Bệnh học viêm - bài giảng lí thuyết giải phấu bệnh
- 2. Overview of Inflammation (p. 44) • Viêm là phản ứng của mô sống động mạch máu đến chấn thương • Inflammation is the response of vascularized living tissue to injury. It may be evoked by microbial infections, physical agents, chemicals, necrotic tissue, or immune reactions. Inflammation is intended to contain and isolate injury, to destroy invading microorganisms and inactivate toxins, and to prepare the tissue for healing and repair
- 3. Viêm được đặc trưng bởi : • • Two main components—a vascular wall response and an inflammatory cell response • Effects mediated by circulating plasma proteins and by factors produced locally by the vessel wall or inflammatory cells • Termination when the offending agent is eliminated and the secreted mediators are removed; active anti-inflammatory mechanisms are also involved • Tight association with healing; even as inflammation destroys, dilutes, or otherwise contains injury it sets into motion events that ultimately lead to repair of the damage • A fundamentally protective response; however, inflammation can also be harmful, for example, by causing life-threatening hypersensitivity reactions or relentless and progressive organ damage from chronic inflammation and subsequent fibrosis (e.g., rheumatoid arthritis, atherosclerosis)
- 4. Acute and chronic patterns: • Acute inflammation: Early onset (i.e., seconds to minutes), short duration (i.e., minutes to days), involving fluid exudation (edema) and polymorphonuclear cell (neutrophil) emigration Chronic inflammation: Later onset (i.e., days) and longer duration (i.e., weeks to years), involving lymphocytes and macrophages, with blood vessel proliferation and fibrosis (scarring)
- 5. There are five classic clinical signs of inflammation (most prominent in acute inflammation): • • Warmth (Latin: calor) due to vascular dilation • Erythema (Latin: rubor) due to vascular dilation and congestion • Edema (Latin: tumor) due to increased vascular permeability • Pain (Latin: dolor) due to mediator release • Loss of function (Latin: functio laesa) due to pain, edema, tissue injury, and/or scar
- 6. Acute Inflammation (p. 45) • Acute inflammation has three major components: • Alterations in vascular caliber, leading to increased blood flow • Structural changes in the microvasculature, permitting plasma proteins and leukocytes to leave the circulation to produce inflammatory exudates • Leukocyte emigration from blood vessels and accumulation at the site of injury with activation
- 7. Reactions of Blood Vessels in Acute Inflammation (p. 46) • Normal fluid exchange in vascular beds depends on an intact endothelium and is modulated by two opposing forces: • Hydrostatic pressure causes fluid to move out of the circulation. • Plasma colloid osmotic pressure causes fluid to move into the capillaries.
- 8. Changes in Vascular Flow and Caliber (p. 46) • Beginning immediately after injury, the vascular wall develops changes in caliber and permeability that affect flow. The changes develop at various rates depending on the nature of the injury and its severity. • Vasodilation causes increased flow into areas of injury, thereby increasing hydrostatic pressure. • Increased vascular permeability causes exudation of protein-rich fluid (see later discussion). • The combination of vascular dilation and fluid loss leads to increased blood viscosity and increased concentration of red blood cells (RBCs). Slow movement of erythrocytes (stasis) grossly manifests as vascular congestion (erythema). • With stasis, leukocytes—mostly neutrophils—accumulate along the endothelium (marginate) and are activated by mediators to increase adhesion molecule expression and migrate through the vessel wall
- 9. Increased Vascular Permeability (p. 47) Increased vascular permeability can be induced by several different pathways: 1. Contraction of venule endothelium to form intercellular gaps: • Most common mechanism of increased permeability • Elicited by chemical mediators (e.g., histamine, bradykinin, leukotrienes, etc.) • Occurs rapidly after injury and is reversible and transient (i.e., 15 to 30 minutes), hence the term immediate-transient response • A similar response can occur with mild injury (e.g., sunburn) or inflammatory cytokines but is delayed (i.e., 2 to 12 hours) and protracted (i.e., 24 hours or more)
