculosis. Conditions for formation of granulomas. Formation of granulomatous inflammation seems to require the presence of indigestible foreign material (derived from bacteria or other sources) and/or a cell-mediated immune reaction against the injurious agent (type IV hypersensitivity reaction). The finding of granulomatous infammation in a biopsy specimen can be very useful in limiting the number of possible causes of the inflammatory process.

Examples of granulomatous inflammation: •

Specific Infections:Mycobacteria (tuberculosis, leprosy, syphilis, brucellosis, fungi, parasites (e.g. Schistosoma).

•

Foreign bodies: Endogenous: e.g. keratin, necrotic boneor adipose tissue, uric acid crystals (gout). Exogenous: e.g. wood, grit, silica or asbestos dust, talc, suture material, silicone, prostheses.

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Specific chemicals: Beryllium.

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Drugs: Hepatic sulphonamides.

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Unknown: Sarcoidosis, Crohn's disease.

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Cell Types in Granulomatous Inflammation: 1.

Langhans type giant cell and epithelioid macrophages in tuberculous granuloma. The central giant cell has a peripheral ring of nuclei in the cytoplasm. A second group of similar nuclei just to the right of this cell represents a second giant cell, probably smaller and cut rather tangentially in the plane of section. The surrounding cells are almost all epithelioid macrophages.

2. Giant cells in the wall of an artery in giant cell arteritis (temporal arteritis). Giant cell arteritis involves an abnormal inflammatory attack on elasic tissue in the walls of some arteries, commonly the temporal artery and other branches of the external carotid circulation. The elastic tissue is not easily degraded and stimulates the formation of multinucleate giant cells as part of the granulomatous chronic inflammatory process.

3. Foreign body type giant cells (a). These giant cells have formed as a reaction to keratinous material forced into the dermis when an epidermoid cyst underwent rupture.

4. Foreign body type giant cells (b). These foreign body giant cells contain distinctive elongated, apparently empty, clefts which result from the ingestion of crystalline material, largely cholesterol, in an atheromatous plaque. The clefts appear empty in the histological preparation because the lipid-rich ingested material has been dissolved out of the tissue by the solvents used in histological processing.

5. Structure of a granuloma (a). This low power photomicrograph shows numerous discrete, uniformly sized, round granulomas scattered throughout a lymph node. They are composed of epithelioid cells which stand out pale against the darkly staining lymphocytes in which thay are set. Giant cells are not obvious. The capsule of the lymph node can be seen at the top, giving a clue to the size of the structures - probably 0.5 to 1.0 mm across. The disease process here is sarcoidosis, a chronic granulomatous disease of unknown aetiology.

6. Structure of a granuloma (b). This image shows pale staining granulomas composed of rather irregular, confluent aggregates of epithelioid cells with Langhanstype giant cells centrally and a surrouding infiltrate of lymphocytes, seen on the right of the picture. Tuberculous meningitis.