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Module 3 Exam Notes - Inflammation (Pathology)

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Pathology
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Pathology 2420A
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Week 3 - Inflammation GENERAL OBJECTIVES OF MODULE: To acquaint you with an important mechanism of defence and explain and illustrate the various steps involved in the inflammatory response. We'll also look at the factors that initiate and modify the course of the inflammatory reaction. SPECIFIC OBJECTIVES: After completing this module you will be able to: 1. Define and describe inflammation. 2. Explain the series of steps that take place in the capillary bed during an acute inflammatory process (i.e. the vascular events). 3. Describe abnormal permeability at the microcirculation during acute inflammation (in contrast to normal). i. Define and contrast exudate and transudate and their characteristics. 4. Illustrate the cellular events of inflammation. 5. Define chemical mediation in inflammation. Explain the mechanisms of action and effects of: vasoactive amines (e.g. histamine), arachidonic acid metabolites, and plasma protease systems (e.g. the kinin system, the clotting or coagulation cascade, the complement system). 6. Define chemotaxis and list three common chemotactic factors. 7. List the three most common cells involved in inflammation and their role in the inflammatory response. 8. Describe the steps involved in phagocytosis. 9. List and explain the mechanism of production of the cardinal signs of inflammation. 10. Classify inflammation based on duration. Give examples for each type. 11. Define granuloma. Give three common etiologies. 12. Classify inflammatory exudates. Give examples. 13. Define abscess, empyema and additional special forms of inflammation. 14.List at least two systemic effects of inflammation. Inflammation - Key Terms  Acute - of short duration or occurring suddenly.  Cardinal signs of inflammation: • rubor - redness • tumor - swelling • calor - heat • dolor - pain • functio laesa - loss of function or impaired function  Chemical mediators - a variety of chemicals secreted by various cells and from injured tissue involved in the inflammatory response, e.g. histamine. Responsible for mediating vascular and cellular responses in inflammation.  Chemotaxis - phenomenon that guides and attracts WBCs to the site of injury. Chemotactic agents include some of the chemical mediators, antibodies, products from bacteria and dead tissue.  Chronic - long-standing; occurring over a long period of time.  Exudate - fluid accumulation outside of a vessel; it has a high protein content and contains various types of inflammatory cells.  Hyperemia - excess of blood in a part.  Leukocyte - or white blood cell (WBC); the cell type that predominates in acute inflammation is the polymorphonuclear WBC (PMN) or the neutrophil.  Leukocytosis - a transient increase in the number of leukocytes (WBCs) in the blood.  Monocyte / macrophage - another type of white blood cell; as inflammatory process continues these cells finish off what the neutrophils begin and continue to clean up the debris; macro = large; phage = eater.  Permeability - the degree of selectivity a membrane shows in allowing substances to pass through or in preventing passage; "leakiness"  Phagocytosis - a process in which a cell takes particles and substances into itself for destruction; phago = eating, cyto = cell. E.g. a neutrophil can engulf (phagocytize) foreign particles, bacteria, dead material or other debris.  Pyrogen - a fever-producing substance.  Transudate - in this case the fluid contains little, if any protein or cells, and is usually due to changes in hydrostatic pressure or osmotic pressure in the blood vessel (also see later module on "Blood Flow and Body Fluids").  Vasodilation - increase in size or diameter of a blood vessel; brought about by chemical mediator Definition Inflammation: Inflammation is the non-specific, dynamic response of a living organism to tissue injury. This injury may be the result of physical trauma or chemical injury, infection with a microorganism, immune reactions or ischemia. The purpose of the inflammatory reaction is to destroy or limit the spread of the injurious agent and to allow for repair or replacement of damaged tissue. Whenever tissues are injured, e.g. cut, burned, or infected by a microorganism - a series of reactions will occur at the site of injury. That series of reactions constitutes an inflammatory reaction. The purpose of these reactions is: 1. To destroy or limit the spread of the injurious agent. 2. To allow for repair or replacement of the damaged tissue. The definition of inflammation is very broad. It is perhaps best described as being the characteristic response of living tissues to an injury. Three points require amplification: 1. Inflammation is a dynamic, ever-changing process consisting of a chain of reactions which succeed or overlap each other. It is not a static situation. 