Pathology_Robbins

Pathology_Robbins. Mitochondria may be viewed as “mini-factories” that produce life-sustaining energy in the form of ATP. Not surprisingly, therefore, they also are critical players in cell injury and death. Mitochondria are sensitive to many types of injurious stimuli, including hypoxia, chemical toxins, and radiation ( Fig. 2.19 ). Mitochondrial changes occur in necrosis and apoptosis. They may result in several biochemical abnormalities: Failure of oxidative phosphorylation leads to progressive depletion of ATP, culminating in necrosis of the cell, as described earlier. Abnormal oxidative phosphorylation also leads to the formation of ROS, which have many deleterious effects, as already described. Damage to mitochondria is often associated with the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial ATP Production Leakage ofgeneration of ROS


Pathology_Robbins

Pathology_Robbins. Damage to mitochondria is often associated with the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial ATP Production Leakage ofgeneration of ROS Fig. 2.19 Role of mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis. This pathway of apoptosis is described in more detail later. ATP, Adenosine triphosphate; ROS, reactive oxygen species. permeability transition pore. The opening of this channel leads to the loss of mitochondrial membrane potential and pH changes, further compromising oxidative phosphorylation. • Mitochondria also contain proteins such as cytochrome c that, when released into the cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis, as discussed earlier.


Pathology_Robbins

Pathology_Robbins. • Mitochondria also contain proteins such as cytochrome c that, when released into the cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis, as discussed earlier. Increased membrane permeability leading ultimately to overt membrane damage is a feature of most forms of cell injury that culminate in necrosis. The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma membrane, and membranes of lysosomes. As noted earlier, increased permeability of the plasma membrane and lysosomal membranes is not a feature of apoptosis. Mitochondrial membrane damage. As discussed earlier, damage to mitochondrial membranes results in decreased production of ATP, with many deleterious effects culminating in necrosis.


Pathology_Robbins

Pathology_Robbins. Mitochondrial membrane damage. As discussed earlier, damage to mitochondrial membranes results in decreased production of ATP, with many deleterious effects culminating in necrosis. Plasma membrane damage. Plasma membrane damage leads to loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores. Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell. Activation of these enzymes leads to enzymatic digestion of cell components, and the cells die by necrosis. Differentinitiatingeventscausecellinjuryanddeathbydiversemechanisms. HypoxiaandischemialeadtoATPdepletionandfailureofmanyenergy-dependentfunctions,resultingfirstinreversibleinjuryand,ifnotcorrected,innecrosis.


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Pathology_Robbins. DNAdamage(e.g.,byradiation)alsocaninduceapoptosisifitisnotrepaired. Inflammationisassociatedwithcellinjurybecauseofthedamagingactionsoftheproductsofinflammatoryleukocytes. We have now concluded the discussion of cell injury and cell death. As we have seen, these processes are the root cause of many common diseases. We end this chapter with brief considerations of three other processes: cellular adaptations to stresses; intracellular accumulations of various substances and extracellular deposition of calcium, both of which are often associated with cell injury; and aging.


Pathology_Robbins

Pathology_Robbins. Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy), or to the demands of mechanical stress (in the case of bones and muscles). Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury, but at the expense of normal function, such as squamous metaplasia of bronchial epithelium in smokers. Physiologic and pathologic adaptations can take several distinct forms, as described in the following text.


Pathology_Robbins

Pathology_Robbins. Hypertrophy is an increase in the size of cells resulting in an increase in the size of the organ. In contrast, hyperplasia (discussed next) is an increase in cell number. Stated another way, in pure hypertrophy there are no new cells, just bigger cells containing increased amounts of structural proteins and organelles. Hyperplasia is an adaptive response in cells capable of replication, whereas hypertrophy occurs when cells have a limited capacity to divide. Hypertrophy and hyperplasia also can occur together, and obviously both result in an enlarged organ. Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by growth factor or hormonal stimulation. The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth muscle hyperplasia (


Pathology_Robbins

Pathology_Robbins. The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth muscle hyperplasia ( Fig. 2.20 ). In contrast, in response to increased workload the striated muscle cells in both the skeletal muscle and the heart undergo only hypertrophy because adult muscle cells have a limited capacity to divide. Therefore, the chiseled physique of the avid weightlifter stems solely from the hypertrophy of individual skeletal muscles. An example of pathologic hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease ( Fig. 2.21 ). The differences between normal, adapted, and irreversibly injured cells are illustrated by the responses of the heart to different types of


Pathology_Robbins

Pathology_Robbins. Fig. 2.21 ). The differences between normal, adapted, and irreversibly injured cells are illustrated by the responses of the heart to different types of Fig. 2.20 Physiologichypertrophyoftheuterusduringpregnancy.(A)Grossappearanceofanormaluterus(right) andagraviduterus(left) thatwasremovedforpostpartumbleeding.(B)Smallspindle-shapeduterinesmoothmusclecellsfromanormaluterus.(C)Large,plumphypertrophiedsmoothmusclecellsfromagraviduterus;comparewithB.(B andC, Samemagnification.) http://ebooksmedicine.net Cell death Reversibly injured myocyte Ischemia leading to cell injury Adapted myocyte (hypertrophy) Adaptation: response to increased load


Pathology_Robbins

Pathology_Robbins. Cell death Reversibly injured myocyte Ischemia leading to cell injury Adapted myocyte (hypertrophy) Adaptation: response to increased load Fig. 2.21 Therelationshipamongnormal,adapted,reversiblyinjured,anddeadmyocardialcells.Thecellularadaptationdepictedhereishypertrophy,thecauseofreversibleinjuryisischemia,andtheirreversibleinjuryisischemiccoagulativenecrosis.Intheexampleofmyocardialhypertrophy(lower left),theleftventricularwallisthickerthan2cm(normal,1–1.5cm).Reversiblyinjuredmyocardiumshowsfunctionaleffectswithoutanygrossorlightmicroscopicchanges,orreversiblechangessuchascellularswellingandfattychange(shown here).Inthespecimenshowingnecrosis(lower right) thetransmurallightareaintheposterolateralleftventriclerepresentsanacutemyocardialinfarction.Allthreetransversesectionsofmyocardiumwerestainedwithtriphenyltetra-zoliumchloride,anenzymesubstratethatcolorsviablemyocardiummagenta.Failuretostainisduetoenzymelossaftercelldeath.


Pathology_Robbins

Pathology_Robbins. stress. Myocardium subjected to a persistently increased workload, as in hypertension or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to generate the required higher contractile force. If, on the other hand, the myocardium is subjected to reduced blood flow (ischemia) due to an occluded coronary artery, the muscle cells may undergo injury.


Pathology_Robbins

Pathology_Robbins. The mechanisms driving cardiac hypertrophy involve at least two types of signals: mechanical triggers, such as stretch, and soluble mediators that stimulate cell growth, such as growth factors and adrenergic hormones. These stimuli turn on signal transduction pathways that lead to the induction of a number of genes, which in turn stimulate synthesis of many cellular proteins, including growth factors and structural proteins. The result is the synthesis of more proteins and myofilaments per cell, which increases the force generated with each contraction, enabling the cell to meet increased work demands. There may also be a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the fetal β form of the myosin heavy chain, which produces slower, more energetically economical contraction.


Pathology_Robbins

Pathology_Robbins. An adaptation to stress such as hypertrophy can progress to functionally significant cell injury if the stress is not relieved. Whatever the cause of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the increased burden. When this happens in the heart, several degenerative changes occur in the myocardial fibers, of which the most important are fragmentation and loss of myofibrillar contractile elements. Why hypertrophy progresses to these regressive changes is incompletely understood. There may be finite limits on the abilities of the vasculature to adequately supply the enlarged fibers, the mitochondria to supply ATP, or the biosynthetic machinery to provide sufficient contractile proteins or other cytoskeletal elements. The net result of these degenerative changes is ventricular dilation and ultimately cardiac failure.


Pathology_Robbins

Pathology_Robbins. Hyperplasia is an increase in the number of cells in an organ that stems from increased proliferation, either of differentiated cells or, in some instances, less differentiated progenitor cells. As discussed earlier, hyperplasia takes place if the tissue contains cell populations capable of replication; it may occur concurrently with hypertrophy and often in response to the same stimuli. Hyperplasia can be physiologic or pathologic; in both situations, cellular proliferation is stimulated by growth factors that are produced by a variety of cell types.


