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Pathology_Robbins. Genetic defects in the generation of ROS are the cause of an immunodeficiency disease called chronic granulomatous disease, described in Chapter 5. Nitric Oxide. NO, a soluble gas produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial killing. There are three different types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). eNOS and nNOS are constitutively expressed at low levels, and the NO they generate acts to maintain vascular tone and as a neurotransmitter, respectively. iNOS, the type that is involved in microbial killing, is expressed when macrophages are activated by cytokines (e.g., IFN-γ) or microbial products, and induces the production of NO. In macrophages, NO reacts with superoxide (O2 • ) to generate the highly reactive free radical peroxynitrite (ONOO•) ( Fig. 3.7C ). These nitrogen-derived free radicals, similar to ROS, attack and damage the lipids, proteins, and nucleic acids of microbes and host cells.


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Pathology_Robbins. Fig. 3.7C ). These nitrogen-derived free radicals, similar to ROS, attack and damage the lipids, proteins, and nucleic acids of microbes and host cells. In addition to its role as a microbicidal substance, NO produced by endothelial cells relaxes vascular smooth muscle and promotes vasodilation. It is not clear if this action of NO plays an important role in the vascular reactions of acute inflammation.


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Pathology_Robbins. Granule Enzymes and Other Proteins. Neutrophils and monocytes contain granules packed with enzymes and anti-microbial proteins that degrade microbes and dead tissues and may contribute to tissue damage. These granules are actively secretory and thus distinct from classical lysosomes. Neutrophils have two main types of granules. The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. The larger azurophil (or primary) granules contain MPO, bactericidal factors (such as defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Phagocytic vesicles containing engulfed material may fuse with these granules (and with lysosomes, as described earlier), and the ingested materials are destroyed. In addition, both types of granules also undergo exocytosis (degranulation), leading to the extracellular release of granule


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Pathology_Robbins. as described earlier), and the ingested materials are destroyed. In addition, both types of granules also undergo exocytosis (degranulation), leading to the extracellular release of granule contents.


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Pathology_Robbins. Different granule enzymes serve different functions. Acid proteases degrade bacteria and debris within phagolysosomes, which are acidified by membrane-bound proton pumps. Neutral proteases are capable of degrading various extracellular components, such as collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes. Neutrophil elastase combats infections by degrading virulence factors of bacteria. Macrophages also contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator.


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Pathology_Robbins. Because of the destructive effects of granule enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues. These harmful proteases, however, are normally controlled by a system of anti-proteases in the serum and tissue fluids. Foremost among these is α1-anti-trypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α1-anti-trypsin deficiency (Chapter 13). http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that concentrate anti-microbial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines, and complement proteins). The extracellular traps consist of a viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as anti-microbial peptides and enzymes (


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Pathology_Robbins. Fig. 3.8 ). NETs provide an additional mechanism of killing microbes that does not involve phagocytosis. In the process of NET formation, the nuclei of the neutrophils are lost, leading to the death of the cells, sometimes called NETosis, representing a distinctive form of cell death affecting neutrophils. NETs also have been detected in the blood during sepsis. The nuclear chromatin in the NETs, which includes histones and associated DNA, may be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins (Chapter 5). Leukocytes are important mediators of injury to normal cells and tissues under several circumstances:


Pathology_Robbins

Pathology_Robbins. Leukocytes are important mediators of injury to normal cells and tissues under several circumstances: As part of a normal defense reaction against infectious microbes, when tissues at or near the site of infection suffer collateral damage. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases such as hepatitis, the prolonged host response contributes more to the pathology than does the microbe itself. When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. When the host “hyper-reacts” against usually harmless environmental substances, as in allergic diseases, including asthma, and some drug reactions.


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Pathology_Robbins. When the host “hyper-reacts” against usually harmless environmental substances, as in allergic diseases, including asthma, and some drug reactions. Leukocytes damage tissues by releasing injurious molecules. The potentially toxic contents of granules are released by leukocytes into the extracellular milieu by several mechanisms. Controlled secretion of granule contents following degranulation is a normal response of activated leukocytes. If phagocytes encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances (“frustrated phagocytosis”) triggers strong activation and also the release of large amounts of granule enzymes into the extracellular environment. Some phagocytosed substances, such as urate and silica crystals, may damage the membrane of the phagolysosome and also lead to the release of damaging contents.


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Pathology_Robbins. Fig. 3.8 Neutrophil extracellular traps (NETs). (A) Healthy neutrophils with nuclei stained red and cytoplasm green. (B) Release of nuclear material from neutrophils (note that two have lost their nuclei), forming extracellular traps. (C) An electron micrograph of bacteria (staphylococci) trapped in NETs. (From Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make NETs, Nat Rev Microbiol 5:577, 2007, with permission.) http://ebooksmedicine.net Other Functional Responses of Activated Leukocytes


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Pathology_Robbins. Other Functional Responses of Activated Leukocytes In addition to eliminating microbes and dead cells, activated leukocytes play several other roles in host defense. Importantly, these cells, especially macrophages, produce cytokines that can either amplify or limit inflammatory reactions, growth factors that stimulate the proliferation of endothelial cells and fibroblasts and the synthesis of collagen, and enzymes that remodel connective tissues. Because of these activities, macrophages also have centrial roles in orchestrating chronic inflammation and tissue repair, after the inflammation has subsided. These functions of macrophages are discussed later in the chapter.


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Pathology_Robbins. In this discussion of acute inflammation, we emphasize the importance of neutrophils and macrophages. However, it has become clear that some T lymphocytes, which are cells of adaptive immunity, also contribute to acute inflammation. The most important of these cells are those that produce the cytokine IL-17 (so-called “TH17 cells”), which are discussed in more detail in Chapter 5. IL-17 induces the secretion of chemokines that recruit other leukocytes. In the absence of effective TH17 responses, individuals are susceptible to fungal and bacterial infections, and the skin abscesses that develop are “cold abscesses,” lacking the classic features of acute inflammation, such as warmth and redness. Termination of the Acute Inflammatory Response


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Pathology_Robbins. Such a powerful system of host defense, with its inherent capacity to cause tissue injury, needs tight controls to minimize damage. In part, inflammation declines after the offending agents are removed simply because the mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release. Neutrophils also have short half-lives in tissues and die by apoptosis within hours to a day or two after leaving the blood. In addition, as inflammation develops, the process itself triggers a variety of stop signals that actively terminate the reaction. These active termination mechanisms include a switch in the type of arachidonic acid metabolite produced, from proinflammatory leukotrienes to anti-inflammatory lipoxins (described later), and the liberation of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10, from macrophages and other cells. Other control mechanisms that have


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Pathology_Robbins. (described later), and the liberation of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10, from macrophages and other cells. Other control mechanisms that have been demonstrated experimentally include neural impulses (cholinergic discharge), which inhibit the production of TNF in macrophages.


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Pathology_Robbins. 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 by granule enzymes. Neutrophils can extrude their nuclear contents to form extracellular nets that trap and destroy microbes. Granule enzymes may be released into the extracellular environment. The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) also are capable of damaging normal tissues (the pathologic consequences of inflammation). Anti-inflammatory mediators terminate the acute inflammatory reaction when it is no longer needed.