2. The injury must be non-lethal. If the injury is of such severity to destroy the tissue at the outset, no inflammatory response can occur in that time. 3. The inflammatory reaction is non-specific. Many diverse injuries can cause inflammation and the initial stages of the inflammatory action are identical in almost all of the tissues, irrespective of the type of injury. The intensity, duration and outcome of the inflammatory reaction are modified by factors pertaining to the host as well as to the injurious insult. Some causes of an inflammatory reaction are: 1. Infection - i.e. invasion and multiplication within tissues by organisms. These, of course, include various bacteria, fungi, viruses and protozoa, which in many instances, cause damage by release of toxins which directly or indirectly destroy host cells. 2. Trauma - this includes penetrating injury (e.g. stab wound, a wood sliver), blunt trauma, thermal injury (excessive heat or cold), chemical injury (acid or alkali). 3. Immunologically-mediated (humoral or cellular). 4. As a result of the loss of blood supply (ischemia). * Do not confuse inflammation with infection. An infection almost always will cause an inflammatory reaction. However, as noted above, the etiologies of an inflammatory reaction are diverse, i.e. infection by a microorganism is one of the triggers of the inflammatory reaction, but not the only one. Usually, a relatively large inflammatory reaction will occur in response to an infection. --------------------------------------------------------------------------------------------------------------------- In order to study the inflammatory reaction, it is customary to divide it into its various components. The sequence can be divided into vascular and cellular events, both of them mediated by chemical factors (mediators). However, it must be remembered that these events occur concomitantly. * There are 3 major components of the inflammatory response: 1) Vascular events (taking place in arterioles, capillaries, venules) 2) Cellular events (major players here are the white blood cells (WBCs)) and 3) Chemical events (release of mediators that cause the changes in cells and vessels). Vascular Events Immediately following an injury, there is frequently a transient vasoconstriction of arterioles. This is mediated by nerves to the smooth muscle within the arteriolar walls (i.e. it is aneurogenic response). This process is brief and usually lasts up to five minutes. The transient vasoconstriction is followed by the hemodynamically more important vasodilatation of venules, capillaries, and arterioles.  Opening of precapillary sphincters of arterioles.  Opening up of new capillary beds.  Opening of arterial venous shunts in capillary bed. This results in increased blood flow to the injured area and thus, on gross examination, the area appears red or hyperemic. With very mild injuries, the vascular changes may not proceed any further than this stage. With more severe injury, the vasodilation is soon followed by slowing of the blood flow. Vascular events occurring in the capillary bed include:  a transient vasoconstriction (neurally-mediated)  followed by vasodilatation of vessels (chemically-mediated) o opening of precapillary sphincters of arterioles; opening up of new capillary beds; opening of arterial venous shunts in capillary bed) ---> all of these result in increased blood flow to the affected area (so clinically we see the redness (rubor) and heat (calor) of inflammation) Vasodilatation is often accompanied by increased vascular permeability. This refers to the outpouring of fluids and proteins from the blood vessels. This affects firstly and predominantly venules; however, capillaries and arterioles are also involved. Local hemoconcentration - The viscosity of blood is increased as a result of fluid loss from the vessel. This will lead to packing or sludging of red blood cells, therefore slowing blood flow. Occasionally, the blood flow is slowed to the point of stasis or thrombosis (clotting). Thrombosis in vessels may also occur due to a second mechanism in severe injuries in instances in which there is direct damage to endothelial cells which, in turn, initiate the formation of blood clots in the damaged areas. The cellular elements in a blood vessel normally travel in a stream in the centre of the vessel. As a result of loss of fluid because of increased vascular permeability and of slowing of blood flow in the vessel, the circulating cellular elements, including white blood cells, become displaced to the periphery of vessels where they come in to contact with the endothelial cells. This is referred to as margination. The process of the escape of plasma and plasma proteins along with white blood cells from the vessel is known as exudation. This inflammatory exudate accounts for an increase in the volume of interstitial fluid (edema) and tissue swelling at the local site of injury. There are two events in the inflammatory response that are responsible for the increased vascular permeability: 1. Rise in hydrostatic pressure within the microcirculation. Arteriolar vasodilatation is followed by a rise in pressure within the capillaries and venules. This results in the passive transport of a large volume of fluid along with small molecules into the interstitium (space between tissues). 