Pathology_Robbins

Pathology_Robbins. Hyperplasia can be physiologic or pathologic; in both situations, cellular proliferation is stimulated by growth factors that are produced by a variety of cell types. • The two types of physiologic hyperplasia are (1) hormonal hyperplasia, exemplified by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and (2) compensatory hyperplasia, in which residual tissue grows after removal or loss of part of an organ. For example, when part of a liver is resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal size. The stimuli for hyperplasia in this setting are polypeptide growth factors produced by uninjured hepatocytes as well as nonparenchymal cells in the liver (Chapter 3). After restoration of the liver mass, various growth inhibitors turn off cell proliferation. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. • Most forms of pathologic hyperplasia are caused by excessive hormonal or growth factor stimulation. For example, after a normal menstrual period there is a burst of uterine epithelial proliferation that is normally tightly regulated by the stimulatory effects of pituitary hormones and ovarian estrogen and the inhibitory effects of progesterone. A disturbance in this balance leading to increased estrogenic stimulation causes endometrial hyperplasia, which is a common cause of abnormal menstrual bleeding. Benign prostatic hyperplasia is another common example of pathologic hyperplasia induced in responses to hormonal stimulation by androgens. Stimulation by growth factors also is involved in the hyperplasia that is associated with certain viral infections; for example, papillomaviruses cause skin warts and mucosal lesions that are composed of masses of hyperplastic epithelium. Here the growth factors may be encoded by viral genes or by the genes of the infected host cells.


Pathology_Robbins

Pathology_Robbins. An important point is that in all of these situations, the hyperplastic process remains controlled; if the signals that initiate it abate, the hyperplasia disappears. It is this responsiveness to normal regulatory control mechanisms that distinguishes pathologic hyperplasias from cancer, in which the growth control mechanisms become permanently dysregulated or ineffective (Chapter 6). Nevertheless, in many cases, pathologic hyperplasia constitutes a fertile soil in which cancers may eventually arise. For example, patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer (Chapter 19). Atrophy is shrinkage in the size of cells by the loss of cell substance. When a sufficient number of cells are involved, the entire tissue or organ is reduced in size, or atrophic ( Fig. 2.22 ). Although atrophic cells may have diminished function, they are not dead.


Pathology_Robbins

Pathology_Robbins. Fig. 2.22 ). Although atrophic cells may have diminished function, they are not dead. Causes of atrophy include a decreased workload (e.g., immobilization of a limb to permit healing of a fracture), loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging (senile atrophy). Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in menopause) and others are pathologic (e.g., denervation), the fundamental cellular changes are similar. They represent a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is achieved between cell size and diminished blood supply, nutrition, or trophic stimulation. Cellular atrophy results from a combination of decreased protein synthesis and increased protein degradation. Protein synthesis decreases because of reduced metabolic activity.


Pathology_Robbins

Pathology_Robbins. Cellular atrophy results from a combination of decreased protein synthesis and increased protein degradation. Protein synthesis decreases because of reduced metabolic activity. The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse may activate ubiquitin ligases, which attach multiple copies of the small peptide ubiquitin to cellular proteins and target them for degradation in proteasomes. This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including the cachexia associated with cancer. In many situations, atrophy also is associated with autophagy, with resulting increases in the number of autophagic vacuoles. As discussed previously, autophagy is the process in which the starved cell eats its own organelles in an attempt to survive.


Pathology_Robbins

Pathology_Robbins. Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse environment. Metaplasia is thought to arise by the reprogramming of stem cells http://ebooksmedicine.net Fig. 2.23 Metaplasiaofnormalcolumnar(left) tosquamousepithelium(right) inabronchus,shownschematically(A)andhistologically(B). to differentiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cells.


Pathology_Robbins

Pathology_Robbins. to differentiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cells. Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium of habitual cigarette smokers, in whom the normal ciliated columnar epithelial cells of the trachea and bronchi often are replaced by strati fied squamous epithelial cells (Fig. 2.23 ). The rugged stratified squamous epithelium may be able to survive the noxious chemicals in cigarette smoke that the more fragile specialized epithelium would not tolerate. Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance of particulate matter. Epithelial metaplasia is therefore a double-edged sword. Because vitamin A is essential for normal epithelial differentiation, its deficiency also may induce squamous metaplasia in the respiratory epithelium.


Pathology_Robbins

Pathology_Robbins. Metaplasia need not always occur in the direction of columnar to squamous epithelium; in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium. Metaplasia also may occur in mesenchymal cells, but in these situations it is generally a reaction to some pathologic alteration and not an adaptive response to stress. For example, bone is occasionally formed in soft tissues, particularly in foci of injury. The influences that induce metaplastic change in an epithelium, if persistent, may predispose to malignant transformation. In fact, squamous metaplasia of the respiratory epithelium often coexists with lung cancers composed of malignant squamous cells. It is thought that cigarette smoking initially causes squamous metaplasia, and cancers arise later in some of these altered foci.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Under some circumstances, cells may accumulate abnormal amounts of various substances, which may be harmless or may cause varying degrees of injury. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, and it may be synthesized by the affected cells or it may be produced elsewhere. The main pathways of abnormal intracellular accumulations are inadequate removal and degradation or excessive production of an endogenous substance, or deposition of an abnormal exogenous material ( Fig. 2.24 ). Selected examples of each are described as follows.


Pathology_Robbins

Pathology_Robbins. Fig. 2.24 ). Selected examples of each are described as follows. Fatty Change. Fatty change, also called steatosis, refers to any accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but also may occur in heart, skeletal muscle, kidney, and other organs. Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations. This process is discussed in more detail in Chapter 16.


Pathology_Robbins

Pathology_Robbins. Cholesterol and Cholesteryl Esters. Cellular cholesterol metabolism is tightly regulated to ensure normal generation of cell membranes (in which cholesterol is a key component) without significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes, mostly characterized by increased intake or decreased catabolism of lipids. Of these, atherosclerosis is the most important. The role of lipid and cholesterol deposition in the pathogenesis of atherosclerosis is discussed in Chapter 10. Proteins. Morphologically visible protein accumulations are less common than lipid accumulations; they may occur when excesses are presented to the cells or if the cells http://ebooksmedicine.net 52CHAPTER 2 Cell Injury, Cell Death, and Adaptations Defect in protein folding, transport Accumulation of abnormal proteins Lack of enzyme


Pathology_Robbins

Pathology_Robbins. Defect in protein folding, transport Accumulation of abnormal proteins Lack of enzyme Lysosomal storage disease: accumulation of endogenous materials Ingestion of indigestible materials Accumulation of exogenous materials Fig. 2.24 Mechanisms of intracellular accumulation: (1) Abnormal metabolism, as in fatty change in the liver. (2) Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly. (3) A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases. (4) An inability to degrade phagocytosed particles, as in carbon pigment accumulation.


Pathology_Robbins

Pathology_Robbins. synthesize excessive amounts. In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules. However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syndrome), much more of the protein is reabsorbed, and vesicles containing this protein accumulate, giving the histologic appearance of pink, hyaline cytoplasmic droplets. The process is reversible: if the proteinuria abates, the protein droplets are metabolized and disappear. Another example is the marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. Other examples of protein aggregation are discussed elsewhere in this book (e.g., “alcoholic hyaline” in the liver in Chapter 16; neurofibrillary tangles in neurons in Chapter 23).


Pathology_Robbins

Pathology_Robbins. Glycogen. Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. In poorly controlled diabetes mellitus, the prime example of abnormal glucose metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. Glycogen also accumulates within cells in a group of related genetic disorders collectively referred to as glycogen storage diseases, or glycogenoses (Chapter 7). Pigments. Pigments are colored substances that are either exogenous, coming from outside the body, such as carbon, or are endogenous, synthesized within the body itself, such as lipofuscin, melanin, and certain derivatives of hemoglobin.


Pathology_Robbins

Pathology_Robbins. The most common exogenous pigment is carbon, a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis) (Chapter 13). Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) with aging or atrophy. Lipofuscin represents complexes of lipid and protein that are produced by the free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is a marker of past free radical injury. The brown pigment ( Fig. 2.25 ), when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.