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Pathology_Robbins. Anti-inflammatory mediators terminate the acute inflammatory reaction when it is no longer needed. The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Although the harried student may find the list of mediators daunting (as do professors!), it is worthy of note that this knowledge has been used to design a large armamentarium of anti-inflammatory agents that are used every day by many people and which include familiar drugs such as aspirin and acetaminophen. The most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation ( Table 3.5 ). We begin by summarizing the general properties of the Table 3.5 Principal Mediators of Inflammation Prostaglandins Mast cells, Vasodilation, pain, fever leukocytes http://ebooksmedicine.net mediators of inflammation and then discuss some of the more important molecules.


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Pathology_Robbins. Mediators may be produced locally by cells at the site of inflammation, or may be derived from circulating inactive precursors that are activated at the site of inflammation. Cell-derived mediators are rapidly released from intracellular granules (e.g., amines) or are synthesized de novo (e.g., prostaglandins, leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are tissue macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia also can be induced to elaborate some of the mediators. Therefore, cell-derived mediators are most important for reactions against offending agents in tissues. Plasma-derived mediators (e.g., complement proteins) are present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. They are produced mainly in the liver, are effective against


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Pathology_Robbins. as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. They are produced mainly in the liver, are effective against circulating microbes, and also can be recruited into tissues.


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Pathology_Robbins. Active mediators are produced only in response to various molecules that stimulate inflammation, including microbial products and substances released from necrotic cells. Many of these stimuli trigger well-defined receptors and signaling pathways, as described earlier. The usual requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed. Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions. These built-in control mechanisms are discussed with each class of mediator.


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Pathology_Robbins. One mediator can stimulate the release of other mediators. For instance, products of complement activation stimulate the release of histamine, and the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but also may have different and even opposing activities, thus providing mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator. Vasoactive Amines: Histamine and Serotonin


Pathology_Robbins

Pathology_Robbins. The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. The richest sources of histamine are mast cells, which are normally present in the connective tissue adjacent to blood vessels. Histamine also is found in blood basophils and platelets. It is stored in mast cell granules and is released by degranulation in response to a variety of stimuli, including (1) physical injury, such as trauma, cold, or heat, by unknown mechanisms; (2) binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions (Chapter 5); and (3) products of complement called anaphylatoxins (C3a and C5a), described later. Antibodies and complement products bind to specific receptors on mast cells and trigger signaling pathways that induce rapid degranulation. Neuropeptides (e.g.,


Pathology_Robbins

Pathology_Robbins. (C3a and C5a), described later. Antibodies and complement products bind to specific receptors on mast cells and trigger signaling pathways that induce rapid degranulation. Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) also may trigger release of histamine.


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Pathology_Robbins. Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered the principal mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in postcapillary venules, as discussed earlier. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. The antihistamine drugs that are commonly used to treat some inflammatory reactions, such as allergies, are H1 receptor antagonists that bind to and block the receptor. Histamine also causes contraction of some smooth muscles, but leukotrienes, described later, are much more potent and relevant for causing spasms of bronchial muscles, for example, in asthma.


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Pathology_Robbins. Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It also is a vasoconstrictor, but the importance of this action in inflammation is unclear.


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Pathology_Robbins. The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid present in membrane phospholipids, and they stimulate vascular and cellular reactions in acute inflammation. Arachidonic acid is a 20-carbon polyunsaturated fatty acid that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. Most cellular arachidonic acid is esterified and incorporated into membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) trigger the release of arachidonic acid from membranes by activating cellular phospholipases, mainly phospholipase A2. Once freed from the membrane, arachidonic acid is rapidly converted to bioactive mediators. These mediators, also called eicosanoids (because they are derived from 20-carbon fatty acids; Greek eicosa = 20), are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and


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Pathology_Robbins. from 20-carbon fatty acids; Greek eicosa = 20), are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and lipoxins) (


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Pathology_Robbins. Fig. 3.9 ). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation ( Table 3.6


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Pathology_Robbins. Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are generated by the actions of two cyclooxygenases called COX-1 and COX-2. COX-1 is produced in response to inflammatory stimuli and also is constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in http://ebooksmedicine.net inhibitors, aspirin, indomethacin Lipoxygenase inhibitors the kidneys, cytoprotection in the gastrointestinal tract). In Prostaglandins are named based on structural features contrast, COX-2 is induced by inflammatory stimuli and coded by a letter (e.g., PGD, PGE, PGF, PGG, and PGH) thus generates the PGs that are involved in inflammatory and a subscript numeral (e.g., 1, 2), which indicates the reactions, but it is low or absent in most normal tissues. number of double bonds in the compound. The most important


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Pathology_Robbins. in inflammatory and a subscript numeral (e.g., 1, 2), which indicates the reactions, but it is low or absent in most normal tissues. number of double bonds in the compound. The most important prostaglandins in inflammation are PGE2, PGD2, PGF2a, PGI2 (prostacyclin), and TXA2 (thromboxane A2), Table 3.6 Principal Actions of Arachidonic Acid Metabolites in each of which is derived by the action of a specific enzyme Inflammation on an intermediate in the pathway. Some of these enzymes Action Eicosanoid have restricted tissue distribution and functions.


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Pathology_Robbins. • PGD2 is the major prostaglandin made by mast cells; Vasodilation Prostaglandins PGI2 (prostacyclin), PGE1, PGE2, PGD2 along with PGE2 (which is more widely distributed), it causes vasodilation and increases the permeability of Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4 postcapillary venules, thus potentiating exudation and resultant edema. PGD2 also is a chemoattractant for Increased vascular permeability Leukotrienes C4, D4, E4 neutrophils. Chemotaxis, leukocyte adhesion Leukotriene B4 • Platelets contain the enzyme thromboxane synthase, Smooth muscle contraction Prostaglandins PGC4, PGD4, PGE4 which is responsible for synthesizing TXA2, the major platelet eicosanoid. TXA2 is a potent platelet-aggregating agent and vasoconstrictor, and thus promotes thrombosis.


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Pathology_Robbins. In contrast, vascular endothelium contains prostacyclin synthase, which is responsible for the formation of prostacyclin (PGI2) and its stable end product PGF1a. Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation, and thus serves to prevent thrombus formation on normal endothelial cells. A thromboxane– prostacyclin imbalance has been implicated in coronary and cerebral artery thrombosis (Chapter 4). In addition to their local effects, prostaglandins are involved in the pathogenesis of pain and fever, two common systemic manifestations of inflammation. PGE2 makes the skin hypersensitive to painful stimuli, and causes fever during infections (described later).


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Pathology_Robbins. Leukotrienes are produced in leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. The synthesis of leukotrienes involves multiple steps, the first of which generates leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages, and is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes. The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules.