2. Widening of the inter-endothelial cell junctions. These cells contain myofibrils within the cytoplasm and these allow for contraction of the cells. This is the mechanism by which large molecules may escape, resulting in a protein-rich exudate. Vasodilatation of vessels in the inflammatory vascular response is accompanied byincreased vascular permeability. The chemicals (notably histamine in the early stages) that cause vasodilatation also cause increased permeability within the vessels via an action on the endothelial cells that line the vessel wall and cause them to contract ---> creating 'spaces' between these cells through which fluid, proteins, and even cells (aninflammatory exudate) can now escape. This is the swelling or 'tumor' of inflammation. This flow of fluid out of the vessels is also aided by the increased blood flow which increases the pressure within capillaries and venules in that area (recall your Starling's forces from last year's physiology; this is hydrostatic pressure pushing fluid out of the vessels). An inflammatory exudate is characterized by having: 1. A high specific gravity (> 1.020). 2. High protein levels - > 2 - 4 gms per dl. 3. Numerous cells or cell fragments. In contrast, a transudate is due to a rise in hydrostatic pressure, reduced plasma proteins (oncotic pressure), lymphatic obstruction or Na+ retention. It consists of fluid similar to water with a low specific gravity (<1.0120) with little to no protein or cells (or cell fragments). Transudates are NOT associated with inflammation but with clinical situations such as: heart failure, venous obstruction, malnutrition, among others (also see later Module on Disturbances of Blood Flow and Body Fluids). The escape of plasma and plasma proteins, and even cells, from the vessel is known asexudation. This inflammatory exudate has:  high protein levels (> 2-4 gm/dl)  numerous cells and cell fragments  a high specific gravity This inflammatory exudate causes an increase in the volume of interstitial or extracellular fluid (inflammatory edema) and tissue swelling at the local site of injury. In contrast a transudate, is not related to the inflammatory response, but occurs when there is a rise in hydrostatic pressure in the vessel, a decrease in plasma proteins (and hence osmotic pressure) or lymphatic obstruction. It consists of fluid similar to water with NO or little cells or proteins, and hence a specific gravity close to that of water (<1.012). WHAT MECHANISMS ARE RESPONSIBLE FOR THE VASCULAR EVENTS (VASODILATATION AND INCREASED PERMEABILITY)? NEUROGENIC MEDIATORS  Operate in the very early phases of inflammatory reaction.  Fleeting arteriolar vasoconstriction.  The mechanism of neurogenic mediation was suggested by Sir Thomas Lewis in l927 and constitutes the first part (pallor) of Lewis' triple response. Even without neuroconnections (denervation), the major aspects of acute inflammation occur. The reason for this is that the main mediators of the vascular changes are chemical. Neurogenic mediators have probably a secondary and less important role in mammals. CHEMICAL MEDIATORS A. Cell-Derived Vasoactive Mediators i. Histamine - This is the major mediator in the early phases of the acute inflammatory reaction.  Major source is mast cells - these are ubiquitous throughout the body and occur in connective tissue often adjacent to blood vessels. Histamine is contained within granules of the mast cell. Histamine is also found in granules of basophils and platelets (along with heparin). When mast cells are injured or appropriately activated, they degranulate, i.e. contents of the granules are released. Mast cells degranulate in response to: 1. Physical injury - trauma, heat, irradiation. 2. Certain chemical agents - toxins, bee venom, proteins from neutrophils. 3. Immunological process - immune complexes, fragments of the complement system. Histamine has two major functions: 2. Dilatation of arterioles (vasodilatation). 