Pathology_Robbins

Pathology_Robbins. Fig. 2.25 ), when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. Melanin is an endogenous, brown-black pigment that is synthesized by melanocytes located in the epidermis and acts as a screen against harmful UV radiation. Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (e.g., in freckles), as can dermal macrophages. Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of these Fig. 2.25 Lipofuscingranulesincardiacmyocytes(depositsindicatedbyarrows).


Pathology_Robbins

Pathology_Robbins. Fig. 2.25 Lipofuscingranulesincardiacmyocytes(depositsindicatedbyarrows). ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction ( Fig. 2.26 ). Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosiderin, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis are described in Chapter 16. Pathologic calcification, a common process in a wide variety of disease states, is the result of an abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other minerals. It can occur in two ways.


Pathology_Robbins

Pathology_Robbins. • Dystrophic calcification. In this form, calcium metabolism is normal but it deposits in injured or dead tissue, such as areas of necrosis of any type. It is virtually ubiquitous in the arterial lesions of advanced atherosclerosis (Chapter 10). Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury, it also may be a cause of organ dysfunction. For example, calcification can develop in aging or damaged heart valves, resulting in severely compromised valve motion. Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in elderly persons (Chapter 11).


Pathology_Robbins

Pathology_Robbins. Dystrophic calcification is initiated by the extracellular deposition of crystalline calcium phosphate in membrane-bound vesicles, which may be derived from injured cells, or the intracellular deposition of calcium in the mitochondria of dying cells. It is thought that the extracellular calcium is concentrated in vesicles by its affinity for membrane phospholipids, whereas phosphates accumulate as a result of the action of membrane-bound phosphatases. The crystals are then propagated, forming larger deposits.


Pathology_Robbins

Pathology_Robbins. • Metastatic calcification. This form is associated with hypercalcemia and can occur in normal tissues. The major causes of hypercalcemia are (1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of parathyroid hormone–related protein by other malignant tumors; (2) destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases); (3) vitamin D–related disorders including vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor); and (4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism.


Pathology_Robbins

Pathology_Robbins. Metastaticcalcification:depositionofcalciuminnormaltissues,causedbyhypercalcemia(usuallyaconsequenceofparathyroidhormoneexcess) Individuals age because their cells age. Although public attention on the aging process has traditionally focused on its cosmetic manifestations, aging has important health consequences, because age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease. Perhaps one of the most striking discoveries about cellular aging is that it is not simply a consequence of cells’ “running out of steam,” but in fact is regulated by a limited number of genes and signaling pathways that are evolutionarily conserved from yeast to mammals. Cellular aging is the result of a progressive decline in the life span and functional activity of cells. Several abnormalities contribute to the aging of cells (


Pathology_Robbins

Pathology_Robbins. Cellular aging is the result of a progressive decline in the life span and functional activity of cells. Several abnormalities contribute to the aging of cells ( Fig. 2.27 • Accumulation of mutations in DNA. A variety of metabolic insults over time may result in damage to nuclear and mitochondrial DNA. ROS induced by toxins and radiation exposure contribute to DNA damage associated with aging. Although most DNA damage is repaired by DNA repair enzymes, some persists and accumulates as cells age, especially if repair mechanisms become inefficient over time. Accumulation of mutations in nuclear and mitochondrial DNA ultimately compromise the functional activities and survival of cells.


Pathology_Robbins

Pathology_Robbins. • Decreased cellular replication. Normal cells (other than stem cells) have a limited capacity for replication, and after a fixed number of divisions, they become arrested in a terminally nondividing state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells. Cells from children have the capacity to undergo more rounds of replication than do cells from older people. In contrast, cells from patients with Werner syndrome, a rare disease characterized by premature aging, have a markedly reduced in vitro life span. Replicative senescence occurs in aging cells because of progressive shortening of telomeres, which ultimately results in cell cycle arrest. Telomeres are short repeated sequences of DNA present at the ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. Telomeric DNA also binds proteins that shield it, preventing activation of a


Pathology_Robbins

Pathology_Robbins. for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. Telomeric DNA also binds proteins that shield it, preventing activation of a DNA damage response. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As they shorten, the ends of chromosomes cannot be protected and are sensed in cells as broken DNA, which signals cell cycle arrest. Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. Telomerase is expressed in germ cells and is present at low levels in stem cells, but absent in most somatic cells (


Pathology_Robbins

Pathology_Robbins. Fig. 2.28 ). Therefore, as mature somatic cells age, their telomeres become shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely. This is discussed more fully in Chapter 6. Telomere shortening also may decrease the regenerative capacity of stem cells, further contributing to cellular aging. Despite such alluring observations, however, the relationship of telomerase activity and telomere length to aging has yet to be fully established. Abnormalities in telomere maintenance have been implicated in many diseases, such as aplastic anemia and other cytopenias (thought to be caused by a failure of hematopoietic stem cells), premature greying of hair, skin pigment and nail abnormalities, pulmonary and liver fibrosis, and others. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Accumulation of mutations in DNA Cellular replication DECREASED CELL FUNCTIONS, CELL LOSS CELL LOSS Altered transcription Proteins, damaged proteins Insulin/IGF signaling DNA repair Protein homeostasis TOR DECREASED CELL FUNCTIONS COUNTERACTS AGING ROS? Defective DNA repair CELLULAR AGING Fig. 2.27 Mechanismsthatcauseandcounteractcellularaging.DNAdamage,replicativesenescence,anddecreasedandmisfoldedproteinsareamongthebest-describedmechanismsofcellularaging.Someenvironmentalinfluences,suchascalorierestriction,counteractagingbyactivatingvarioussignalingpathwaysandtranscriptionfactors.IGF, Insulin-likegrowthfactor;ROS, reactiveoxygenspecies;TOR, targetofrapamycin.


Pathology_Robbins

Pathology_Robbins. These disorders are sometimes considered the prototypic “telomeropathies.” • Defective protein homeostasis. With the passage of time, cells are unable to maintain normal protein homeostasis, because of increased turnover and decreased synthesis caused by reduced translation of proteins and defective activity of chaperones (which promote normal protein folding) and proteasomes (which destroy misfolded proteins). The resultant decrease in intracellular proteins can have many deleterious effects on cell survival, replication, and functions. The concomitant accumulation of misfolded proteins exacerbates the loss of functional proteins and can trigger apoptosis. • There has been great interest in defining biochemical signaling pathways that counteract the aging process, not only because of their obvious therapeutic potential Senescence Depletion of stem/ of mature cells progenitor cells


Pathology_Robbins

Pathology_Robbins. Senescence Depletion of stem/ of mature cells progenitor cells Fig. 2.28 Theroleoftelomeresandtelomeraseinreplicativesenescenceofcells.(A)Mechanismsandconsequencesoftelomereattrition.Repeatedcelldivisionassociatedwithagingleadstoprogressiveshorteningoftelomeres,whichtriggerssenescenceandlossofstemcellpools.(B)Telomereattritionischaracteristicofsomaticcells.Stemcellsmaintaintheirtelomeresandare,therefore,capableofmorecyclesofreplication.Cancercellsfrequentlyactivatetelomeraseandarethusabletomaintaintelomeres. http://ebooksmedicine.net 56CHAPTER 2CellInjury,CellDeath,andAdaptations (the search for the “elixir of youth”) but also because elucidating these pathways might tell us about the mechanisms that cause aging. Calorie restriction has been found to slow down aging and prolong life in every species tested from flies to mice. It is now thought that calorie restriction alters signaling pathways that influence aging (


Pathology_Robbins

Pathology_Robbins. Fig. 2.27 ). Among the biochemical alterations associated with calorie restriction that have been described as playing a role in counteracting the aging process is reduced activation of insulin-like growth factor receptor signaling, which involves a downstream network of kinases and transcription factors. Reduced IGF-1 signaling leads to lower rates of cell growth and metabolism and possibly reduced errors in DNA replication, better DNA repair and improve protein homeostasis. Calorie restriction also serves to improve immunity. All of these inhibit aging.