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Pathology_Robbins. Lipoxins also are generated from arachidonic acid by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They also are unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes. Pharmacologic Inhibitors of Prostaglandins and Leukotrienes


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Pathology_Robbins. The importance of eicosanoids in inflammation has driven attempts to develop drugs that inhibit their production or actions and thus suppress inflammation. These anti-inflammatory drugs include the following: • Cyclooxygenase inhibitors include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. They inhibit both COX-1 and COX-2 and thus block all prostaglandin synthesis (hence their efficacy in treating pain and fever); aspirin does this by irreversibly inactivating cyclooxygenases. Selective COX-2 inhibitors are a newer class of these drugs that are 200to 300-fold more potent in blocking COX-2 than COX-1. There has been great interest in COX-2 as a therapeutic target because of the possibility that COX-1 is responsible for the production of prostaglandins that are involved in both inflammation and physiologic functions such as protecting gastric epithelial cells from acid-induced injury, whereas COX-2 generates prostaglandins that are involved only in


Pathology_Robbins

Pathology_Robbins. that are involved in both inflammation and physiologic functions such as protecting gastric epithelial cells from acid-induced injury, whereas COX-2 generates prostaglandins that are involved only in inflammation. If this idea is correct, the selective COX-2 inhibitors should be anti-inflammatory without having the toxicities of the nonselective inhibitors, such as gastric ulceration. However, these distinctions are not absolute, as COX-2 also seems to play some role in normal homeostasis. Furthermore, selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGI2), which prevents thrombosis, while leaving intact the COX-1-mediated production by platelets of TXA2, which induces platelet aggregation. Thus, selective COX-2 inhibition may tilt the balance toward vascular thrombosis, especially in combination with other factors that increase the risk of thrombosis. Nevertheless,


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Pathology_Robbins. aggregation. Thus, selective COX-2 inhibition may tilt the balance toward vascular thrombosis, especially in combination with other factors that increase the risk of thrombosis. Nevertheless, these drugs are used in individuals who do not have risk factors for cardiovascular disease and when the drugs’ benefits outweigh their risks.


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Pathology_Robbins. Lipoxygenase inhibitors. 5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g., zileuton) are useful in the treatment of asthma. Corticosteroids are broad-spectrum anti-inflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines (e.g., IL-1 and TNF), and iNOS. Leukotriene receptor antagonists block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma.


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Pathology_Robbins. Leukotriene receptor antagonists block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma. Cytokines are proteins secreted by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions. By convention, growth factors that act on epithelial and mesenchymal cells are not grouped under cytokines. The general properties and functions of cytokines are discussed in Chapter 5. Here the cytokines involved in acute inflammation are reviewed ( Table 3.7


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Pathology_Robbins. Table 3.7 TNF and IL-1 serve critical roles in leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels. Activated macrophages and dendritic cells mainly produce these cytokines; TNF also is produced by T lymphocytes and mast cells, and some epithelial cells produce IL-1 as well. Microbial products, foreign bodies, necrotic cells, and a variety of other inflammatory stimuli can stimulate the secretion of TNF and IL-1. The production of TNF is induced by signals through TLRs and other microbial sensors, and the synthesis of IL-1 is stimulated by the same signals, but the generation of the biologically active form of this cytokine is dependent on the inflammasome, described earlier. http://ebooksmedicine.net IL-6 Macrophages, Systemic effects (acute phase other cells response) IL-17 T lymphocytes Recruitment of neutrophils and monocytes IL-17 T lymphocytes Recruitment of neutrophils and monocytes


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Pathology_Robbins. IL-6 Macrophages, Systemic effects (acute phase other cells response) IL-17 T lymphocytes Recruitment of neutrophils and monocytes IL-17 T lymphocytes Recruitment of neutrophils and monocytes The most important cytokines involved in inflammatory reactions are listed. Many other cytokines may play lesser roles in inflammation.There is also considerable overlap between the cytokines involved in acute and chronic inflammation. Specifically, all the cytokines listed under acute inflammation may also contribute to chronic inflammatory reactions. IFN-γ, Interferon-γ; IL-1, interleukin-1; NK, natural killer; TNF, tumor necrosis factor. The actions of TNF and IL-1 contribute to the local and systemic reactions of inflammation ( Fig. 3.10 ). The most important roles of these cytokines in inflammation are the following:


Pathology_Robbins

Pathology_Robbins. The actions of TNF and IL-1 contribute to the local and systemic reactions of inflammation ( Fig. 3.10 ). The most important roles of these cytokines in inflammation are the following: Endothelial activation. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly Eand P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and chemokines, and eicosanoids; and increased procoagulant activity of the endothelium.


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Pathology_Robbins. Activation of leukocytes and other cells. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial cells and other mesenchymal cells. IL-1 and IL-6 also stimulate the generation of a subset of CD4+ helper T cells called TH17 cells, described later and in Chapter 5. Systemic acute-phase response. IL-1 and TNF (as well as IL-6) induce the systemic acute-phase responses associated with infection or injury, including fever (described later in the chapter). They also are implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS), resulting from disseminated bacterial infection (sepsis) and other serious conditions, described later.


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Pathology_Robbins. • TNF regulates energy balance by promoting lipid and protein catabolism and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterized by weight loss, muscle atrophy, and anorexia that accompanies some chronic infections and cancers. As mentioned earlier, TNF antagonists have been remarkably effective in the treatment of chronic inflammatory diseases, particularly rheumatoid arthritis, psoriasis, and some types of inflammatory bowel disease. One complication of this therapy is increased susceptibility to mycobacterial infection, resulting from reduced ability of macrophages to kill intracellular microbes. Although many of the actions of TNF and IL-1 are overlapping, IL-1 antagonists are not as effective, for reasons that remain obscure. Also, blocking either cytokine has no effect on the outcome of sepsis, perhaps because other cytokines contribute to this serious systemic inflammatory reaction.


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Pathology_Robbins. Chemokines are a family of small (8–10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. About 40 different chemokines and 20 different receptors for chemokines have been identified. They are classified into four major groups, according to the arrangement of cysteine (C) residues in the proteins: C-X-C chemokines have one amino acid residue separating the first two of the four conserved cysteines. These chemokines act primarily on neutrophils. IL-8 (now called CXCL8) is typical of this group. It is secreted by activated macrophages, endothelial cells, and other cell types, and causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils. Its most important inducers are microbial products and cytokines, mainly IL-1 and TNF.


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Pathology_Robbins. C-C chemokines have the first two conserved cysteine residues adjacent. The C-C chemokines, which include monocyte chemoattractant protein (MCP-1, CCL2), eotaxin (CCL11), and macrophage inflammatory protein1α (MIP-1α, CCL3), mainly serve as chemoattractants for monocytes, eosinophils, basophils, and lymphocytes. Although most of the chemokines in this class have overlapping actions, eotaxin selectively recruits eosinophils. C chemokines lack the first and third of the four conserved cysteines. The C chemokines (e.g., lymphotactin, XCL1) are relatively specific for lymphocytes.


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Pathology_Robbins. C chemokines lack the first and third of the four conserved cysteines. The C chemokines (e.g., lymphotactin, XCL1) are relatively specific for lymphocytes. CX3C chemokines contain three amino acids between the first two cysteines. The only known member of this class is called fractalkine (CX3CL1). This chemokine exists in two forms: a cell surface-bound protein induced on endothelial cells by inflammatory cytokines that promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane-bound protein, that has potent chemoattractant activity for the same cells. Chemokines mediate their activities by binding to seven-transmembrane G protein–coupled receptors. These http://ebooksmedicine.net Mediators of Inflammation 75 TNF, Increased expression of adhesion molecules IL-1, Leukocytes chemokines


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Pathology_Robbins. Mediators of Inflammation 75 TNF, Increased expression of adhesion molecules IL-1, Leukocytes chemokines IL-1, IL-6, receptors usually exhibit overlapping ligand specificities, and leukocytes generally express multiple receptors. As discussed in Chapter 5, certain chemokine receptors (CXCR4, CCR5) act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV), the cause of AIDS, and are thus involved in binding and entry of the virus into cells. Chemokines bind to proteoglycans and are displayed at high concentrations on the surface of endothelial cells and in the extracellular matrix. They have two main functions:


Pathology_Robbins

Pathology_Robbins. Chemokines bind to proteoglycans and are displayed at high concentrations on the surface of endothelial cells and in the extracellular matrix. They have two main functions: Acute inflammation. Most chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and also serve as chemoattractants, thereby guiding leukocytes to sites of infection or tissue damage. Because they mediate aspects of the inflammatory reaction, they are sometimes called inflammatory chemokines. Their production is induced by microbes and other stimuli. Maintenance of tissue architecture. Some chemokines are produced constitutively by stromal cells in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues, such as T and B lymphocytes in discrete areas of the spleen and lymph nodes (Chapter 5).


