Acute Inflammation PDF

The survival of all organisms requires that they eliminate foreign invaders, such as infectious pathogens, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response intended to eliminate the initial cause of cell...

The survival of all organisms requires that they eliminate foreign invaders, such as infectious pathogens, and damaged tissues. These functions are mediated by a complex host response called inflammation. Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult Inflammation can be acute or chronic 1. Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. 2. Chronic inflammation may be more insidious, is of longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring). these basic forms of inflammation can overlap, and many variables modify their course and histologic appearance. The external manifestations of inflammation, often called its cardinal signs, result from the vascular changes and cell recruitment: 1. heat (calor) 2. redness (rubor) 3. swelling (tumor). 4. pain (dolor) and 5. loss of function (functio laesa) 1 The major local manifestations of acute inflammation, compared to normal (1)Vascular dilation and increased blood flow (causing erythema and warmth), (2)extravasation and deposition of plasma fluid and proteins (edema), and (3)leukocyte (mainly neutrophil) emigration and accumulation in the site of injury. 2  General Features of Inflammation Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage. The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various cells. The steps of the inflammatory response can be remembered as the five Rs: (1)Recognition of the injurious agent, (2) Recruitment of leukocytes (3) Removal of the agent (4)Regulation (control) of the response (5)Resolution (repair). The outcome of acute inflammation is either elimination of the noxious stimulus followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation. ACUTE INFLAMMATION Acute inflammation is a rapid response to injury or microbes and other foreign substances that is designed to deliver leukocytes and plasma proteins to sites of injury. Once there, leukocytes clear the invaders and begin the process of digesting and getting rid of necrotic tissues 3 Acute inflammation has two major components: 1) Vascular changes: alterations in vessel caliber resulting in increased blood flow (vasodilation) and structural changes that permit plasma proteins to leave the circulation (increased vascular permeability). 2) Cellular events: emigration of the leukocytes from the microcirculation and accumulation in the focus of injury (cellular recruitment and activation). The principal leukocytes in acute inflammation are neutrophils (polymorphonuclear leukocytes). Stimuli for Acute Inflammation Acute inflammatory reactions may be triggered by a variety of stimuli. Infections (bacterial, viral, fungal, parasitic) are among the most common and medically important causes of inflammation. Trauma (blunt and penetrating) and physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) injure host cells and elicit inflammatory reactions. Tissue necrosis (from any cause), including ischemia (as in a myocardial infarct) and physical and chemical injury. Foreign bodies (splinters, dirt, sutures) Immune reactions (also called hypersensitivity reactions) against environmental substances or against self tissues. Because these stimuli for the inflammatory responses cannot be eliminated, such reactions tend to be persistent, often have features of chronic inflammation, and are important causes of morbidity and mortality. The term "immune mediated inflammatory disease" is sometimes used to refer to this group of disorders. 4 Vascular Changes 1. Changes in Vascular Caliber and Flow Body Changes in blood vessels begin rapidly after infection or injury but may develop at variable rates, depending on the nature and severity of the original inflammatory stimulus. After transient vasoconstriction (lasting only for seconds), arteriolar vasodilation occurs, resulting in locally increased blood flow and engorgement of the down-stream capillary beds. This vascular expansion is the cause of the redness (erythema) and warmth characteristically seen in acute inflammation.As the microvasculature becomes more permeable, protein-rich fluid moves into the extravascular tissues. This causes the red blood cells to become more concentrated, thereby increasing blood viscosity and slowing the circulation. These changes are reflected microscopically by numerous dilated small vessels packed with erythrocytes and slowly flowing blood, a process called stasis.As stasis develops, leukocytes (principally neutrophils) begin to accumulate along the vascular endothelial surface, a process called margination. This is the first step in the journey of the leukocytes through the vascular wall into the interstitial tissue. 2. Increased Vascular Permeability the early phase of inflammation, arteriolar vasodilation and increased volume of blood flow lead to a rise in intravascular hydrostatic pressure, resulting in movement of fluid from capillaries into the tissues.This fluid, called a transudate ,is essentially an ultrafiltrate of blood plasma and contains little protein. However, transudation is soon eclipsed by increasing vascular permeability that allows the movement of protein-rich fluid and even cells (called an exudate )into the interstitium. The loss of protein-rich fluid into the perivascular space reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial fluid. The net result is outflow of water and ions into the extravascular tissues. Fluid accumulation in extravascular spaces is called edema ;the fluid may be a transudate or exudate. Whereas exudates are typical of inflammation, transudates accumulate in various non-inflammatory conditions. 