Pathology_Robbins

Pathology_Robbins. • Persistent inflammation. As individuals age, the accumulation of damaged cells, lipids, and other endogenous substances may activate the inflammasome pathway (Chapter 5), resulting in persistent low-level inflammation. Inflammation in turn induces chronic diseases, such as atherosclerosis and type 2 diabetes. Cytokines produced during inflammatory reactions may themselves induce cellular alterations that exacerbate aging, and chronic metabolic disorders may accelerate the aging process. Clinical observations and epidemiologic studies have shown that physical activity and, as mentioned previously, calorie restriction slow the aging process, whereas stresses, perhaps acting via increased production of glucocorticoids, accelerate aging. Alas, the precise mechanisms underlying these effects remain to be defined, and for now we all remain vulnerable to the ravages of age. Resultsfromacombinationofmultiple,progressivecellularalterations,including:


Pathology_Robbins

Pathology_Robbins. Resultsfromacombinationofmultiple,progressivecellularalterations,including: Replicativesenescence:reducedcapacityofcellstodividesecondarytoprogressiveshorteningofchromosomalends(telomeres) Defectiveproteinhomeostasis:lossofnormalproteinsandaccumulationofmisfoldedproteins Agingisexacerbatedbychronicdiseases,especiallythoseassociatedwithprolongedinflammation,andbystress,andissloweddownbycalorierestrictionandexercise. It should be apparent that the various forms of cellular derangements and adaptations described in this chapter cover a wide spectrum, ranging from reversible and irreversible forms of acute cell injury, to adaptations in cell size, growth, and function, to largely unavoidable consequences of aging. Reference is made to these many different alterations throughout this book, because all instances of organ injury and ultimately all cases of clinical disease arise from derangements in cell structure and function.


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Pathology_Robbins. Calado RT, Young NS: Telomere diseases, N Engl J Med 361:2353, 2009. [An excellent review of the basic biology of telomeres, and how their abnormalities may contribute to cancer, aging, and other diseases.] Chipuk JE, Moldoveanu T, Llambl F, et al: The BCL-2 family reunion, Mol Cell 37:299, 2010. [A review of the biochemistry and biology of the BCL-2 family of apoptosis-regulating proteins.] Choi AMK, Ryter S, Levine B: Autophagy in human health and disease, N Engl J Med 368:7, 2013. [An excellent discussion of the mechanisms and significance of autophagy.] Conrad M, Angeli JPF, Vandenabeele P, et al: Regulated necrosis: disease relevance and therapeutic opportunities, Nat Rev Drug Discov, 15:348, 2016. [A review of newly discovered pathways of cell death and possible therapeutic interventions.] Dong Z, Saikumar P, Weinberg JM, et al: Calcium in cell injury and death, Ann Rev Pathol 1:405, 2006. [A review of the links between calcium and cell injury.]


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Pathology_Robbins. Dong Z, Saikumar P, Weinberg JM, et al: Calcium in cell injury and death, Ann Rev Pathol 1:405, 2006. [A review of the links between calcium and cell injury.] Frey N, Olson EN: Cardiac hypertrophy: the good, the bad, and the ugly, Annu Rev Physiol 65:45, 2003. [Excellent discussion of the mechanisms of muscle hypertrophy, using the heart as the paradigm.] Hotchkiss RS, Strasser A, McDunn JE, et al: Cell death, N Engl J Med 361:1570, 2009. [Excellent review of the major pathways of cell death (necrosis, apoptosis, and autophagy-associated death), and their clinical implications and therapeutic targeting.] Kenyon CJ: The genetics of ageing, Nature 464:504, 2010. [An excellent review of the genes that influence aging, based on human genetic syndromes and studies with mutant model organisms.]


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Pathology_Robbins. Kenyon CJ: The genetics of ageing, Nature 464:504, 2010. [An excellent review of the genes that influence aging, based on human genetic syndromes and studies with mutant model organisms.] Lambeth JD, Neish AS: Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited, Ann Rev Pathol Mech Dis 9:47, 2014. [A discussion of reactive oxygen species and their roles in physiology and cell injury.] Lopez-Otin C, Blasco MA, Partridge L, et al: The hallmarks of aging, Cell 153:1194, 2013. [A landmark review that suggests nine hallmarks of aging and directions for future research.] Marquez FC, Volovik Y, Cohen E: The roles of cellular and organismal aging in the development of late-onset maladies, Ann Rev Pathol Mech Dis 10:1, 2015. [A review of the many ways by which cellular aging contributes to the development of chronic diseases.]


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Pathology_Robbins. McKinnell IW, Rudnicki MA: Molecular mechanisms of muscle atrophy, Cell 119:907, 2004. [Discussion of the mechanisms of cellular atrophy.] Nathan C, Cunningham-Bussel A: Beyond oxidative stress: an immunologist’s guide to reactive oxygen species, Nat Rev Immunol 13:349, 2013. [An excellent modern review of the production, catabolism, targets, and actions of reactive oxygen species, and their roles in inflammation.] Newgard CB, Sharpless NE: Coming of age: molecular drivers of aging and therapeutic opportunities, J Clin Invest 3:946, 2013. [A summary of key molecular pathways in aging.] Oakes SA, Papa FR: The role of endoplasmic reticulum stress in human pathology, Ann Rev Pathol Mech Dis 10:173, 2015. [An up-todate review of the unfolded protein response and the pathogenic importance of cell injury caused by misfolded proteins.]


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Pathology_Robbins. Tosh D, Slack JM: How cells change their phenotype, Nat Rev Mol Cell Biol 3:187, 2002. [Review of metaplasia and the roles of stem cells and genetic reprogramming.] Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, et al: Regulated necrosis: the expanding network of non-apoptotic cell death pathways, Nat Rev Mol Cell Biol 15:135, 2014. [A current review of various forms of programmed non-apoptotic pathways of cell death.] http://ebooksmedicine.net studentconsult.com Overview of Inflammation: Definitions and General Features Causes of Inflammation Recognition of Microbes and Damaged Cells Reactions of Blood Vessels in Acute Inflammation Leukocyte Recruitment to Sites of Inflammation Phagocytosis and Clearance of the Offending Agent Other Functional Responses of Activated Leukocytes Termination of the Acute Inflammatory Response Mediators of Inflammation Vasoactive Amines: Histamine and Serotonin Other Mediators of Inflammation Morphologic Patterns of Acute Inflammation


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Pathology_Robbins. Termination of the Acute Inflammatory Response Mediators of Inflammation Vasoactive Amines: Histamine and Serotonin Other Mediators of Inflammation Morphologic Patterns of Acute Inflammation Purulent (Suppurative) Inflammation, Abscess Outcomes of Acute Inflammation Causes of Chronic Inflammation Cells and Mediators of Chronic Systemic Effects of Inflammation Overview of Tissue Repair Clinical Examples of Abnormal Wound Healing OVERVIEW OF INFLAMMATION: DEFINITIONS AND GENERAL FEATURES Inflammation is a response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents.


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Pathology_Robbins. Although in common medical and lay parlance, inflammation suggests a harmful reaction, it is actually a protective response that is essential for survival. It serves to rid the host of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues). The mediators of defense include phagocytic leukocytes, antibodies, and complement proteins ( Fig.


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Pathology_Robbins. Fig. 3.1 ). Most of these normally circulate in the blood, where they are sequestered so they cannot damage normal tissues but can be rapidly recruited to any site in the body. Some of the cells involved in inflammatory responses also reside in tissues, where they function as sentinels on the lookout for threats. The process of inflammation delivers leukocytes and proteins to foreign invaders, such as microbes, and to damaged or necrotic tissues, and it activates the recruited cells and molecules, which then function to eliminate the harmful or unwanted substances. Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores. The typical inflammatory reaction develops through a series of sequential steps: The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules.