3. Increased permeability in venules and capillaries. ii. Arachidonic Acid Metabolites - They are derived from cell membrane phospholipids. Release of arachidonic acid by phospholipases (lysosomes) is induced by mechanical, chemical and physical stimuli. The end products are prostaglandins and leukotrienes. Prostaglandins produce vasodilatation and increased permeability. Leukotrienes increase permeability and have chemotactic activity. Diagram of ARACHIDONIC ACID METABOLISM B. Plasma-Derived Vasoactive Mediators i. Kinins - The kinins, of which bradykinin is the most important, are a group of plasma and tissue proteases which are activated by actions of various clotting or complement system fragments. Bradykinin has four functions: 1. Arteriolar dilatation. 2. Increased capillary and venule permeability. 3. Increased migration of white blood cells to site of injury (chemotaxis). 4. Produce pain. Like histamine, the effects of bradykinin are transitory and are most important during the early phases of inflammation. ii. Complement system - In brief, complement consists of at least 11 different proteins circulating in the blood in an inactive form. Upon activation of the system - for example, by contact with antigen-antibody complexes - various by-products of complement are released. Some of these fragments of complement have the property of increasing vascular permeability, while others are responsible for attracting white blood cells into a site of inflammation. iii. Clotting Factors - The clotting (coagulation) system forms a fibrinous exudate or meshwork at the inflamed site to trap cells, microorganisms and foreign bodies. This prevents the spread of infection and inflammation into the surrounding tissues; keeps cell debris, bacteria and foreign bodies at the site of greatest phagocytic activity; and forms a clot that stops the bleeding and provides a framework for repair and healing. The main substance of this mesh is an insoluble protein called fibrin which is the end product of thecoagulation cascade. Miscellaneous - There are a wide variety of compounds which have a variable role in the inflammatory response. Some of these include neutrophil enzymes or lysozymes which are liberated at the inflammatory site and are responsible for the further release of mediators such as histamines, kinins, etc. Some of these enzymes also have the property of digesting organic material. Also of inflammatory significance are cytokines (products of stimulated lymphocytes), interferon and tumour necrosis factor. In summary, histamine, perhaps soon followed by the kinins, initiates the early vascular phenomenon. Fractions of complement are also involved at an early stage. Later, the changes of increased vascular permeability are due to compounds such as prostaglandins, lysozymes and SRS (slow reacting substance of anaphylaxis). Chemical mediators are of two types: 1. those derived from cells (e.g. histamine released by mast cells during initial cell damage) or breakdown of plasma membranes (e.g. phospholipases that initiate the conversion of arachidonic acid (AA) to various prostaglandins (PGs) and leukotrienes (LTs) from cell membrane phospholipids); 2. those mediators that are activated in the plasma (e.g. complement fractions, products of the kinin system, products of the coagulation cascade). Be familiar with what each of these chemical mediators can do - histamine probably being the most important promoting vasodilation and increased vascular permeability in the initial response. PGs - vasodilatation (PGI2 or prostacyclin) and increased permeability; LTs - increase permeability and are chemotactic factors. Complement factors (C3a and C5a increase permeability and cause vasodilation; C5a is also a chemotactic factor; C3b is an opsonin and enhances phagocytosis); kinins, bradykinin - vasodilation, increased permeability, chemotaxis and pain. There is a nice summary table in the text (8th edition - Table 2-4, see p. 46) Also in terms of clinical relevance various anti-inflammatory agents we use in treatment act to inhibit the production or action of these chemical mediators, e.g anti-histamines, aspirin (non- steroidal anti-inflammatory agents - block AA breakdown to PGs), COX-2 inhibitors (Vioxx - block cycloxygenase and breakdownof AA to PGs), corticosteroids (block initial breakdown of membrane phospholipids to AA). Cellular Changes When we were considering the effects upon blood vessels during the inflammatory process, we noted that, as a result of stagnation of blood flow, the cellular elements tended to become arranged around the periphery of the blood vessel, i.e. margination. At this point, the white blood cells become sticky and actually adhere to the endothelium, i.e.pavementing. The process of pavementing, is related to, the presence of cell adhesion molecules in both endothelial cells and leukocytes. Diagrammatic representation of the cellular changes taking place in the acute inflammatory response. Margination of WBCs (PMNs or neutrophils) is followed by pavementing and adherence of the cells to the endothelial basement membrane. Cell adhesion molecules promote adherence. Once migration through the