- 10. 2. Direct endothelial injury: • • Severe necrotizing injury (e.g., burns) causes endothelial cell necrosis and detachment that affects venules, capillaries, and arterioles • Recruited neutrophils may contribute to the injury (e.g., through reactive oxygen species) • Immediate and sustained endothelial leakage
- 11. 3. Increased transcytosis: • Transendothelial channels form by interconnection of vesicles derived from the vesiculovacuolar organelle • Vascular endothelial growth factor (VEGF) and other factors can induce vascular leakage by increasing the number of these channels 4. Leakage from new blood vessels: • Endothelial proliferation and capillary sprouting (angiogenesis) result in leaky vessels • Increased permeability persists until the endothelium matures and intercellular junctions form
- 12. Responses of Lymphatic Vessels (p. 47) • Lymphatics and lymph nodes filter and “police” extravascular fluids. With the mononuclear phagocyte system, they represent a secondary line of defense when local inflammatory responses cannot contain an infection. • In inflammation, lymphatic flow is increased to drain edema fluid, leukocytes, and cell debris from the extravascular space. • In severe injuries, drainage may also transport the offending agent; lymphatics may become inflamed (lymphangitis, manifest grossly as red streaks), as may the draining lymph nodes (lymphadenitis, manifest as enlarged, painful nodes). The nodal enlargement is usually due to lymphoid follicle and sinusoidal phagocyte hyperplasia (termed reactive lymphadenitis, Chapter 13)
- 13. Reactions of Leukocytes in Inflammation (p. 48) • In most forms of acute inflammation, neutrophils predominate during the first 6 to 24 hours and are then replaced by monocytes after 24 to 48 hours The process of getting cells from vessel lumen to tissue interstitium is called extravasation and is divided into three steps (Fig. 2-1): • Margination, rolling, and adhesion of leukocytes to the endothelium • Transmigration across the endothelium • Migration in interstitial tissues toward a chemotactic stimulus
- 14. Leukocyte Adhesion to Endothelium (p. 48) With progressive stasis of blood flow, leukocytes become increasingly distributed along the vessel periphery (margination), followed by rolling and then firm adhesion, before finally crossing the vascular wall. Rolling, adhesion, and transmigration occur by interactions between complementary adhesion molecules on leukocytes and endothelium. Expression of these adhesion molecules is enhanced by secreted proteins called cytokines. The major adhesion molecule pairs are listed in Table 2-1: • Selectins (E, P, and L) bind via lectin (sugar-binding) domains to oligosaccharides (e.g., sialylated Lewis X) on cell surface glycoproteins. These interactions mediate rolling. • Immunoglobulin family molecules on endothelial cells include intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1); these bind integrins on leukocytes and mediate firm adhesion. • Integrins are a-b heterodimers (protein pairs) on leukocyte surfaces that bind to members of the immunoglobulin family molecules and to the extracellular matrix. The principal integrins that bind ICAM-1 are b2 integrins LFA-1 and Mac-1 (also called CD11a/CD18 and CD11b/CD18); the principal integrin that binds to VCAM-1 is the b1 integrin VLA4.
- 15. hese modulating molecules induce leukocyte adhesion in inflammation by three general mechanisms: • • Redistribution of preformed adhesion molecules to the cell surface. After histamine exposure, P-selectin is rapidly translocated from the endothelial Weibel-Palade body membranes to the cell surface, where it can bind leukocytes. • Induction of adhesion molecules on endothelium. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) increase endothelial expression of E-selectin, ICAM-1, and VCAM-1; such activated endothelial cells have increased leukocyte adherence. • Increased avidity of binding. This is most important for integrin binding. Integrins are normally present on leukocytes in a lowaffinity form; they are converted to high-affinity forms by a variety of chemokines. Such activation causes firm adhesion of the leukocytes to the endothelium and is required for subsequent transmigration.
- 16. Leukocyte Migration through Endothelium • Transmigration (also called diapedesis) is mediated by homotypic (like-like) interactions between platelet-endothelial cell adhesion molecule-1 ¼ CD31 (PECAM-1) on leukocytes and endothelial cells. Once across the endothelium and into the underlying connective tissue, leukocytes adhere to the extracellular matrix via integrin binding to CD44.