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Pathology_Robbins. Although the role of chemokines in inflammation is well established, it has proved difficult to develop chemokine antagonists that suppress inflammation, perhaps because of the functional redundancy of these proteins. The list of cytokines implicated in inflammation is huge and constantly growing. In addition to the ones described earlier, two that have received considerable interest are IL-6, made by macrophages and other cells, which is involved in local and systemic reactions, and IL-17, produced mainly by T lymphocytes, which promotes neutrophil recruitment. IL-6 receptor antagonists are used in the treatment of rheumatoid arthritis, and IL-17 antagonists are very effective in psoriasis and other inflammatory diseases. Type I interferons, whose normal function is to inhibit viral replication, contribute to some of the systemic manifestations of inflammation. Cytokines also play key roles in chronic inflammation; these are described later in the chapter.


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Pathology_Robbins. The complement system is a collection of soluble proteins and their membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions. There are more than 20 complement proteins, some of which are numbered C1 through C9. They function in both innate and adaptive immunity for defense against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization. The activation and functions of complement are outlined in Fig. 3.11 Complement proteins are present in inactive forms in the plasma, and many of them are activated to become proteolytic enzymes that degrade other complement proteins, thus forming an enzymatic cascade capable of tremendous amplification. The critical step in complement activation is the proteolysis of the third (and most EFFECTOR FUNCTIONS C5a, C3a: Inflammation


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Pathology_Robbins. EFFECTOR FUNCTIONS C5a, C3a: Inflammation Recruitment and Destruction of microbes activation of leukocytes by leukocytes Fig. 3.11 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC). abundant) component, C3. Cleavage of C3 can occur by one of three pathways: The classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen The alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, and other substances, in the absence of antibody The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1


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Pathology_Robbins. The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1 All three pathways of complement activation lead to the formation of an enzyme called the C3 convertase, which splits C3 into two functionally distinct fragments, C3a and C3b. C3a is released, and C3b becomes covalently attached to the cell or molecule where the complement is being activated. More C3b then binds to the previously generated fragments to form C5 convertase, which cleaves C5 to release C5a and leave C5b attached to the cell surface. C5b binds the late components (C6–C9), culminating in the formation of the membrane attack complex (MAC, composed of multiple C9 molecules). The enzymatic activity of complement proteins provides such tremendous amplification that millions of molecules of C3b can deposit on the surface of a microbe within 2 or 3 minutes! The complement system has three main functions (


Pathology_Robbins

Pathology_Robbins. The complement system has three main functions ( Fig. 3.11 • Inflammation.C5a, and, to a lesser extent, C4a and C3a, are cleavage products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis (Chapter 5). C5a also is a chemotactic agent for neutrophils, monocytes, eosinophils, and basophils. In addition, C5a activates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes, causing release of more inflammatory mediators. Opsonization and phagocytosis. C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for these complement fragments.


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Pathology_Robbins. Cell lysis. The deposition of the MAC on cells drills holes in the cell membrane, making the cells permeable to water and ions and resulting in their osmotic death (lysis). This function of complement is important mainly for the killing of microbes with thin cell walls, such as Neisseria bacteria. Hence, deficiency of the terminal components of complement predisposes to infections by the Neisseria species meningococci and gonococci. In patients with complement deficiencies, these microbes can cause serious disseminated infections.


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Pathology_Robbins. The activation of complement is tightly controlled by cell-associated and circulating regulatory proteins. Different regulatory proteins inhibit the production of active complement fragments or remove fragments that deposit on cells. These regulators are expressed on normal host cells and thus prevent healthy tissues from being injured at sites of complement activation. Regulatory proteins can be overwhelmed when large amounts of complement are deposited on host cells and in tissues, as happens in autoimmune diseases, in which individuals produce complement-fixing antibodies against their own cell and tissue antigens (Chapter 5). The most important of these regulatory proteins are the following: C1 inhibitor blocks the activation of C1, the first protein of the classical complement pathway. Inherited deficiency of this inhibitor is the cause of hereditary angioedema.


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Pathology_Robbins. C1 inhibitor blocks the activation of C1, the first protein of the classical complement pathway. Inherited deficiency of this inhibitor is the cause of hereditary angioedema. Decay accelerating factor (DAF) and CD59 are two proteins that are linked to plasma membranes by a glycophosphatidyl (GPI) anchor. DAF prevents formation of C3 convertases and CD59 inhibits formation of the MAC. An acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells (which are sensitive to complement-mediated cell lysis). This gives rise to a disease called paroxysmal nocturnal hemoglobinuria (PNH) (Chapter 12).


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Pathology_Robbins. Other complement regulatory proteins proteolytically cleave active complement components. For instance, Factor H is a plasma protein that serves as a cofactor for the proteolysis of the C3 convertase; its deficiency results in excessive complement activation. Mutations in Factor H are associated with a kidney disease called the hemolytic uremic syndrome (Chapter 14), as well as increased permeability of retinal vessels in wet macular degeneration of the eye. The complement system contributes to disease in several ways. The activation of complement by antibodies or antigen–antibody complexes deposited on host cells and tissues is an important mechanism of cell and tissue injury (Chapter 5). Inherited deficiencies of complement proteins cause increased susceptibility to infections, and, as mentioned earlier, deficiencies of regulatory proteins cause a variety of disorders. Other Mediators of Inflammation


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Pathology_Robbins. Other Mediators of Inflammation PAF is a phospholipid-derived mediator that was discovered as a factor that caused platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased vascular permeability. Despite these documented actions, trials of PAF antagonists in various inflammatory conditions have been disappointing. Products of Coagulation


Pathology_Robbins

Pathology_Robbins. Studies performed more than 50 years ago suggested that inhibiting coagulation reduced the inflammatory reaction to some microbes, leading to the idea that coagulation and inflammation are linked processes. This concept was supported by the discovery of protease-activated receptors (PARs), which are activated by thrombin (the protease that cleaves fibrinogen to produce a fibrin clot). PARs are expressed on leukocytes, suggesting a role in inflammation, but their clearest role is in platelets, in which thrombin activation of a PAR known as the thrombin receptor is a potent trigger of platelet aggregation during the process of clot formation (Chapter 4). In fact, it is difficult to dissociate clotting and inflammation, because virtually all forms of tissue injury that lead to clotting also induce inflammation, and inflammation causes changes in endothelial cells that increase the likelihood of abnormal clotting (thrombosis, described in Chapter 4). Whether the products of coagulation,


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Pathology_Robbins. induce inflammation, and inflammation causes changes in endothelial cells that increase the likelihood of abnormal clotting (thrombosis, described in Chapter 4). Whether the products of coagulation, per se, have a significant role in stimulating inflammation is still not established.


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Pathology_Robbins. Kinins are vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin. Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase. Bradykinin has been implicated as a mediator in some forms of allergic reaction, such as anaphylaxis.