Pathology_Robbins

Pathology_Robbins. The typical inflammatory reaction develops through a series of sequential steps: The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules. Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located. The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance. The reaction is controlled and terminated. The damaged tissue is repaired. Inflammation may be of two types, acute and chronic (


Pathology_Robbins

Pathology_Robbins. The reaction is controlled and terminated. The damaged tissue is repaired. Inflammation may be of two types, acute and chronic ( Table 3.1 ). The initial, rapid response to infections and tissue damage is called acute inflammation. It typically develops within minutes or hours and is of short duration, lasting for several hours or a few days. Its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes). When acute inflammation achieves its desired goal of eliminating the offenders, the reaction subsides and residual injury is repaired. But if the initial response fails to clear the stimulus, the reaction progresses to a protracted type http://ebooksmedicine.net INFLUX OF LEUKOCYTES, PRODUCTION STIMULUSPLASMA PROTEINS OF MEDIATORS Recognition by macrophages, other sentinel cells in tissues Mediators (amines, cytokines) Recruitment of leukocytes


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Pathology_Robbins. INFLUX OF LEUKOCYTES, PRODUCTION STIMULUSPLASMA PROTEINS OF MEDIATORS Recognition by macrophages, other sentinel cells in tissues Mediators (amines, cytokines) Recruitment of leukocytes Vasodilation, EliminationEdema of microbes, Cytokines, Fig. 3.1 Sequence of events in an inflammatory reaction. Macrophages and other cells in tissues recognize microbes and damaged cells and liberate mediators, which trigger the vascular and cellular reactions of inflammation. Recruitment of plasma proteins from the blood is not shown. of inflammation that is called chronic inflammation. As discussed later in this chapter, chronic inflammation may follow acute inflammation or arise de novo. It is of longer duration and is associated with more tissue destruction, the presence of lymphocytes and macrophages, the proliferation of blood vessels, and fibrosis.


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Pathology_Robbins. Inflammation is induced by chemical mediators that are produced by host cells in response to injurious stimuli. When a microbe enters a tissue or the tissue is


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Pathology_Robbins. Table 3.1 Features of Acute and Chronic Inflammation injured, the presence of the infection or damage is sensed by resident cells, including macrophages, dendritic cells, mast cells, and other cell types. These cells secrete molecules (cytokines and other mediators) that induce and regulate the subsequent inflammatory response. Inflammatory mediators are also produced from plasma proteins that react to the microbes or to products of necrotic cells. Some of these mediators promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. Mediators also activate the recruited leukocytes, enhancing their ability to destroy and remove the offending agent. Understanding the role of chemical mediators is important because most anti-inflammatory drugs target specific mediators. We shall discuss the mediators of inflammation in detail later, after we review the main steps in inflammatory reactions.


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Pathology_Robbins. The external manifestations of inflammation, often called its cardinal signs, are heat (calor in Latin), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa). The first four of these were described more than 2000 years ago by a Roman encyclopedist named Celsus, who wrote the then-famous text De Medicina, and the fifth was added in the late 19th century by Rudolf Virchow, known as the “father of modern pathology.” These manifestations occur as consequences of the vascular changes and leukocyte recruitment and activation, as will be evident from the discussion that follows.


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Pathology_Robbins. Although normally protective, in some situations, the inflammatory reaction becomes the cause of disease, and the damage it produces is its dominant feature. For example, inflammatory reactions to infections are often accompanied by local tissue damage and its associated signs and symptoms (e.g., pain and functional impairment). Typically, however, these harmful consequences are self-limited and resolve as the inflammation abates, leaving little or no permanent damage. In contrast, there are many diseases in which the inflammatory reaction is misdirected (e.g., against self tissues in autoimmune diseases), occurs against normally harmless environmental substances that evoke an immune response (e.g., in allergies), or is excessively prolonged (e.g., in infections by microbes that resist eradication).


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Pathology_Robbins. Inflammatory reactions underlie common chronic diseases, such as rheumatoid arthritis, atherosclerosis, and lung fibrosis, as well as life-threatening hypersensitivity reactions to insect bites, drugs, and toxins (Table 3.2 ). For this reason our pharmacies abound with anti-inflammatory drugs, which ideally would control the harmful sequelae of inflammation yet not interfere with its beneficial effects. In fact, inflammation may contribute to a variety of diseases that are thought to be primarily metabolic, degenerative, or genetic disorders, such as type 2 diabetes, Alzheimer disease, and cancer. Hence, anti-inflammatory drugs may well have a broader role than currently indicated. In recognition of the wide-ranging harmful consequences of inflammation, the lay press has rather melodramatically referred to it as “the silent killer.”


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Pathology_Robbins. Not only excessive inflammation but also defective inflammation is responsible for serious illness. Too little inflammation, which is typically manifested by increased susceptibility to infections, is most often caused by a reduced number of leukocytes resulting from replacement of the bone marrow by cancers and suppression of the Arthritis Lymphocytes, macrophages; antibodies? Listed are selected examples of diseases in which the inflammatory response plays a significant role in tissue injury. Some, such as asthma, can present with acute inflammation or a chronic illness with repeated bouts of acute exacerbation.These diseases and their pathogenesis are discussed in relevant chapters.


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Pathology_Robbins. marrow by therapies for cancer and graft rejection. Recall that leukocytes, the cells of the inflammatory response, arise from progenitors in the bone marrow, hence any compromise of marrow function will diminish the generation of mature leukocytes. Inherited genetic abnormalities of leukocyte function are rare disorders but they provide valuable information about the mechanisms of leukocyte responses. These conditions are described in Chapter 5, in the context of immunodeficiency diseases.


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Pathology_Robbins. Inflammation is terminated when the offending agent is eliminated. The reaction resolves because mediators are broken down and dissipated, and leukocytes have short life spans in tissues. In addition, anti-inflammatory mechanisms are activated, serving to control the response and prevent it from causing excessive damage to the host. After inflammation has achieved its goal of eliminating the offending agents, it sets into motion the process of tissue repair. Repair consists of a series of events that heal damaged tissue. In this process, the injured tissue is replaced through regeneration of surviving cells and filling of residual defects with connective tissue (scarring). This chapter describes the etiology of and stimuli for inflammation, and then the sequence of events, mediators, and morphologic patterns of acute inflammation. This is followed by a discussion of chronic inflammation, and then the process of tissue repair.


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Pathology_Robbins. Inflammatory reactions may be triggered by a variety of stimuli: • Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation. Different infectious pathogens elicit distinct inflammatory responses, from mild acute inflammation that causes little or no lasting damage and successfully eradicates the infection, to severe systemic reactions that can be fatal, to prolonged chronic reactions that cause extensive tissue injury. The morphologic pattern of the response can be useful in identifying its etiology, as discussed later in this chapter.


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Pathology_Robbins. Tissue necrosis elicits inflammation regardless of the cause of cell death, which may include ischemia (reduced blood flow, the cause of myocardial infarction), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals). Several molecules released from necrotic cells are known to trigger inflammation; some of these are described later. Foreign bodies (splinters, dirt, sutures) may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes. Even some endogenous substances stimulate potentially harmful inflammation if large amounts are deposited in tissues; such substances include urate crystals (in the disease gout), and cholesterol crystals (in atherosclerosis).


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Pathology_Robbins. Immune reactions (also called hypersensitivity) are reactions in which the normally protective immune system damages the individual’s own tissues. The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be inappropriate reactions against environmental substances, as in allergies, or against microbes. Inflammation is a major cause of tissue injury in these diseases (Chapter 5). Because the stimuli for the inflammatory responses in autoimmune and allergic diseases (self and environmental antigens) cannot be eliminated, these reactions tend to be persistent and difficult to cure, are often associated with chronic inflammation, and are important causes of morbidity and mortality.


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Pathology_Robbins. The first step in inflammatory responses is the recognition of microbes and necrotic cells by cellular receptors and circulating proteins. The cells and receptors that recognize invaders evolved as adaptations of multicellular organisms to the presence of microbes in the environment, and the responses they trigger are critical for survival.


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Pathology_Robbins. • Cellular receptors for microbes. Phagocytes, dendritic cells (cells in epithelia and all tissues whose function is to capture microbes), and many other cells express receptors that detect the presence of infectious pathogens. The best defined of these receptors belong to the family of Toll-like receptors (TLRs), which are named for the founding member, Toll, a gene that was discovered in Drosophila (Chapter 5). TLRs are located in plasma membranes and endosomes, so they are able to detect extracellular and ingested microbes. Other microbial sensors are present in the cytoplasm of cells. TLRs recognize motifs common to many microbes, often called pathogen-associated molecular patterns (PAMPs). Recognition of microbes by these receptors stimulates the production and expression of a number of secreted and membrane proteins. These proteins include cytokines that induce inflammation, anti-viral cytokines (interferons), and cytokines and membrane proteins that promote lymphocyte


Pathology_Robbins

Pathology_Robbins. a number of secreted and membrane proteins. These proteins include cytokines that induce inflammation, anti-viral cytokines (interferons), and cytokines and membrane proteins that promote lymphocyte activation and even more potent immune responses. We will return to TLRs in more detail in Chapter 5, when we discuss innate immunity, the early defense against infections.