- 17. Chemotaxis of Leukocytes (p. 50) • After emigrating through interendothelial junctions and traversing the basement membrane, leukocytes move toward sites of injury along gradients of chemotactic agents (chemotaxis). For neutrophils, Chemotaxis involves binding of chemotactic agents to specific leukocyte surface G protein–coupled receptors; these trigger the production of phosphoinositol second messengers, in turn causing increased cytosolic calcium and guanosine triphosphatase (GTPase) activities that polymerize actin and facilitate cell movement. Leukocytes move by extending pseudopods that bind the extracellular matrix and then pull the cell forward (front-wheel drive).
- 18. Recognition of Microbes and Dead Tissues (p. 51) • Having arrived at the appropriate site, leukocytes distinguish offending agents and then destroy them. To accomplish this, inflammatory cells express a variety of receptors that recognize pathogenic stimuli, and deliver activating signals (Fig. 2-2). • Receptors for microbial products: These include toll-like receptors (TLRs), one of 10 different mammalian proteins that recognize distinct components in different classes of microbial pathogens. Thus, some TLRs participate in cellular responses to bacterial lipopolysaccharide (LPS) or unmethylated CpG nucleotide fragments, whereas others respond to double-stranded RNA made by some viral infections. TLRs can be on the cell surface or within endosomal vesicles depending on the likely location of the pathogen (extracellular versus ingested). They function through receptor-associated kinases that in turn induce production of cytokines and microbicidal substances.
- 19. • • G protein–coupled receptors: These receptors typically recognize bacterial peptides containing N-formyl methionine residues, or they are stimulated by the binding of various chemokines (see preceding discussion), complement fragments, or arachidonic acid metabolites (e.g., prostaglandins and leukotrienes). Ligand binding triggers migration and production of microbicidal substances. • Receptors for opsonins: Molecules that bind to microbes and render them more “attractive” for ingestion are called opsonins; these include antibodies, complement fragments, and certain lectins (sugar-binding proteins). Binding of opsonized (coated) particles to their leukocyte receptor leads to cell activation and phagocytosis (see later). • Cytokine receptors: Inflammatory mediators (cytokines) bind to cell surface receptors and induce cellular activation. One of the most important is interferon-g, produced by activated T cells and natural killer cells, and the major macrophage-activating cytokine.
- 20. Removal of the Offending Agents (p. 52) • Recognition through any of the preceding receptors induces leukocyte activation (see Fig. 2-2). The most essential functional consequences of activation are enhanced phagocytosis and intracellular killing, although the release of cytokines, growth factors, and inflammatory mediators (e.g., prostaglandins) is also important. Phagocytosis (p. 52) Phagocytosis begins with leukocyte binding to the microbe; this is facilitated by opsonins, the most important being the immunoglobulin Fc fragment and the complement fragment C3b. Macrophage integrins, and the macrophage mannose and scavenger receptors (mannose is expressed as a terminal sugar on many microbes), are also important recognition proteins for phagocytosis.
- 21. • Engulfment (p. 53) After binding to receptors, cytoplasmic pseudopods enclose the particle and eventually pinch off to make a phagosome vesicle. Subsequent fusion of phagosomes and lysosomes (forming a phagolysosome) discharges lysosomal contents into the space around the microbe but can also occasionally dump lysosomal granules into the extracellular space. Killing and Degradation (p. 53) Killing of phagocytosed particles is most efficient in activated leukocytes, and is accomplished largely by reactive oxygen species (ROS). Phagocytosis stimulates an oxidative burst—a surge of oxygen consumption with production of reactive oxygen metabolites through activation of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. The enzyme converts oxygen to superoxide anion (O2• ), eventually resulting in hydrogen peroxide (H2O2). Lysosomal myeloperoxidase (MPO) then converts H2O2 and Cl into the highly bactericidal HOCl (hypochlorite—the active ingredient in bleach). Although the MPO system is the most efficient mechanism, other reactive oxygen species of the oxidative burst can also kill bacteria. Notably reactive nitrogen species such as peroxynitrite radical (ONOO•) derived from nitric oxide (NO) and superoxide are also highly microbicidal.