endothelial cellular junctions has taken place, neutrophils are attracted to the area of injury by a number of chemotactic factors and there they phagocytose the invading organism or agent. Emigration - White blood cells are actively motile - they form pseudopods and can move in an amoeboid fashion. Neutrophils and monocytes are the most rapid travellers and lymphocytes are the least rapid. These white cells travel along the endothelium until they reach the widened endothelial cell junction where they are actually able to pass through that space. This process is active and requires energy. Red blood cells often leave the vascular lumen behind a white blood cell. This is a passive phenomenon and results from hydrostatic pressures forcing red blood cells out of the permeable vessel. The first cells to appear in injured tissues are neutrophils (dependent on C5a generation, in the first 6 - 24 hours) followed by monocytes (24 - 48 hours). This is due to the various timing of expression of CAMs & release of chemical mediators at different phases of inflammation. Once outside the blood vessel, monocytes are referred to as macrophages or histiocytes. Once fluid starts leaving the vessel during the inflammatory response you now get a relative concentration of blood cells (red cells and white cells or hemoconcentration) and a general slowing of the blood. These cellular elements, that under normal conditions travel in the centre of the vessel, now shift towards the margins of the vessel - margination. * Margination is the first step in the cellular events:  these cells now become sticky and adhere to the sides of the vessel wall (to the endothelial cells) -->pavementing and adhesion (cell adhesion molecules play a role here)  cells can then migrate through the spaces opened up between endothelial cells -- > migration (or emigration or transmigration) and  they are attracted to the site of injury by chemotactic factors (that may be released by an infectious organism, by the damaged host tissue, or as part of the activation of inflammatory intermediates, e.g. complement fractions) --> chemotaxis  once at the site of damage neutrophils and macrophages can ingest and digest cell debris, opsonized bacteria or foreign substances (recall examples of opsonins such as IgG, C3b) - ->phagocytosis. Chemotaxis - The reaction of inflammatory cells to substances in their environment determines the direction of locomotion of the cell or organism. This movement along a chemical gradient is a process called chemotaxis. Chemotactic factors for neutrophils include: 1. Complement fractions. 2. Bacterial and viral products. 3. Collagen breakdown fragments. 4. Components of the kinin system. 5. Breakdown fragments of fibrin Chemotaxis is the attraction of cells to the site of injury (by the release of factors from injured cells, infectious organisms or inflammatory mediators). Movement is along a chemical gradient towards the site of injury. The finding of a large number of neutrophils at a site of injury constitutes a major histological feature of acute inflammation. As mentioned above, in most acute reactions, neutrophils appear first and are followed by macrophages. This is due to their greater mobility and also because there are many more neutrophils than monocytes in the circulation. After two or three days, macrophages begin to outnumber neutrophils in most inflammatory reaction sites (an exception to this would be in those instances in which the injurious stimulus continues to operate). The normal life span of macrophages is much greater (months to years) versus the life span of an average neutrophil (2-4 days). Also, macrophages are relatively resistant to the lower pH (acidity) which is found at inflammatory sites. During acute inflammation - neutrophils are the most important cells (produce many substances that augment the inflammatory response - vasodilatation, increased permeability, chemotaxis,phagocytosis, etc that help to stop or contain the injurious agent) - followed by macrophages (ingest cellular debris) and - as inflammation becomes chronic then lymphocytes (humoral and cellular immunity) come into play and prominence. Phagocytosis – The process of ingestion of particulate matter, i.e. bacteria, foreign debris, by the cell. It literally means "cell-eating". It may be regarded as the culmination of an inflammatory reaction. Cells with the greatest phagocytotic properties are neutrophils and macrophages. Eosinophils are also phagocytotic; however, lymphocytes and plasma cells are not. After foreign material comes in contact with the cell membrane, the cytoplasm of the neutrophil or macrophage flows around the particle trapping it within a sack. Thus, the foreign material becomes bound by a membrane derived from the plasma membrane (phagosome). Lysosomes then fuse to the sack and release their enzymes directly into this sack or vacuole. Phagocytosis is the process whereby some of the debris at an inflammatory site is removed (this is done primarily by macrophages), the remainder is removed by lymphatics. Phagocytosis is also the main mechanism for bacterial killing and degradation. Phagocytosis or ingestion of cellular debris or foreign substances by macrophages or neutrophils. See the figure in the notes for a list of steps. 