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Pathology_Robbins. http://ebooksmedicine.net


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Pathology_Robbins. Sensors of cell damage. All cells have cytosolic receptors that recognize molecules that are liberated or altered as a consequence of cell damage, and are hence appropriately called damage-associated molecular patterns (DAMPs). These molecules include uric acid (a product of DNA breakdown), ATP (released from damaged mitochondria), reduced intracellular K+ concentrations (reflecting loss of ions because of plasma membrane injury), DNA (when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally), and many others. The receptors activate a multiprotein cytosolic complex called the inflammasome, which induces the production of the cytokine interleukin-1 (IL-1). IL-1 recruits leukocytes and thus induces inflammation (discussed later). Gain-of-function mutations in the cytosolic receptors are the cause of rare diseases known as autoinflammatory syndromes that are characterized by spontaneous inflammation; IL-1 antagonists are effective treatments for


Pathology_Robbins

Pathology_Robbins. in the cytosolic receptors are the cause of rare diseases known as autoinflammatory syndromes that are characterized by spontaneous inflammation; IL-1 antagonists are effective treatments for these disorders. The inflammasome also has been implicated in inflammatory reactions to urate crystals (the cause of gout), cholesterol crystals (in atherosclerosis), lipids (in metabolic syndrome and obesity-associated diabetes), and amyloid deposits in the brain (in Alzheimer disease). These disorders are discussed in relevant chapters.


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Pathology_Robbins. Circulating proteins. Several plasma proteins recognize microbes and function to destroy blood-borne microbes and to stimulate inflammation at tissue sites of infection. The complement system reacts against microbes and produces mediators of inflammation (discussed later). A circulating protein called mannose-binding lectin recognizes microbial sugars and promotes ingestion of microbes and activation of the complement system. Other proteins called collectins also bind to microbes and promote their phagocytosis. Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but also may cause tissue damage. The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various cells.


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Pathology_Robbins. The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are derived from plasma proteins and various cells. The steps of the inflammatory response can be remembered as the five Rs:(1) recognition of the injurious agent,(2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of the response, and (5) resolution (repair). The causes of inflammation include infections, tissue necrosis, foreign bodies, trauma, and immune responses. Epithelial cells, tissue macrophages and dendritic cells, leukocytes, and other cell types express receptors that sense the presence of microbes and necrotic cells. Circulating proteins recognize microbes that have entered the blood. The outcome of acute inflammation is either elimination of the noxious stimulus followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation.


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Pathology_Robbins. Acute inflammation has three major components: (1) dilation of small vessels, leading to an increase in blood flow, (2) increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent ( Fig. 3.1 ). When an injurious agent, such as an infectious microbe or dead cells, is encountered, phagocytes that reside in all tissues try to eliminate these agents. At the same time, phagocytes and other sentinel cells in the tissues recognize the presence of the foreign or abnormal substance and react by liberating soluble molecules that mediate inflammation. Some of these mediators act on small blood vessels in the vicinity and promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located.


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Pathology_Robbins. Reactions of Blood Vessels in Acute Inflammation The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury. The escape of fluid, proteins, and blood cells from the vascular system into interstitial tissues or body cavities is known as exudation (


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Pathology_Robbins. Fig. 3.2 ). An exudate is an extravascular fluid that has a high protein concentration and contains cellular debris. Its presence implies that there is an increase in the permeability of small blood vessels, typically during an inflammatory reaction. In contrast, a transudate is a fluid with low protein content, little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalance across vessels with normal vascular permeability (Chapter 4). Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate. Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells, and, in many cases, microbes. Changes in vascular flow and caliber begin early after injury and consist of the following:


Pathology_Robbins

Pathology_Robbins. Changes in vascular flow and caliber begin early after injury and consist of the following: Vasodilation is induced by the action of several mediators, notably histamine, on vascular smooth muscle. It is one of the earliest manifestations of acute inflammation, and may be preceded by transient vasoconstriction. Vasodilation first involves the arterioles and then leads to the opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness (erythema) at the site of inflammation. Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid (an exudate) into the extravascular tissues. The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small http://ebooksmedicine.net A. NORMAL B. EXUDATE (high protein content, and may contain some white and red cells) C. TRANSUDATE (low protein content, few cells)


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Pathology_Robbins. A. NORMAL B. EXUDATE (high protein content, and may contain some white and red cells) C. TRANSUDATE (low protein content, few cells) Increased hydrostatic pressure (venous outflow obstruction, [e.g., congestive heart failure]) Decreased colloid osmotic pressure (decreased protein synthesis [e.g., liver disease]; increased protein loss [e.g., kidney disease]; protein malnutrition [e.g., kwashiokor])


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Pathology_Robbins. Decreased colloid osmotic pressure (decreased protein synthesis [e.g., liver disease]; increased protein loss [e.g., kidney disease]; protein malnutrition [e.g., kwashiokor]) Fig. 3.2 Formation of exudates and transudates. (A) Normal hydrostatic pressure (blue arrow) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrow), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. (B) An exudate is formed in inflammation because vascular permeability increases as a result of retraction of endothelial cells, creating spaces through which fluid and proteins can pass. (C) A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure.


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Pathology_Robbins. vessels, and increased viscosity of the blood. These changes result in stasis of blood flow, engorgement of small vessels jammed with slowly moving red cells, seen histologically as vascular congestion and externally as localized redness (erythema) of the involved tissue. • As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is described later. Several mechanisms are responsible for increased vascular permeability in acute inflammation ( Fig. 3.3 ), which include:


Pathology_Robbins

Pathology_Robbins. Several mechanisms are responsible for increased vascular permeability in acute inflammation ( Fig. 3.3 ), which include: Retraction of endothelial cells resulting in opening of inter-endothelial spaces is the most common mechanism of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. It occurs rapidly after exposure to the mediator (within 15 to 30 minutes) and is usually short-lived; hence, it is referred to as the immediate transient response, to distinguish it from the delayed prolonged response that follows endothelial injury, described next. The main sites for this rapid increase in vascular permeability are postcapillary venules.


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Pathology_Robbins. Endothelial injury, resulting in endothelial cell necrosis and detachment. Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or is induced by the actions of microbes and microbial toxins that target endothelial cells. Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired. • Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process, documentedinexperimentalmodels, mayinvolve intracellular channels that open in response to certain factors, such as vascular endothelial growth factor (VEGF), that promote vascular leakage. Its contribution to the vascular permeability seen in acute inflammation in humans is unclear.


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Pathology_Robbins. Although these mechanisms of increased vascular permeability are described separately, all probably contribute in varying degrees in responses to most stimuli. For example, at different stages of a thermal burn, leakage results from endothelial retraction caused by inflammatory mediators and direct and leukocyte-dependent endothelial injury. Responses of Lymphatic Vessels and Lymph Nodes


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Pathology_Robbins. In addition to blood vessels, lymphatic vessels also participate in acute inflammation. The system of lymphatics and lymph nodes filters and polices the extravascular fluids. Lymphatics drain the small amount of extravascular fluid that seeps out of capillaries under normal circumstances. In inflammation, lymph flow is increased to help drain edema fluid that accumulates because of increased vascular permeability. In addition to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph. Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis). Inflamed lymph nodes are often enlarged because of increased cellularity. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis (Chapter 12). For clinicians the presence of red streaks near a skin wound is a telltale


Pathology_Robbins

Pathology_Robbins. cellularity. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis (Chapter 12). For clinicians the presence of red streaks near a skin wound is a telltale sign of an infection in the wound. This streaking follows the course of the lymphatic channels and indicates the presence of lymphangitis; it may be accompanied by painful enlargement of the draining lymph nodes, indicating lymphadenitis.


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Pathology_Robbins. Leukocyte Recruitment to Sites of Inflammation Leukocytes that are recruited to sites of inflammation perform the key function of eliminating the offending Vasodilation is induced by inflammatory mediators such as histamine (described later), and is the cause of erythema and stasis of blood flow. Increased vascular permeability is induced by histamine, kinins, and other mediators that produce gaps between endothelial cells, by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the endothelium. Increased vascular permeability allows plasma proteins and leukocytes, the mediators of host defense, to enter sites of infection or tissue damage. Fluid leak from blood vessels (exudation) results in edema. Lymphatic vessels and lymph nodes also are involved in inflammation, and often show redness and swelling.