- 22. • Defects in Leukocyte Function (p. 55) Defects in leukocyte function (at any stage from endothelial adherence to microbicidal activity) interfere with inflammation and dramatically increase infection susceptibility. Defects, either genetic or acquired, include: • Genetic deficiencies in adhesion molecules: Leukocyte adhesion deficiency type I is due to defective synthesis of b2 integrins (LFA-1 and Mac-1); type II deficiency is due to a defect in fucose Acute and Chronic Inflammation 31 metabolism causing loss of sialyl-Lewis X (ligand for E- and Pselectin). • Genetic defects in phagolysosome formation: In Che ´diak-Higashi syndrome, neutrophils have aberrant organellar fusion with defective lysosomal enzyme delivery to phagosomes. • Genetic defects in microbicidal activity: In chronic granulomatous disease, there are inherited defects in NADPH oxidase, leading to a defect in the respiratory burst, superoxide and H2O2 production, and the MPO bactericidal mechanism. • Acquired deficiencies of neutrophils: Called neutropenia, this is the most common clinical cause of leukocyte defects; it may be caused by cancer chemotherapy or by metastatic tumor replacing normal bone marrow.
- 23. Defects in Leukocyte Function (p. 55) • Defects in leukocyte function (at any stage from endothelial adherence to microbicidal activity) interfere with inflammation and dramatically increase infection susceptibility. Defects, either genetic or acquired, include: • Genetic deficiencies in adhesion molecules: Leukocyte adhesion deficiency type I is due to defective synthesis of b2 integrins (LFA-1 and Mac-1); type II deficiency is due to a defect in fucose Acute and Chronic Inflammation 31 metabolism causing loss of sialyl-Lewis X (ligand for E- and Pselectin). • Genetic defects in phagolysosome formation: In Che ´diak-Higashi syndrome, neutrophils have aberrant organellar fusion with defective lysosomal enzyme delivery to phagosomes. • Genetic defects in microbicidal activity: In chronic granulomatous disease, there are inherited defects in NADPH oxidase, leading to a defect in the respiratory burst, superoxide and H2O2 production, and the MPO bactericidal mechanism. • Acquired deficiencies of neutrophils: Called neutropenia, this is the most common clinical cause of leukocyte defects; it may be caused by cancer chemotherapy or by metastatic tumor replacing normal bone marrow.
- 24. Termination of the Acute Inflammatory Response (p. 56) • Inflammation declines, in part, because mediators are produced only transiently and typically have short half-lives; however, because of its inherent capacity to damage tissues, inflammation must also be tightly and actively regulated. Thus, even as inflammation is developing, stop signals are also being triggered. These include a switch from pro-inflammatory arachidonate metabolites (leukotrienes) to anti-inflammatory forms (lipoxins, described later), production of anti-inflammatory cytokines such as transforming growth factor-b (TGF-b) and interleukin-10 (IL-10), synthesis of fatty acid–derived anti-inflammatory mediators (resolvins and protectins), and neural impulses that inhibit macrophage TNF production.
- 26. Cell-Derived Mediators • Vasoactive Amines: Histamine and Serotonin (p. 57) Released from preformed cellular stores, these are among the first mediators in inflammation. They cause arteriolar dilation and increased permeability of venules. Mast cells are the major source of histamine, though basophils and platelets also contribute. Mast cell release is caused by physical Serotonin (5-hydroxytryptamine) has activities similar to histamine; major sources are platelets and neuroendocrine cells (not mast cells). Platelet release of both histamine and serotonin is stimulated by contact with collagen, thrombin, adenosine diphosphate (ADP), and antigen-antibody complexes, one of several links between clotting and inflammation.
- 27. Arachidonic Acid Metabolites: Prostaglandins, Leukotrienes, and Lipoxins (p. 58) • Activated cells release membrane-bound arachidonic acid (AA) through the enzymatic activity of phospholipase A2. The 20-carbon polyunsaturated AA is then catabolized to generate short-range lipid mediators (eicosanoids) through the activities of two major enzyme classes (Fig. 2-3). Eicosanoids bind to membrane G protein–coupled receptors and can mediate almost every aspect of inflammation (Table 2-3): • Cyclooxygenases (COX-1 is constitutively expressed; COX-2 is inducible) generate prostaglandins and thromboxanes. These enzymes are irreversibly inhibited by aspirin and reversibly inhibited by other non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroid anti-inflammatory effects include blockade of the transcription of phospholipase A2 and COX-2. • Lipoxygenases produce leukotrienes (pro-inflammatory mediators) and lipoxins (anti-inflammatory mediators). Cell-cell interactions are important in both leukotriene and lipoxin biosynthesis. AA products can diffuse from one cell to another, thereby allowing cells unable to otherwise synthesize specific eicosanoids to produce them from intermediates generated in other cells. Compounds that block 5-lipoxygenase activity have antiinflammatory activity.