1. opsonization (e.g. by IgG, C3b) 2. recognition of foreign substance and adherence to WBC membrane 3. engulfment of foreign substance by WBC (to form a phagosome) 4. fusion with lysosome (phagolysosome) in the WBC and release of lytic enzymes Remember NOT ALL white blood cells are phagocytic. Neutrophils, macrophages (and to a certain extent eosinophils) are, but lymphocytes and plasma cells ARE NOT Factors affecting phagocytosis: Opsonins - These are substances which coat bacteria and render them more susceptible to phagocytosis. They are usually immunoglobulins (e.g. IgG) or complement fractions (e.g. C3b). What is the fate of the engulfed material? 1. In many instances, the material is destroyed. For example, bacteria may be destroyed and digested by the lysosomal enzymes within the neutrophil or macrophage. 2. However, in some cases, it is the white blood cell that may be destroyed by the foreign particle. For example, a particularly virulent bacteria may cause death of the ingesting cell. 3. A third possibility is that the organisms may survive for some time within the macrophages. This occurs in cases of tuberculosis in which the tuberculous bacillus remains viable within macrophages for many months or even years and movement of the macrophage through the lymphatics to the lymph nodes actually results in the spread of infection. Cardinal Signs of Inflammation 1. Redness or rubor - dilatation and congestion of blood vessels. 2. Swelling or tumor - exudation of fluid (increased vascular permeability) and cells. 3. Heat or calor - mechanisms for this are poorly understood; however, greater blood flow to the region may be a contributing factor. 4. Pain or dolor - pressure upon nerves by the edema fluid. Also direct effect of bradykinins and prostaglandins. 5. Loss of function (functio laesa) - secondary to reflex inhibition of muscular movements associated with pain. Also, mechanical disability may be produced by the swelling and pain. READ CASE STUDY Classifications of Inflammation Inflammation may be classified according to: A. Duration B. Type of exudate formed C. Location and special forms 1. Type of Inflammation Based on Duration - Acute or chronic. - No sharp line of division exists between these forms. A. Acute: o In a clinical sense, acute inflammation is usually of sudden onset and accompanied by one or more of the cardinal signs. It also generally lasts a matter of hours or days. Acute reactions occur when the injury is transient, e.g. physical trauma, burn, or an infection in which the organism is rapidly eradicated by the body's defence mechanisms. o In a pathological sense, acute inflammation has, as its dominant morphological changes, the vascular and exudative changes described, i.e. exudation of fluid and accumulation of cells. The cellular infiltrate contains numerous neutrophils.  sudden onset, accompanied by 1 or more of cardinal signs (redness, swelling, heat, pain, limited function).  Duration - hours to days.  Morphologically - vascular and exudative changes (vasodilatation and increased permeability, inflammatory exudate), numerous neutrophils (review case of acute inflammation - acute appendicitis)  Examples: a cut or scrape, a burn, a bee sting, acute pneumonia. B. Chronic Inflammation: This results from an injurious agent which persists in the tissues and continues to cause damage, e.g. foreign body (wood splinter) which remains in the tissue, organisms which are not eradicated. Chronic inflammation can arise basically under two different sets of circumstances: a. Evolution of acute to chronic inflammation: This occurs characteristically in certain infections. As the agent persists in the tissue, so does the inflammatory reaction to that agent. An example of chronic inflammation would be a staphylococcal infection of bone (osteomyelitis). At first, one sees the typical changes associated with an acute inflammatory reaction. However, usually there is a mass of bone that becomes necrotic and this becomes a suitable place in which the bacteria can persist and which is very difficult for the body defences to reach. Also, it is difficult for antibiotics to reach the bacteria in necrotic tissue. Thus, the battle between organisms and host continues to rage for many weeks or even years. The inflammatory reaction with chronicity takes on two new facets: i. A proliferation of connective tissue (predominantly fibroblasts) and vessels (angiogenesis).
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