Pathology_Robbins

Pathology_Robbins. Lymphatic vessels and lymph nodes also are involved in inflammation, and often show redness and swelling. agents. The most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis, namely, neutrophils and macrophages. Neutrophils are produced in the bone marrow and rapidly recruited to sites of inflammation. Macrophages are slower responders. The principal functions of these cell types differ in subtle but important ways—neutrophils use cytoskeletal rearrangements and enzyme assembly to mount rapid, transient responses, whereas macrophages, being long-lived, make slower but more prolonged responses that often rely on new gene transcription (


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Pathology_Robbins. Table 3.3 ). Macrophages are discussed in more detail later, in the context of chronic inflammation. These leukocytes ingest and destroy bacteria and other microbes, as well as necrotic tissue and foreign substances. Macrophages also produce growth factors that aid in repair. A price that is paid for the defensive potency of leukocytes is that, when strongly activated, they may induce tissue damage and prolong inflammation, because the leukocyte products that destroy microbes and help “clean up” necrotic tissues can also produce “collateral damage” of normal host tissues. When there is systemic activation of inflammation, as may occur when there is invasion of the bloodstream by bacteria, the resulting systemic inflammatory response may even be lethal.


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Pathology_Robbins. The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines. Leukocytes normally flow rapidly in the blood, and in inflammation, they have to be stopped and then brought to the offending agent or the site of tissue damage, outside the vessels. This process can be divided into phases, consisting first of adhesion of leukocytes to endothelium at the site of inflammation, then transmigration of the leukocytes through the vessel wall, and movement of the cells toward the offending agent. Different molecules play important roles in each of these steps ( Fig. 3.4 Leukocyte Adhesion to Endothelium


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Pathology_Robbins. Fig. 3.4 Leukocyte Adhesion to Endothelium When blood flows from capillaries into postcapillary venules, circulating cells are swept by laminar flow against the vessel wall. Red cells, being smaller, tend to move faster than the larger white cells. As a result, red cells are confined to the central axial column, and leukocytes are pushed out toward the wall of the vessel, but the flow prevents the cells from attaching to the endothelium. As the blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called margination. By moving close to the vessel wall, leukocytes are able to detect and react to changes in the endothelium. If the endothelial cells are activated by cytokines and other mediators produced locally, they express adhesion molecules to which the http://ebooksmedicine.net


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Pathology_Robbins. Table 3.3 Properties of Neutrophils and Macrophages • Many tissue-resident macrophages: stem cells in yolk sac or fetal liver (early in development) Life span in tissues 1–2 days Inflammatory macrophages: days or weeks Tissue-resident macrophages: years Responses to activating stimuli Rapid, short-lived, mostly degranulation More prolonged, slower, often dependent on new gene and enzymatic activity transcription Reactive oxygen species Rapidly induced by assembly of phagocyte Less prominent oxidase (respiratory burst) Nitric oxide Low levels or none Induced following transcriptional activation of iNOS Cytokine production Low levels or none Major functional activity, requires transcriptional activation of cytokine genes NET formation Rapidly induced, by extrusion of nuclear No contents Secretion of lysosomal enzymes Prominent Less


Pathology_Robbins

Pathology_Robbins. NET formation Rapidly induced, by extrusion of nuclear No contents Secretion of lysosomal enzymes Prominent Less HSC, Hematopoietic stem cells; iNOS, inducible nitric oxide synthase; NET, neutrophil extracellular traps. This table lists the major differences between neutrophils and macrophages.The reactions summarized above are described in the text. Note that the two cell types share many features, such as phagocytosis, ability to migrate through blood vessels into tissues, and chemotaxis. leukocytes attach loosely. These cells bind and detach and thus begin to tumble on the endothelial surface, a process called rolling. The cells finally come to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).


Pathology_Robbins

Pathology_Robbins. The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines. Cytokines are secreted by cells in tissues in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present. The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins ( Table 3.4 ). These molecules are expressed on leukocytes and endothelial cells, as are their ligands.


Pathology_Robbins

Pathology_Robbins. • Selectins mediate the initial weak interactions between leukocytes and endothelium. Selectins are receptors expressed on leukocytes and endothelium that contain an extracellular domain that binds sugars (hence the lectin part of the name). The three members of this family are E-selectin (also called CD62E), expressed on endothelial cells; P-selectin (CD62P), present on platelets and endothelium; and L-selectin (CD62L), found on the surface of most leukocytes. The ligands for selectins are sialic acid-containing oligosaccharides bound to glycoprotein backbones. The endothelial selectins are typically expressed at low levels or not at all on unactivated endothelium, and are upregulated after stimulation by cytokines and other mediators. Therefore, binding of leukocytes is largely restricted to the endothelium at sites of infection or tissue injury (where the mediators are produced). For example, in unactivated endothelial cells, P-selectin is found primarily in intracellular


Pathology_Robbins

Pathology_Robbins. restricted to the endothelium at sites of infection or tissue injury (where the mediators are produced). For example, in unactivated endothelial cells, P-selectin is found primarily in intracellular Weibel-Palade bodies; however, within minutes of exposure to mediators such as histamine or thrombin, P-selectin is distributed to the cell surface. Similarly, E-selectin and the ligand for L-selectin are expressed on endothelium only after stimulation by IL-1 and tumor necrosis factor (TNF), cytokines that are produced by tissue macrophages, dendritic cells, mast cells, and endothelial cells themselves following encounters with microbes and dead tissues. (These and other cytokines are described in more detail later.) Leukocytes express L-selectin at the tips of their microvilli and also express ligands for Eand P-selectins, all of which bind to the complementary molecules on the endothelial cells. These are low-affinity interactions with a fast off rate, and they are easily disrupted by


Pathology_Robbins

Pathology_Robbins. ligands for Eand P-selectins, all of which bind to the complementary molecules on the endothelial cells. These are low-affinity interactions with a fast off rate, and they are easily disrupted by the flowing blood. As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface. These weak selectin-mediated rolling interactions slow down the leukocytes and give them the opportunity to recognize additional adhesion molecules on the endothelium.


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Pathology_Robbins. • Firm adhesion of leukocytes to endothelium is mediated by a family of leukocyte surface proteins called integrins. Integrins are transmembrane two-chain glycoproteins that mediate the adhesion of leukocytes to endothelium and of various cells to the extracellular matrix. They are normally expressed on leukocyte plasma membranes in a low-affinity form and do not adhere to their specific ligands until the leukocytes are activated by chemokines. Chemokines are chemoattractant cytokines that are secreted by many cells at sites of inflammation, bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. When the rolling leukocytes encounter the displayed chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, thus converting to a high-affinity form. At the same time, other cytokines, notably TNF and IL-1, activate endothelial cells to increase their expression of ligands for integrins.


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Pathology_Robbins. cluster together, thus converting to a high-affinity form. At the same time, other cytokines, notably TNF and IL-1, activate endothelial cells to increase their expression of ligands for integrins. These ligands include inter-cellular adhesion molecule-1 (ICAM-1), which binds to the integrins leukocyte function–associated antigen-1 (LFA-1) (also called CD11aCD18) and macrophage-1 http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Sialyl–Lewis X–modified glycoprotein E-selectin P-selectin Leukocyte Macrophage with microbes Cytokines (TNF, IL-1) Integrin (low-affinity state) Integrin (high-affinity state) Proteoglycan ROLLING INTEGRIN ACTIVATION BY CHEMOKINES MIGRATION THROUGH ENDOTHELIUM STABLE ADHESION Integrin ligand (ICAM-1) Chemokines Microbes Fibrin and fibronectin (extracellular matrix) PECAM-1 (CD31)


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Pathology_Robbins. Fig. 3.4 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and move toward chemoattractants emanating from the source of injury. Different molecules play predominant roles at each step of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Inter-cellular adhesion molecule-1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor. Table 3.4 Endothelial and Leukocyte Adhesion Molecules Ig CD31 Endothelial cells, leukocytes CD31 (homotypic interaction)