- 28. Platelet-Activating Factor (p. 60) • Platelet-activating factor (PAF) is a phospholipid-derived mediator produced by mast cells, platelets, leukocytes, and endothelium. Besides platelet aggregation and granule release (hence its name), PAF can elicit most of the vascular and cellular reactions of inflammation: vasodilation and increased vascular permeability (i.e., 100 to 10,000 times more potent than histamine), bronchoconstriction, increased leukocyte adhesion, chemotaxis, and the oxidative burst.
- 29. Reactive Oxygen Species • Oxygen-derived free radicals (including O2• , H2O2, and hydroxyl radical) are released extracellularly from leukocytes after phagocytosis and after exposure to chemokines, immune complexes, or microbial products • ROS effects include: • Endothelial cell damage causing increased vascular permeability • Injury to multiple cell types (e.g., tumor cells, red cells, parenchymal cells) • Inactivation of anti-proteases (e.g., a1-anti-trypsin), resulting in unopposed protease activity
- 30. Outcomes of Acute Inflammation • three general outcomes: • Complete resolution occurs with regeneration of native cells and restoration to normalcy • Healing by connective tissue replacement (fibrosis) occurs after substantial tissue destruction, when inflammation occurs in non-regenerating tissues, or in the setting of abundant fibrin exudation (also called organization). • Progresses to chronic inflammation, outlined in greater detail later.
- 31. Morphologic Patterns of Acute Inflammation • Serous Inflammation (p. 67) Serous inflammation is marked by fluid transudates reflecting moderately increased vascular permeability. Such accumulations in the peritoneal, pleural, and pericardial cavities are called effusions; serous fluid can also accumulate elsewhere (e.g., burn blisters in skin)
- 32. Fibrinous Inflammation (p. 67) • Fibrinous inflammation is a more marked increase in vascular permeability, with exudates containing large amounts of fibrinogen. The fibrinogen is converted to fibrin through coagulation system activation. Involvement of serosal surfaces (e.g., pericardium or pleura) is referred to as fibrinous pericarditis or pleuritis. Fibrinous exudates can be resolved by fibrinolysis and macrophage clearance of debris. Larger exudates that cannot be cleared will be converted to fibrous scar (organization) by the ingrowth of vessels and fibroblasts.
- 33. Suppurative or Purulent Inflammation; Abscess (p. 68) • This pattern is characterized by purulent exudates (pus) consisting of neutrophils, necrotic cells, and edema. An abscess is a localized collection of purulent inflammation accompanied by liquefactive necrosis, often in the setting of bacterial seeding. With time, these may be walled off and then organized into fibrous scar. Ulcers (p. 68) Ulcers are local erosions of epithelial surfaces produced by sloughing of inflamed necrotic tissue (e.g., gastric ulcers).
- 34. Summary of Acute Inflammation (p. 68) • When encountering an injurious agent (e.g., microbe or dead cells), phagocytes attempt to eliminate these agents and secrete cytokines, eicosanoids, and other mediators. These mediators, in turn, act on vascular wall cells to induce vasodilation and on endothelial cells specifically to promote plasma efflux and further leukocyte recruitment. Recruited leukocytes are activated and will phagocytize offending agents, as well as produce additional mediators. As the injurious agent is eliminated, anti-inflammatory counterregulatory mechanisms quench the process, and the host returns to a normal state of health. If the injurious agent cannot be effectively eliminated, the result may be chronic inflammation.