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Pathology_Robbins. Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, including substance P and neurokinin A, are produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and in increasing vascular permeability. When Lewis discovered the role of histamine in inflammation, one mediator was thought to be enough. Now, we are wallowing in them! Yet, from this large compendium, it is likely that a few mediators are most important for the reactions of acute inflammation in vivo, and these are summarized in Table 3.8 . This list is compiled in part from the Table 3.8 Role of Mediators in Different Reactions of Inflammation


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Pathology_Robbins. Table 3.8 . This list is compiled in part from the Table 3.8 Role of Mediators in Different Reactions of Inflammation Reaction of Inflammation Principal Mediators Increased vascular Histamine permeability C3a and C5a (by liberating vasoactive amines from mast cells, other cells) Leukotrienes C4, D4, E4 Chemotaxis, leukocyte TNF, IL-1 recruitment and Chemokines activation C3a, C5a Fever IL-1,TNF Prostaglandins Tissue damage Lysosomal enzymes of leukocytes Reactive oxygen species http://ebooksmedicine.net observed anti-inflammatory effects of antagonists to these molecules, thus highlighting the importance of basic biology to the practice of medicine. The redundancy of the mediators and their actions ensures that this protective response remains robust and is not readily subverted. Vasoactive amines, mainly histamine: vasodilation and increased vascular permeability


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Pathology_Robbins. Vasoactive amines, mainly histamine: vasodilation and increased vascular permeability 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 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 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 Kinins:produced by proteolytic cleavage of precursors;mediate vascular reaction, pain


Pathology_Robbins

Pathology_Robbins. Kinins:produced by proteolytic cleavage of precursors;mediate vascular reaction, pain The morphologic hallmarks of acute inflammatory reactions are dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissue. The vascular and cellular reactions account for the signs and symptoms of the inflammatory response. Increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins (edema) and account for the redness (rubor), warmth (calor), and swelling (tumor) that accompany acute inflammation. Leukocytes that are recruited and activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage and loss of function (functio laesa). During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor).


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Pathology_Robbins. Although these general features are characteristic of most acute inflammatory reactions, special morphologic patterns are often superimposed on them, depending on the severity of the reaction, its specific cause, and the particular tissue and site involved. The importance of recognizing distinct gross and microscopic patterns of inflammation is that they often provide valuable clues about the underlying cause. Serous inflammation is marked by the exudation of cell-poor fluid into spaces created by injury to surface epithelia Fig. 3.12 Serous inflammation. Low-power view of a cross section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion.


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Pathology_Robbins. or into body cavities lined by the peritoneum, pleura, or pericardium. Typically, the fluid in serous inflammation is not infected by destructive organisms and does not contain large numbers of leukocytes (which tend to produce purulent inflammation, described later). In body cavities the fluid may be derived from the plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation); accumulation of fluid in these cavities is called an effusion. (Effusions consisting of transudates also occur in noninflammatory conditions, such as reduced blood outflow in heart failure, or reduced plasma protein levels in some kidney and liver diseases.) The skin blister resulting from a burn or viral infection represents accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin (Fig. 3.12


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Pathology_Robbins. A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus. With a large increase in vascular permeability, higher-molecularweight proteins such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium ( Fig. 3.13A ), and pleura. Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum (


Pathology_Robbins

Pathology_Robbins. Fig. 3.13A ), and pleura. Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum ( Fig. 3.13B ). Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages. If the fibrin is not removed, with time, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac leads to opaque fibrous thickening of the pericardium and epicardium in the area of exudation and, if the fibrosis is extensive, obliteration of the pericardial space. Purulent (Suppurative) Inflammation,Abscess Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. The most frequent cause of purulent (also called suppurative) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 3.13 Fibrinous pericarditis. (A) Deposits of fibrin on the pericardium. (B) A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P). inflammation is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria. A common example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of pus caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by seeding of pyogenic bacteria into a tissue (


Pathology_Robbins

Pathology_Robbins. Fig. 3.14 ). Abscesses have a central region that appears as a mass of necrotic leukocytes and tissue cells. There is usually a zone of preserved neutrophils around this necrotic focus, and outside this region there may be vascular dilation and parenchymal and fibroblastic proliferation, indicating chronic inflammation and repair. In time the abscess may become walled off and ultimately replaced by connective tissue. When persistent or at critical locations (such as the brain), abscesses may have to be drained surgically. An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue (


Pathology_Robbins

Pathology_Robbins. An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue ( Fig. 3.15 ). Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in (1) the mucosa of the mouth, stomach, intestines, or genitourinary tract, and (2) the skin and subcutaneous tissue of the lower extremities in older persons who have circulatory disturbances that predispose to extensive ischemic necrosis. Acute and chronic inflammation often coexist in ulcers, such as peptic ulcers of the stomach or duodenum and diabetic ulcers of the legs. 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 fibroblast proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells.


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Pathology_Robbins. Although, as might be expected, many variables may modify the basic process of inflammation, including the Fig. 3.14 Purulent inflammation. (A) Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneumonia. (B) The abscess contains neutrophils and cellular debris, and is surrounded by congested blood vessels. http://ebooksmedicine.net Fig. 3.15 The morphology of an ulcer. (A) A chronic duodenal ulcer. (B) Low-power cross-section view of a duodenal ulcer crater with an acute inflamma tory exudate in the base. nature and intensity of the injury, the site and tissue affected, and the responsiveness of the host, acute inflammatory reactions typically have one of three outcomes


Pathology_Robbins

Pathology_Robbins. nature and intensity of the injury, the site and tissue affected, and the responsiveness of the host, acute inflammatory reactions typically have one of three outcomes Fig. 3.16): • Complete resolution. In a perfect world, all inflammatory reactions, after they have succeeded in eliminating the offending agent, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics.


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Pathology_Robbins. • Healing by connective tissue replacement (scarring, or fibrosis). This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all Clearance of injurious stimuli Clearance of mediators and acute inflammatory cells • Replacement of injured cells • Normal function FIBROSIS • Loss of function CHRONIC INFLAMMATION • Angiogenesis • Mononuclear cell infiltrate • Fibrosis (scar) Progression Healing Pus formation (abscess) Healing Healing Fig. 3.16 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation.The components of the various reactions and their functional outcomes are listed. http://ebooksmedicine.net these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue.


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Pathology_Robbins. http://ebooksmedicine.net these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue. • Progression of the response to chronic inflammation. Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing. Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations. It may follow acute inflammation, as described earlier, or may begin insidiously, as a smoldering, sometimes progressive, process without any signs of a preceding acute reaction. Causes of Chronic Inflammation Chronic inflammation arises in the following settings:


Pathology_Robbins

Pathology_Robbins. Causes of Chronic Inflammation Chronic inflammation arises in the following settings: Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity (Chapter 5). The inflammatory response sometimes takes a specific pattern called granulomatous inflammation (discussed later). In other cases, unresolved acute inflammation evolves into chronic inflammation, such as when an acute bacterial infection of the lung progresses to a chronic lung abscess.


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Pathology_Robbins. Hypersensitivity diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system (Chapter 5). In autoimmune diseases, self (auto) antigens evoke a self-perpetuating immune reaction that results in chronic inflammation and tissue damage; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In allergic diseases, chronic inflammation is the result of excessive immune responses against common environmental substances, as in bronchial asthma. Because these autoimmune and allergic reactions are triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages.


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Pathology_Robbins. Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis (Chapter 13). Atherosclerosis (Chapter 10) is a chronic inflammatory process affecting the arterial wall that is thought to be induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids. Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not convention ally thought of as inflammatory disorders. These include neurodegenerative diseases such as Alzheimer disease, metabolic syndrome and the associated type 2 diabetes, and certain cancers in which inflammatory reactions promote tumor development. The role of inflammation in these conditions is discussed in the relevant chapters.