5  Vascular Reactions in Acute Inflammation Vasodilation is induced by chemical mediators such as histamine (described later), and is the cause of erythema and stasis of blood flow. Increased vascular permeability is induced by histamine, kinins and other mediators that produce gaps between endothelial cells, by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the endothelium; increased vascular permeability allows plasma proteins and leukocytes to enter sites of infection or tissue damage; fluid leak through blood vessels results in edema. Several mechanisms for increased vascular permeability 1. formation of endothelial gaps in venules 2. direct endothelial cell injury 3. leukocyte-dependant injury 4. junctional retraction Cellular Events: )Leukocyte Recruitment and Activation) an important function of the inflammatory response is to deliver leukocytes to the site of injury and to activate them. Leukocytes ingest offending agents, kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. A price that is paid for the defensive potency of leukocytes is that, once activated, they may induce tissue damage and prolong inflammation, since the leukocyte products that destroy microbes can also injure normal host tissues. Therefore, key to the normal function of leukocytes in host defense is to ensure that they are recruited and activated only when needed (i.e., in response to foreign invaders and dead tissue 6  Leukocyte Recruitment The sequence of events in the recruitment of leukocytes from the vascular lumen to the extravascular space consists of (1)margination, adhesion to endothelium, and rolling along the vessel wall; (2)firm adhesion to the endothelium; (3) transmigration between endothelial cells; and (4) migration in interstitial tissues toward a chemotactic stimulus. Rolling, adhesion, and transmigration are mediated by the binding of complementary adhesion molecules on leukocytes and endothelial surfaces. Chemical mediators-chemoattractants and certain cytokines-affect these processes by modulating the surface expression or avidity of the adhesion molecules and by stimulating directional movement of the leukocytes. Emigration of neutrophils Sequence of events in leukocytes emigration in inflammation: 1. Margination 2. rolling 3. adhesion 4. transmigration and movement toward injurious agent (stimulus) 7 Sequence of events in leukocytes emigration in inflammation: 1. Margination 2. rolling 3. adhesion 4. transmigration and movement toward injurious agent (stimulus) Leukocyte (neutrophil) migration through blood vessels The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process - selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, intercellular adhesion molecule 1; IL-1, interleukin 1; PECAM-1, platelet endothelial cell adhesion molecule 1; TNF, tumor necrosis factor. 8  Chemotaxis After extravasating from the blood, leukocytes migrate toward sites of infection or injury along a chemical gradient by a process called chemotaxis. Both exogenous and endogenous substances can be chemotactic for leukocytes, including (1)bacterial products, particularly peptides with N-formylmethionine termini; (2) cytokines, especially those of the chemokine family; (3) components of the complement system, particularly C5a; and (4) products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B( 4LTB)4.These mediators, which are described in more detail later, are produced in response to infections and tissue damage and during immunologic reactions. Leukocyte infiltration in all these situations results from the actions of various combinations of mediators. SUMMARY Leukocyte Recruitment to Sites of Inflammation Leukocytes are recruited from the blood into the extravascular tissue where infectious pathogens or damaged tissues may be located, migrate to the site of infection or tissue injury, and are activated to perform their functions.Leukocyte recruitment is a multi-step process consisting of loose attachment to and rolling on endothelium (mediated by selectins); firm attachment to endothelium (mediated by integrins); and migration through inter-endothelial spaces.Various cytokines promote expression of selectins and integrin ligands on endothelium (TNF, IL-1), increase the avidity of integrins for their ligands (chemokines), and promote directional migration of leukocytes (also chemokines); many of these cytokines are produced by tissue macrophages and other cells responding to the pathogens or damaged tissues.Neutrophils predominate in the early inflammatory infiltrate and are later replaced by macrophages. 