- 35. Chronic Inflammation (p. 70) • Chronic inflammation is a prolonged process (i.e., weeks or months) in which active inflammation, tissue destruction, and healing all proceed simultaneously. It occurs: • Following acute inflammation, as part of the normal healing process • Due to persistence of an inciting stimulus or repeated bouts of acute inflammation • As a low-grade, smoldering response without prior acute inflammation
- 36. Causes of Chronic Inflammation (p. 70) • • Persistent infection by intracellular microbes (e.g., tubercle bacilli, viruses) of low direct toxicity but nevertheless capable of evoking immunologic responses • Immune reactions, particularly those against one’s own tissues (e.g., autoimmune diseases), or abnormally regulated responses to normal host flora (inflammatory bowel disease) or benign environmental substances (allergy) (Chapter 6) 44 General Pathology • Prolonged exposure to potentially toxic exogenous substances (e.g., silica, causing pulmonary silicosis) or endogenous substances (e.g., lipids, causing atherosclerosis)
- 37. Morphologic Features (p.70) • In contrast to acute inflammation—characterized by vascular changes, edema, and neutrophilic infiltration—chronic inflammation is typified by: • Infiltration with mononuclear inflammatory cells, including macrophages, lymphocytes, and plasma cells • Tissue destruction, induced by persistent injury and/or inflammation • Attempts at healing by connective tissue replacement, accomplished by vascular proliferation (angiogenesis) and fibrosis
- 38. Role of Macrophages in Chronic Inflammation (p. 71) • Macrophages are the dominant cellular players in chronic inflammation. • Macrophages derive from circulating monocytes induced to emigrate across the endothelium by chemokines. After reaching the extravascular tissue, monocytes transform into the phagocytic macrophage (Fig. 2-7). • Macrophages are activated through cytokines produced by immune-activated T cells (especially IFN-g) or by nonimmune factors (e.g., endotoxin). Depending on the nature of the stimulus (e.g., IFN-g versus interleukin-4), macrophages produce proinflammatory mediators intended to increase their microbicidal capacity, or drive the process of wound repair, through production of mediators that cause fibroblast proliferation, connective tissue production, and angiogenesis (see Fig. 2-7). • Although macrophage products are important for host defense, some mediators induce tissue damage. These include reactive oxygen and nitric oxide metabolites that are toxic to cells and proteases that degrade extracellular matrix. • In short-lived inflammation with clearance of the initial stimulus, macrophages relatively quickly die off or exit via lymphatics. In chronic inflammation, macrophage accumulation persists by continued recruitment of monocytes and local proliferation.
- 39. Other Cells in Chronic Inflammation (p. 72) • • Lymphocytes are mobilized in both antibody- and cell-mediated immune reactions. Lymphocytes and macrophages interact in a bi-directional way—activated macrophages present antigen to T cells and also influence T cell activation through surface molecules and cytokines; in turn, activated T lymphocytes (particularly via IFN-g) activate macrophages (Chapter 6). • Plasma cells are terminally differentiated B cells that produce antibodies directed against either foreign antigen or altered tissue components. • Eosinophils are characteristic of immune reactions mediated by IgE and in parasitic infections. Eosinophil recruitment depends on eotaxin, a CC chemokine. Eosinophils have granules containing major basic protein (MBP), a cationic molecule that is toxic to parasites but also lyses mammalian epithelium (Chapter 6). • Mast cells are widely distributed in connective tissues and participate in both acute and chronic inflammation. They express surface receptors that bind the Fc portion of IgE. In acute reactions, binding of specific antigens to these IgE antibodies leads to mast cell degranulation and mediator release (e.g., histamine). This type of response occurs during anaphylactic reactions to foods,
- 40. Granulomatous Inflammation (p. 73) • This distinctive form of chronic inflammation is characterized by focal accumulations of activated macrophages (granulomas); macrophage activation is reflected by enlargement and flattening of the cells (so-called epithelioid macrophages).
- 41. • Nodules of epithelioid macrophages in granulomatous inflammation are surrounded by a collar of lymphocytes elaborating factors necessary to induce macrophage activation. Activated macrophages may fuse to form multi-nucleate giant cells, and central necrosis may be present in some granulomas (particularly from infectious causes). Older granulomas can be surrounded by a rim of fibrosis. • Foreign body granulomas are incited by particles that cannot be readily phagocytosed by a single macrophage but do not elicit a specific immune response (e.g., suture or talc). • Immune granulomas are formed by immune T cell–mediated responses to persistent, poorly degradable antigens. IFN-g from activated T cells causes the macrophage transformation to epithelioid cells and the formation of multinucleate giant cells. The prototypical immune granuloma is caused by the tuberculosis bacillus; in that setting, the granuloma is called a tubercle and classically exhibits central caseous necrosis. • Granulomatous inflammation is a distinctive inflammatory reaction with relatively few (albeit important) possible causes.