Pathology_Robbins

Pathology_Robbins. In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly neutrophilic infiltration, chronic inflammation is characterized by the following: Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells ( Fig. 3.17 Tissue destruction, induced by the persistent offending agent or by the inflammatory cells Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis (proliferation of small blood vessels) and, in particular,


Pathology_Robbins

Pathology_Robbins. Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis (proliferation of small blood vessels) and, in particular, Fig. 3.17 (A) Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). (B) In contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested. http://ebooksmedicine.net Because angiogenesis and fibrosis are also components of wound healing and repair, they are discussed later, in the context of tissue repair. Cells and Mediators of Chronic Inflammation


Pathology_Robbins

Pathology_Robbins. Because angiogenesis and fibrosis are also components of wound healing and repair, they are discussed later, in the context of tissue repair. Cells and Mediators of Chronic Inflammation The combination of leukocyte infiltration, tissue damage, and fibrosis that characterize chronic inflammation is the result of the local activation of several cell types and the production of mediators. Role of Macrophages


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Pathology_Robbins. Role of Macrophages The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, by destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes. Macrophages are professional phagocytes that act as filters for particulate matter, microbes, and senescent cells. They also function as effector cells that eliminate microbes in cellular and humoral immune responses (Chapter 5). But they serve many other roles in inflammation and repair. Here we review the basic biology of macrophages, including their development and functional responses. Macrophages are tissue cells derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk sac and fetal liver during early development (


Pathology_Robbins

Pathology_Robbins. Macrophages are tissue cells derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk sac and fetal liver during early development ( Fig. 3.18 ). Circulating cells of this lineage are known as monocytes. Macrophages are normally diffusely scattered in most connective tissues. In addition, they are found in specific locations in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells comprise the mononuclear phagocyte system, also known by the older (and inaccurate) name of reticuloendothelial system.


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Pathology_Robbins. In inflammatory reactions, progenitors in the bone marrow give rise to monocytes, which enter the blood, migrate into various tissues, and differentiate into macrophages. Entry of blood monocytes into tissues is governed by the same factors that are involved in neutrophil emigration, such as adhesion molecules and chemokines. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. Thus, macrophages often become the dominant cell population in inflammatory reactions within 48 hours of onset. The macrophages that reside in tissues in the steady state (in the absence of tissue injury or inflammation), such as microglia, Kupffer cells, and alveolar macrophages, arise from the yolk sac or fetal liver very early in embryogenesis, populate the tissues, stay for long periods, and are replenished mainly by the proliferation of resident cells.


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Pathology_Robbins. There are two major pathways of macrophage activation, called classical andalternative ( Fig. 3.19 ). Which of these two pathways is taken by a given macrophage depends on the nature of the activating signals. • Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors, and by T cell–derived signals, Activated macrophages in inflammation Macrophages in skin, intestinal tract Resident tissue macrophages Yolk (Kupffer cells, alveolar macrophages, sac microglia, etc.) Progenitor in yolk sac, fetal liver Fig. 3.18 Maturation of mononuclear phagocytes. (A) During inflammatory reactions, the majority of tissue macrophages are derived from hematopoietic precursors. Some long-lived resident tissue macrophages are derived from embryonic precursors that populate the tissues early in development. (B) The morphology of a monocyte and activated macrophage. TLR-ligands, ROS, NO, IL-10, lysosomal TGF-° enzymes


Pathology_Robbins

Pathology_Robbins. TLR-ligands, ROS, NO, IL-10, lysosomal TGF-° enzymes IL-1, TNF, IL-12, IL-6, chemokines Anti-inflammatory effects, wound repair, fibrosis Fig. 3.19 Classical and alternative macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ. They phagocytose and destroy microbes and dead tissues and can potentiate inflammatory reactions. Alternatively activated macrophages are induced by other cytokines and are important in tissue repair and the resolution of inflammation.


Pathology_Robbins

Pathology_Robbins. importantly the cytokine IFN-γ, in immune responses. Classically activated (also called M1) macrophages produce NO and ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory reactions. • Alternative macrophage activation is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.


Pathology_Robbins

Pathology_Robbins. It seems plausible that in response to most injurious stimuli, the first activation pathway is the classical one, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions. In addition, although the concept of M1 and M2 macrophages provides a useful framework for understanding macrophage heterogeneity, numerous other subpopulations have been described and the M1 and M2 subsets are not fixed. The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair, but are also responsible for much of the tissue injury in chronic inflammation. Several functions of macrophages are central to the development and persistence of chronic inflammation and the accompanying tissue injury.


Pathology_Robbins

Pathology_Robbins. Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanoids. Thus, macrophages are central to the initiation and propagation of inflammatory reactions. Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses. These interactions are described further in the discussion of the role of lymphocytes in chronic inflammation, later in this chapter, and in more detail in Chapter 5 where cell-mediated immunity is considered. Their impressive arsenal of mediators makes macrophages powerful allies in the body’s defense against unwanted invaders, but the same weaponry can also induce considerable tissue destruction when macrophages are inappropriately or excessively activated. It is because of these activities of macrophages that tissue destruction is one of the hallmarks of chronic inflammation.


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Pathology_Robbins. In some instances if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way via lymphatics into lymph nodes). In others, macrophage accumulation persists, as a result of continuous recruitment from the circulation and local proliferation at the site of inflammation. Role of Lymphocytes


Pathology_Robbins

Pathology_Robbins. Role of Lymphocytes Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation. Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens (Chapter 5), these cells are often present in chronic inflammation and, when they are activated, the inflammation tends to be persistent and severe. Some of the strongest chronic inflammatory reactions, such as granulomatous inflammation, described later, are dependent on lymphocyte responses. Lymphocytes may be the dominant population in the chronic inflammation seen in autoimmune and other hypersensitivity diseases.


Pathology_Robbins

Pathology_Robbins. By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction. These T cells greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of the innate immune response. There are three subsets of CD4+ T cells that secrete different cytokines and elicit different types of inflammation. TH1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway. TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation. TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils into the reaction.


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Pathology_Robbins. TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils into the reaction. Both TH1 and TH17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseases. TH2 cells are important in defense against helminthic parasites and in allergic inflammation. These T cell http://ebooksmedicine.net (e.g., IL-12, IL-6, IL-23) Activated ActivatedT lymphocyte macrophage(TH1, TH17) Presents antigen to T cells TNF,IL-17, IL-1,TNF chemokines subsets and their functions are described in more detail in Chapter 5. Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation (


Pathology_Robbins

Pathology_Robbins. Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation ( Fig. 3.20 ). Macrophages display antigens to T cells, express membrane molecules (called costimulators) that activate T cells, and produce cytokines (IL-12 and others) that also stimulate T cell responses (Chapter 5). Activated T lymphocytes, in turn, produce cytokines, described earlier, which recruit and activate macrophages, promoting more antigen presentation and cytokine secretion. The result is a cycle of cellular reactions that fuel and sustain chronic inflammation. Activated B lymphocytes and antibody-producing plasma cells are often present at sites of chronic inflammation. The antibodies may be specific for persistent foreign or self antigens in the inflammatory site or against altered tissue components. However, the specificity and even the importance of antibodies in most chronic inflammatory disorders are unclear.