9 Leukocyte Effector Mechanisms Leukocytes can eliminate microbes and dead cells by phagocytosis, followed by their destruction in phagolysosomes.Destruction is caused by free radicals (ROS, NO) generated in activated leukocytes and lysosomal enzymes.Enzymes and ROS may be released into the extracellular environment.The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) are also capable of damaging normal tissues (the pathologic consequences of inflammation). Phagocytosis 10  Sequence of Events in Acute Inflammation The vascular changes in acute inflammation are characterized by increased blood flow secondary to arteriolar and capillary bed dilation (erythema and warmth).Increased vascular permeability, either through widened interendothelial cell junctions of the venules or by direct endothelial cell injury, results in an exudate of protein-rich extravascular fluid (tissue edema).The leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules, then leave the microvasculature and migrate to the site of injury under the influence of chemotactic agents. Phagocytosis, killing, and degradation of the offending agent follow.Genetic or acquired defects in leukocyte functions give rise to recurrent infections. The outcome of acute inflammation may be removal of the exudate with restoration of normal tissue architecture (resolution); transition to chronic inflammation; or extensive destruction of the tissue resulting in scarring. Outcome of acute inflammation 1. Resolution. When the injury is limited or short-lived, when there has been no or minimal tissue damage, and when the tissue is capable of replacing any irreversibly injured cells, the usual outcome is restoration to histologic and functional normalcy. 2.Progression to chronic inflammation may follow acute inflammation if the offending agent is not removed. In some instances, signs of chronic inflammation may be present at the onset of injury (e.g., in viral infections or immune responses to self-antigens). Depending on the extent of the initial and continuing tissue injury, as well as the capacity of the affected tissues to regrow, chronic inflammation may be followed by restoration of normal structure and function or may lead to scarring. 11  3. Scarring or fibrosis results after substantial tissue destruction or when inflammation occurs in tissues that do not regenerate. In addition, extensive fibrinous exudates (due to increased vascular permeability) may not be completely absorbed and are organized by ingrowth of connective tissue, with resultant fibrosis. 4. Abscesses may form in the setting of extensive neutrophilic infiltrates (see later) or in certain bacterial or fungal infections (these organisms are then said to be pyogenic, or "pus forming"). Because of the underlying tissue destruction (including damage to the ECM), the usual outcome of abscess formation is scarring. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION 1. Serous inflammation is characterized by the outpouring of a watery, relatively protein poor fluid that, depending on the site of injury, derives either from the serum or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. The skin blister resulting from a burn or viral infection is a good example of a serous effusion accumulated either within or immediately beneath the epidermis of the skin. Fluid in a serous cavity is called an effusion. 2. Fibrinous inflammation occurs as a consequence of more severe injuries, resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier. Histologically, the accumulated extravascular fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum (Fig. 2-11). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura. Such exudates may be degraded by fibrinolysis, and the accumulated debris may be removed by macrophages, resulting in restoration of the normal tissue structure (resolution). However, failure to completely  12 remove the fibrin results in the ingrowth of fibroblasts and blood vessels (organization), leading ultimately to scarring that may have significant clinical consequences. For example, organization of a fibrinous pericardial exudate forms dense fibrous scar tissue that bridges or obliterates the pericardial space and restricts myocardial function. Serous inflammation (serous pleural effusion) Excessive accumulation of clear, thin fluid within pleural cavity. It is transparent but note the reflection of light in the upper part of the photograph and lung collapse (arrow) due to pressure induced by the fluid. 13 Fibrinous exudate-pericardium there is a lot of fibrin. The visceral and parietal surfaces become stuck together (by fibrin). Separation of the two layers imparts rough irregular appearance (the so called bread and butter). 3. Suppurative (purulent) inflammation is manifested by the presence of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. Certain organisms (e.g., staphylococci) are more likely to induce such localized suppuration and are therefore referred to as pyogenic.Abscesses are focal collections of pus that may be caused by seeding of pyogenic organisms into a tissue or by secondary infections of necrotic foci. Abscesses typically have a central, largely necrotic region rimmed by a layer of preserved neutrophils( Fig. 2-12 ,)with a surrounding zone of dilated vessels and fibroblastic proliferation indicative of early repair. As time passes the abscess may become completely walled off and eventually be replaced by connective tissue. 14 4. An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of inflammatory necrotic tissue ( Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in (1) inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract; and (2) tissue necrosis and subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances that predispose to extensive necrosis. Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist. During the acute stage there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. With chronicity, the margins and base of the ulcer develop scarring with accumulation of lymphocytes, macrophages, and plasma cells. Appendix: acute suppurative inflammation Upper half of excised appendix. Lt: fibrino-purulent serosal exudate Rt: lumen filled with pus 15 Appendix: acute suppurative inflammation Mucosal ulceration and undermining by an extensive neutrophilic exudate Abscess (Furuncle) (boil) Abscess that involves the skin is called “Boil” or “furuncle”. 16 Chronic peptic ulcer stomach Sharply delimited chronic peptic ulcer with converging folds of mucosa in the upper half 17 laryngeal Ulcerations Below the vocal cords in this larynx are large ulcerations. Such subglottic ulcers are produced with prolonged endotracheal intubation in which the cuff of the endotracheal tube fits too tight. Thus, ulcerations can be produce by mechanical forces. In fact, so-called "pressure ulcers" or "decubitus ulcers" can form in the skin over bony prominences in persons who are bedridden for an extended time. 5) Catarrhal inflammation This is a mild and superficial inflammation of the mucous membrane. It is commonly seen in the upper respiratory tract following viral infections where mucous secreting glands are present in large numbers, eg. Rhinitis. 6) Pseudomembranous inflammation The basic elements of pseudomembranous inflammation are extensive confluent necrosis of the surface epithelium of an inflamed mucosa and severe acute inflammation of the underlying tissues.  The fibrinogens in the inflamed tissue coagulate within the necrotic epithelium. And the fibrinogen, the necrotic epithelium, the neutrophilic polymorphs, red blood cells, bacteria and tissue debris form a false (pseudo) membrane which forms a white or colored layer over the surface of inflamed mucosa Pseudomembranous inflammation is exemplified by Dipthetric infection of the pharynx or larynx and Clostridium difficille infection in the large bowel following certain antibiotic use. CHEMICAL MEDIATORS OF INFLAMMATION A. Cell-Derived Mediators: Tissue macrophages, mast cells, and endothelial cells at the site of inflammation, as well as leukocytes that are recruited to the site from the blood, are all capable of producing different mediators of inflammation 1. Vasoactive amines: histamine, serotonin; main effects are vasodilation and increased vascular permeability 2. Arachidonic acid metabolites: prostaglandins and leukotrienes; several forms exist and are involved in vascular reactions, leukocyte chemotaxis, and other reactions of inflammation; antagonized by lipoxins 3. Cytokines: proteins produced by many cell types; usually act at short range; mediate multiple effects, mainly in leukocyte recruitment and migration; principal ones in acute inflammation are TNF, IL-1, and chemokines 4. Reactive oxygen species: role in microbial killing, tissue injury 5. Nitric oxide : vasodilation, microbial killing 6. Lysosomal enzymes: role in microbial killing, tissue injury B. Plasma Protein-Derived Mediators: Circulating proteins of three interrelated systems-the complement, kinin, and coagulation systems-are involved in several aspects of the inflammatory reaction. 1. Complement proteins: Activation of the complement system by microbes or antibodies leads to the generation of multiple breakdown products, which are responsible for leukocyte chemotaxis, opsonization and phagocytosis of microbes and other particles, and cell killing 2. Coagulation proteins: Activated factor XII triggers the clotting, kinin and complement cascades, and activates the fibrinolytic systemKinins: Produced by proteolytic cleavage of precursors; mediate vascular reaction, pain A. Beneficial effects: ♦Dilution of toxins: The concentration of chemical and bacterial toxins at the site of inflammation is reduced by dilution in the exudate and its removal from the site by the flow of exudates from the venules through the tissue to the lymphatics. ♦Protective antibodies: Exudation results in the presence of plasma proteins including antibodies at the site of inflammation. Thus, antibodies directed against thecausative organisms will react and promote microbial destruction by phagocytosis or complementmediated cell lysis. ♦Fibrin formation: This prevents bacterial spread and enhances phagocytosis by leukocytes. ♦Plasma mediator systems provisions: The complement, coagulation, fibrinolytic, &kinin systems are provided to the area of injury by the process of inflammation. ♦Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen andother nutrients to meet the metabolic requirements of the greatly increased number of cells. It also removes their solute waste products via lymphatic channels. ♦Promotion of immunity: Micro-organisms and their toxins are carried by the exudates, either free or in phagocytes, along the lymphaics to local lymph Nodes where they stimulate an immune  response with the generation of antibodies and cellular immune mechanisms of defence. B. Harmful effects Tissue destruction Inflammation may result in tissue necrosis and the tissue necrosis may, in turn, incite inflammation. Swelling The swelling caused by inflammation may have serious mechanical effects at certain locations. Examples include acute epiglottitis with interference inbreathing. Acute meningitis and encephalitis with effects of increased intracranial pressure. Inappropriate response The inflammatory seen in hypersensitivity reactions is inappropriate (i.e. exaggerated).