- 42. • Infectious etiologies: Tuberculosis, leprosy, syphilis, cat-scratch disease, schistosomiasis, certain fungal infections Inflammatory causes: Temporal arteritis, Crohn disease, sarcoidosis Inorganic particulates: Silicosis, berylliosis
- 43. Systemic Effects of Inflammation (p. 74) • Systemic changes associated with inflammation are collectively called the acute phase response, or—in severe cases—the systemic inflammatory response syndrome (SIRS). These represent responses to cytokines produced either by bacterial products (e.g., endotoxin) or by other inflammatory stimuli.
- 44. Fever • Fever occurring when temperature elevation (i.e., 1 to 4 C) is produced in response to pyrogens, substances that stimulate prostaglandin synthesis in the hypothalamus. For example, endotoxin stimulates leukocyte release of IL-1 and TNF to increase cyclooxygenase production of prostaglandins. In the hypothalamus, PGE2 stimulates intracellular second signals (e.g., cyclic AMP) that reset the temperature set point. Thus, aspirin reduces fever by inhibiting cyclooxygenase activity to block prostaglandin synthesis.
- 45. • Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose synthesis increases several hundred-fold in response to inflammatory stimuli (e.g., cytokines such as IL-6 and TNF). Three of the best-known examples are C-reactive protein (CRP), fibrinogen, and serum amyloid A protein (SAA). CRP and SAA bind to microbial cell walls and may act as opsonins and fix complement. They may also help clear necrotic cell nuclei and mobilize metabolic stores. Elevated fibrinogen leads to increased erythrocyte aggregation, leading to an increased erythrocyte sedimentation rate on ex vivo testing. Hepcidin is another acute phase reactant responsible for regulating release of intracellular iron stores; chronically elevated hepcidin is responsible for the iron-deficiency anemia associated with chronic inflammation (Chapter 14).
- 46. • Leukocytosis (increased white cell number in peripheral blood) is a common feature of inflammatory reactions. It occurs by accelerated release of bone marrow cells, typically with increased numbers of immature neutrophils in the blood (shift to the left). Prolonged infection also induces proliferation of bone marrow Acute and Chronic Inflammation 47 precursors due to increased colony-stimulating factor (CSF) production. The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but may reach extraordinarily high levels of 40,000 to 100,000 cells/mL (referred to as leukemoid reactions). Bacterial infections typically increase neutrophil numbers (neutrophilia); viral infections increase lymphocyte numbers (lymphocytosis); parasitic infestations and allergic disorders are associated with increased eosinophils (eosinophilia).
- 47. • Other manifestations of the acute phase response include increased pulse and blood pressure; decreased sweating (due to blood flow diverted from cutaneous to deep vascular beds to limit heat loss); rigors (shivering), chills, anorexia, somnolence, and malaise, probably due to effects of cytokines on the central nervous system (CNS). • In severe bacterial infections (sepsis), the large amounts of organisms and endotoxin in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1. High levels of these cytokines can result in a clinical triad of disseminated intravascular coagulation (DIC), metabolic disturbances, and cardiovascular failure described as septic shock (Chapter 4).
- 48. Consequences of Defective or Excessive Inflammation (p. 75) • • Defective inflammation typically results in increased susceptibility to infections and delayed healing of wounds and tissue damage. Delayed repair occurs because inflammation is essential for clearing damaged tissues and debris, in addition to providing the necessary stimulus to get the repair process started. • Excessive inflammation is the basis of many categories of human disease (e.g., allergies and autoimmune diseases) (Chapter 6). Inflammation also plays a critical role in cancer, atherosclerosis and ischemic heart disease, and some neurodegenerative diseases (e.g., Alzheimer disease). Prolonged inflammation and the accompanying fibrosis also cause pathologic changes in chronic infectious, metabolic, and other disease