Pathology_Robbins

Pathology_Robbins. In some chronic inflammatory reactions, the accumulated lymphocytes, antigen-presenting cells, and plasma cells cluster together to form lymphoid structures resembling the follicles found in lymph nodes. These are called tertiary lymphoid organs; this type of lymphoid organogenesis is often seen in the synovium of patients with longstanding rheumatoid arthritis, in the thyroid in Hashimoto thyroiditis, and in the gastric mucosa in the setting of Helicobacter pylori infection. It has been postulated that the local formation of lymphoid organs may perpetuate the immune reaction, but the significance of these structures is not established. Other cell types may be prominent in chronic inflammation induced by particular stimuli. • Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections (


Pathology_Robbins

Pathology_Robbins. Other cell types may be prominent in chronic inflammation induced by particular stimuli. • Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections ( Fig. 3.21 ). Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also injures host epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections, yet also contribute to tissue damage in immune reactions such as allergies (Chapter 5).


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Pathology_Robbins. • Mast cells are widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions. Mast cells arise from precursors in the bone marrow. They have many similarities with circulating basophils, but they do not arise from basophils, are tissue-resident, and therefore play more significant roles in inflammatory reactions in tissues than basophils do. Mast cells (and basophils) express on their surface the receptor FcεRI, which binds the Fc portion of IgE antibody. In immediate hypersensitivity reactions, IgE bound to the mast cells’ Fc receptors specifically recognizes antigen, and in response the cells degranulate and release mediators, such as histamine and prostaglandins (Chapter 5). This type of response occurs during allergic reactions to foods, insect venom, or drugs, sometimes with catastrophic results (e.g., anaphylactic shock). Mast cells also are present in chronic inflammatory reactions, and because they secrete a


Pathology_Robbins

Pathology_Robbins. Fig. 3.21 A focus of inflammation containing numerous eosinophils. plethora of cytokines, they can promote inflammatory reactions. • Although neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for months, continue to show large numbers of neutrophils, induced either by persistent microbes or by cytokines and other mediators produced by activated macrophages and T lymphocytes. In chronic bacterial infection of bone (osteomyelitis), a neutrophilic exudate can persist for many months. Neutrophils also are important in the chronic damage induced in lungs by smoking and other irritant stimuli (Chapter 13). This pattern of inflammation has been called acute on chronic.


Pathology_Robbins

Pathology_Robbins. Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells. Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate. In this attempt there is often strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues. There are two types of granulomas, which differ in their pathogenesis.


Pathology_Robbins

Pathology_Robbins. There are two types of granulomas, which differ in their pathogenesis. Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response produces granulomas usually when the inciting agent cannot be readily eliminated, such as a persistent microbe or a self antigen. In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.


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Pathology_Robbins. Foreign body granulomas are seen in response to relatively inert foreign bodies, in the absence of T cell– mediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage but are not immunogenic. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it may appear refractile. MORPHOLOGY In the usual H&E stained tissue samples (


Pathology_Robbins

Pathology_Robbins. Fig. 3.22 ), the activated macrophages in granulomas have pink granular cytoplasm with indistinct cell boundaries and are called epithelioid cells. A collar of lymphocytes surrounds the aggregates of epithelioid macrophages. Older granulomas may have a rim of fibroblasts and connective tissue. Frequently, but not invariably, multinucleated giant cells 40 to 50 µm in diameter are found in granulomas; these are called Langhans giant cells.They consist of a large mass of cytoplasm and many nuclei. Granulomas associated with certain infectious organisms (classically Mycobacterium tuberculosis) often contain a central zone of necrosis. Grossly, this has a granular,cheesy appearance and is therefore called caseous necrosis. Microscopically, this necrotic material appears as amorphous, structureless, eosinophilic, granular debris, with loss of cellular details.The granulomas in Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be


Pathology_Robbins

Pathology_Robbins. eosinophilic, granular debris, with loss of cellular details.The granulomas in Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be noncaseating. Healing of granulomas is accompanied by fibrosis that may be extensive.


Pathology_Robbins

Pathology_Robbins. Fig. 3.22 Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple multinucleate giant cells, epithelioid cells, and lymphocytes. Granulomas are encountered in certain specific pathologic states; recognition of the granulomatous pattern is important because of the limited number of conditions (some life threatening) that cause it (


Pathology_Robbins

Pathology_Robbins. Table 3.9 ). In the setting of persistent T cell responses to certain microbes (e.g., M. tuberculosis, Treponema pallidum, or fungi), T cell– derived cytokines are responsible for chronic macrophage activation and granuloma formation. Granulomas may also develop in some immune-mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease and an important cause of granulomatous inflammation in the United States, and in a disease of unknown etiology called sarcoidosis. Tuberculosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified. In this disease the granuloma is referred to as a tubercle. The morphologic patterns in the various granulomatous diseases may be sufficiently different to allow a reasonably accurate diagnosis ( 3.9 ), but it is always necessary to identify the specific etiologic agent by special stains for organisms (e.g., acid-fast stains for


Pathology_Robbins

Pathology_Robbins. different to allow a reasonably accurate diagnosis ( 3.9 ), but it is always necessary to identify the specific etiologic agent by special stains for organisms (e.g., acid-fast stains for tubercle bacilli), by culture methods (e.g., in tuberculosis and fungal diseases), by molecular techniques (e.g., the polymerase chain reaction in tuberculosis), and by serologic studies (e.g., in syphilis).


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Pathology_Robbins. http://ebooksmedicine.net Table 3.9 Examples of Diseases With Granulomatous Inflammation Tuberculosis Mycobacterium tuberculosis Caseating granuloma (tubercle): focus of activated macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing wall of macrophages; plasma cell infiltrate; central cells are necrotic without loss of cellular outline; organisms difficult to identify in tissue Sarcoidosis Unknown etiology Noncaseating granulomas with abundant activated macrophages Chronic inflammation is a prolonged host response to persistent stimuli that may follow unresolved acute inflammation or be chronic from the outset.


Pathology_Robbins

Pathology_Robbins. Chronic inflammation is a prolonged host response to persistent stimuli that may follow unresolved acute inflammation or be chronic from the outset. It is caused by microbes that resist elimination, immune responses against self and environmental antigens, and some toxic substances (e.g., silica); underlies many medically important diseases. It is characterized by coexisting inflammation, tissue injury, attempted repair by scarring, and immune response. The cellular infiltrate consists of macrophages, lymphocytes, plasma cells, and other leukocytes. It is mediated by cytokines produced by macrophages and lymphocytes (notably T lymphocytes); bidirectional interactions between these cells tend to amplify and prolong the inflammatory reaction. Granulomatous inflammation is a morphologically specific pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication.


Pathology_Robbins

Pathology_Robbins. Granulomatous inflammation is a morphologically specific pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication. Inflammation, even if it is localized, is associated with cytokine-induced systemic reactions that are collectively called the acute-phase response. Anyone who has suffered through a severe bout of a bacterial or viral illness (e.g., pneumonia or influenza) has experienced the systemic manifestations of acute inflammation. These changes are reactions to cytokines whose production is stimulated by bacterial products such as LPS, viral double stranded RNA and by other inflammatory stimuli. The cytokines TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction; other cytokines, notably type I interferons, also contribute to the reaction. The acute-phase response consists of several clinical and pathologic changes:


Pathology_Robbins

Pathology_Robbins. Fever, characterized by an elevation of body temperature, usually by 1° to 4°C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is associated with infection. Substances that induce fever are called pyrogens. The increase in body temperature is caused by prostaglandins that are produced in the vascular and perivascular cells of the hypothalamus. Bacterial products, such as LPS (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the enzymes (cyclooxygenases) that convert arachadonic acid into prostaglandins. In the hypothalamus, the prostaglandins, especially PGE2, stimulate the production of neurotransmitters that reset the temperature set point at a higher level. NSAIDs, including aspirin, reduce fever by inhibiting prostaglandin synthesis. How, and even if, fever contributes to the protective host response remains unclear.


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Pathology_Robbins. Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli. Three of the best-known of these proteins are C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. Synthesis of these molecules in hepatocytes is stimulated by cytokines. Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement. Fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual red cells. This is the basis for measuring the erythrocyte sedimentation rate as a simple test for an inflammatory response caused by any stimulus. Acute-phase proteins have beneficial effects during acute inflammation, but prolonged production of these proteins (especially SAA) in states of chronic inflammation can, in some cases, cause secondary amyloidosis


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Pathology_Robbins. have beneficial effects during acute inflammation, but prolonged production of these proteins (especially SAA) in states of chronic inflammation can, in some cases, cause secondary amyloidosis (Chapter 5). Elevated serum levels of CRP serve as a marker for increased risk of myocardial infarction in patients with coronary artery disease. It is postulated that inflammation involving atherosclerotic plaques in the coronary arteries predisposes to http://ebooksmedicine.net thrombosis and subsequent infarction. Another peptide whose production is increased in the acute-phase response is the iron-regulating peptide hepcidin. Chronically elevated plasma concentrations of hepcidin reduce the availability of iron and are responsible for the anemia associated with chronic inflammation (Chapter 12).


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Pathology_Robbins. Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections. The leukocyte count usually climbs to 15,000 or 20,000 cells/mL, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/mL. These extreme elevations are referred to as leukemoid reactions, because they are similar to (and must be distinguished from) the white cell counts observed in leukemia. The leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood, referred to as a shift to the left. Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased production of colony-stimulating factors (CSFs). Thus, if inflammation is sustained the bone marrow output of leukocytes increases, an effect that usually more than


Pathology_Robbins

Pathology_Robbins. bone marrow, caused by increased production of colony-stimulating factors (CSFs). Thus, if inflammation is sustained the bone marrow output of leukocytes increases, an effect that usually more than conpensates for the loss of these cells in the inflammatory reaction. (See also the discussion of leukocytosis in Chapter 12.) Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis). In some allergies and parasitic infestations, there is an increase in the number of blood eosinophils, creating an eosinophilia. Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia).


Pathology_Robbins

Pathology_Robbins. Other manifestations of the acute-phase response include increased heart rate and blood pressure; decreased sweating, mainly because of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; rigors (shivering), chills (search for warmth), anorexia, somnolence, and malaise, probably because of the actions of cytokines on brain cells.


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Pathology_Robbins. In severe bacterial infections (sepsis), the large amounts of bacteria and their products in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1. High blood levels of cytokines cause widespread clinical and pathologic abnormalities such as disseminated intravascular coagulation, hypotensive shock, and metabolic disturbances including insulin resistance and hyperglycemia. This clinical triad is known as septic shock; it is discussed in more detail in Chapter 4. A syndrome similar to septic shock may occur as a complication of noninfectious disorders, such as severe burns, trauma, pancreatitis, and other serious conditions. Collectively these reactions are called systemic inflammatory response syndrome (SIRS). We next consider the process of repair, which is a healing response to tissue destruction resulting from inflammation or other causes. Fever: Cytokines (TNF, IL-1) stimulate production of PGs in hypothalamus


Pathology_Robbins

Pathology_Robbins. Fever: Cytokines (TNF, IL-1) stimulate production of PGs in hypothalamus Production of acute-phase proteins: C-reactive protein, others; synthesis stimulated by cytokines (IL-6, others) acting on liver cells Leukocytosis: Cytokines (CSFs) stimulate production of leukocytes from precursors in the bone marrow In some severe infections, septic shock: Fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF and other cytokines Overview of Tissue Repair Critical to the survival of an organism is the ability to repair the damage caused by toxic insults and inflammation. In fact, the inflammatory response to microbes and injured tissues not only serves to eliminate these dangers but also sets into motion the process of repair.


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Pathology_Robbins. Repair of damaged tissues occurs by two types of reactions: regeneration by proliferation of residual (uninjured) cells and maturation of tissue stem cells, and the deposition of connective tissue to form a scar ( Fig. 3.23 • Regeneration. Some tissues are able to replace the damaged components and essentially return to a normal Mild, superficial injury Severe injury Fig. 3.23 Mechanisms of tissue repair: regeneration and scar formation. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation.


Pathology_Robbins

Pathology_Robbins. state; this process is called regeneration. Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate, for example, in the rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver. In other cases, tissue stem cells may contribute to the restoration of damaged tissues. However, whereas lower animals such as salamanders and fish can regenerate entire limbs or appendages, mammals have a limited capacity to regenerate damaged tissues and organs, and only some components of most tissues are able to fully restore themselves.


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Pathology_Robbins. • Connective tissue deposition (scar formation). If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that may result in formation of a scar. Although the fibrous scar is not normal, it provides enough structural stability that the injured tissue is usually able to function. The term fibrosis is most often used to describe the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarction). If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called organization (as in organizing pneumonia affecting the lung).


Pathology_Robbins

Pathology_Robbins. After many common types of injury, both regeneration and scar formation contribute in varying degrees to the ultimate repair. Both processes involve the proliferation of various cells, and close interactions between cells and the extracellular matrix (ECM). We first discuss the general mechanisms of cellular proliferation and regeneration, and then the salient features of regeneration and healing by scar formation, and conclude with a description of cutaneous wound healing and fibrosis (scarring) in parenchymal organs as illustrations of the repair process. The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on the integrity of the extracellular matrix, and by the development of mature cells from stem cells. Before describing examples of repair by regeneration, we discuss the control of cell proliferation in this process. The general principles of cell proliferation were summarized in Chapter 1.


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Pathology_Robbins. Cell Proliferation: Signals and Control Mechanisms Several cell types proliferate during tissue repair. These include the remnants of the injured tissue (which attempt to restore normal structure), vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process), and fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration).


Pathology_Robbins

Pathology_Robbins. The ability of tissues to repair themselves is determined, in part, by their intrinsic proliferative capacity. In some tissues (sometimes called labile tissues), cells are constantly being lost and must be continually replaced by new cells that are derived from tissue stem cells and rapidly proliferating immature progenitors. These types of tissues include hematopoietic cells in the bone marrow and many surface epithelia, such as the basal layers of the squamous epithelia of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar epithelium of the gastrointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract. These tissues can readily regenerate after injury as long as the pool of stem cells is preserved.


Pathology_Robbins

Pathology_Robbins. Other tissues (called stable tissues) are made up of cells that are normally in the G0 stage of the cell cycle and hence not proliferating, but they are capable of dividing in response to injury or loss of tissue mass. These tissues include the parenchyma of most solid organs, such as liver, kidney, and pancreas. Endothelial cells, fibroblasts, and smooth muscle cells are also normally quiescent but can proliferate in response to growth factors, a reaction that is particularly important in wound healing. Some tissues (called permanent tissues) consist of terminally differentiated nonproliferative cells, such as the majority of neurons and cardiac muscle cells. Injury to these tissues is irreversible and results in a scar, because the cells cannot regenerate. Skeletal muscle cells are usually considered nondividing, but satellite cells attached to the endomysial sheath provide some regenerative capacity for muscle.