Pathology_Robbins

Pathology_Robbins. Table 3.4 Endothelial and Leukocyte Adhesion Molecules Ig CD31 Endothelial cells, leukocytes CD31 (homotypic interaction) CLA, Cutaneous lymphocyte antigen-1; GlyCAM-1, glycan-bearing cell adhesion molecule-1; HEV, high endothelial venule; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; IL-1, interleukin-1; MAdCAM-1, mucosal adhesion cell adhesion molecule-1; PSGL-1, P-selectin glycoprotein ligand-1; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule. http://ebooksmedicine.net antigen (Mac-1) (CD11bCD18), and vascular cell adhesion molecule-1 (VCAM-1), which binds to the integrin very late antigen-4 (VLA-4) (


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net antigen (Mac-1) (CD11bCD18), and vascular cell adhesion molecule-1 (VCAM-1), which binds to the integrin very late antigen-4 (VLA-4) ( Table 3.4 ). The combination of cytokine-induced expression of integrin ligands on the endothelium and increased affinity of integrins on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, and engagement of integrins by their ligands delivers signals leading to cytoskeletal changes that arrest the leukocytes and firmly attach them to the endothelium. The most telling proof of the importance of leukocyte adhesion molecules is the existence of genetic deficiencies in these molecules that result in recurrent bacterial infections as a consequence of impaired leukocyte adhesion and defective inflammation. These leukocyte adhesion deficiencies are described in Chapter 5.


Pathology_Robbins

Pathology_Robbins. After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions. This extravasation of leukocytes, called transmigration, occurs mainly in post-capillary venules, the site at which there is maximal retraction of endothelial cells. Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient (described shortly). In addition, platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31), an adhesion molecule of the immunoglobulin (Ig) superfamily expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium. After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting collagenases, and they enter the extravascular tissue. Typically, the vessel wall is not injured during leukocyte transmigration.


Pathology_Robbins

Pathology_Robbins. Chemotaxis of Leukocytes After exiting the circulation, leukocytes move in the tissues toward the site of injury by a process called chemotaxis, which is defined as locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants, including the following: Bacterial products, particularly peptides with Nformylmethionine termini Cytokines, especially those of the chemokine family Components of the complement system, particularly C5a Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)


Pathology_Robbins

Pathology_Robbins. Components of the complement system, particularly C5a Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4) These chemoattractants are produced by microbes and by host cells in response to infections and tissue damage and during immunologic reactions. All act by binding to seventransmembrane G protein-coupled receptors on the surface of leukocytes. Signals initiated from these receptors activate second messengers that induce polymerization of actin, resulting in increased amounts at the leading edge of the cell and localization of myosin filaments at the back. The leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension, much like the front wheels pull an automobile with front-wheel drive. The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.


Pathology_Robbins

Pathology_Robbins. The nature of the leukocyte infiltrate varies with the age of the inflammatory response and the type of stimulus. In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are gradually replaced by monocyte-derived macro phagesover24to48hours(Fig.3.5 ).Thereareseveralreasons for the early preponderance of neutrophils: they are more numerous in the blood than other leukocytes, they respond more rapidly to chemokines, and they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P-and E-selectins. After entering tissues, neutrophils are short-lived; they undergo apoptosis and disappear within 24 to 48 hours. Macrophages not only survive longer but also may proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions. There are, however, exceptions to this stereotypic pattern of cellular infiltration. In certain


Pathology_Robbins

Pathology_Robbins. in the tissues, and thus they become the dominant population in prolonged inflammatory reactions. There are, however, exceptions to this stereotypic pattern of cellular infiltration. In certain infections—for example, those produced by Pseudomonas bacteria—the cellular infiltrate is dominated by neutrophils for several days; in viral infections, lymphocytes may be the first cells to arrive; some hypersensitivity reactions are dominated by activated lymphocytes, macrophages, and plasma cells (reflecting the immune response); and in allergic reactions, eosinophils may be a prominent cell type.


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Pathology_Robbins. The molecular understanding of leukocyte recruitment and migration has provided a large number of potential therapeutic targets for controlling harmful inflammation. Agents that block TNF, one of the major cytokines in leukocyte recruitment, are among the most successful therapeutics ever developed for chronic inflammatory diseases, and antagonists of leukocyte integrins are approved for inflammatory diseases and are being tested in clinical trials. Predictably, these antagonists not only have the desired effect of controlling the inflammation but can also compromise the ability of treated patients to defend themselves against microbes, which, of course, is the physiologic function of the inflammatory response. Leukocytes are recruited from the blood into the extravascular tissue where infectious pathogens or damaged tissues may be located, migrate to the site of infection or tissue injury, and are activated to perform their functions.


Pathology_Robbins

Pathology_Robbins. Leukocyte recruitment is a multistep process consisting of loose attachment to and rolling on endothelium (mediated by selectins); firm attachment to endothelium (mediated by integrins); and migration through interendothelial gaps. Various cytokines promote the expression of selectins and integrin ligands on endothelium (TNF, IL-1), increase the avidity of integrins for their ligands (chemokines), and promote directional migration of leukocytes (also chemokines).Tissue macrophages and other cells responding to the pathogens or damaged tissues produce many of these cytokines. Neutrophils predominate in the early inflammatory infiltrate and are later replaced by monocytes and macrophages. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Neutrophils predominate in the early inflammatory infiltrate and are later replaced by monocytes and macrophages. http://ebooksmedicine.net Fig. 3.5 Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs show an inflammatory reaction in the myocardium after ischemic necrosis (infarction). (A) Early (neutrophilic) infiltrates and congested blood vessels. (B) Later (mononuclear) cellular infiltrates. (C) The approximate kinetics of edema and cellular infiltration. For simplicity, edema is shown as an acute transient response, although secondary waves of delayed edema and neutrophil infiltration also can occur.


Pathology_Robbins

Pathology_Robbins. Phagocytosis and Clearance of of infection or tissue injury they must be activated to perform their functions. This makes perfect sense because, the Offending Agent while we want our defenders to patrol our body constantly, Recognition of microbes or dead cells induces several it would be wasteful to keep them at a high level of alert responses in leukocytes that are collectively called leuko-and expending energy before they are required. The funccyte activation ( Fig. 3.6 ). After leukocytes (particularly tional responses that are most important for destruction neutrophils and monocytes) have been recruited to a site of microbes and other offenders are phagocytosis and A 1. RECOGNITION AND ATTACHMENT Microbes bind to phagocyte receptors Degradation of microbes 2. ENGULFMENT by lysosomal enzymes Phagocyte membrane in phagolysosome 3. KILLING AND DEGRADATION


Pathology_Robbins

Pathology_Robbins. Fig. 3.7 Phagocytosis and intracellular destruction of microbes. (A) Phagocytosis of a particle (e.g., a bacterium) involves binding to receptors on the leukocyte membrane,engulfment,and fusion of the phagocytic vacuoles with lysosomes.This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes and by reactive oxygen and nitrogen species. (B) In activated phagocytes, cytoplasmic components of the phagocyte oxidase enzyme assemble in the membrane of the phagosome to form the active enzyme, which catalyzes the conversion of oxygen into superoxide ( O2 − ) and H2O2. Myeloperoxidase, present in the granules of neutrophils, converts H2O2 to hypochlorite. (C) Microbicidal reactive oxygen species (ROS) and nitric oxide (NO) kill ingested microbes. During phagocytosis, granule contents may be released into extracellular tissues (not shown). iNOS, Inducible NO synthase; MPO, myeloperoxidase; ROS, reactive oxygen species.


Pathology_Robbins

Pathology_Robbins. intracellular killing. Several other responses aid in the defensive functions of inflammation and may contribute to its injurious consequences. Phagocytosis involves three sequential steps: (1) recognition and attachment of the particle to be ingested by the leukocyte; (2) engulfment, with subsequent formation of a phagocytic vacuole; and (3) killing or degradation of the ingested material ( Fig. 3.7 ). These steps are triggered by activation of phagocytes by microbes, necrotic debris, and various mediators.


Pathology_Robbins

Pathology_Robbins. Recognition by Phagocytic Receptors. Mannose receptors, scavenger receptors, and receptors for various opsonins bind and ingest microbes. The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls, whereas mammalian glycoproteins and glycolipids contain terminal sialic acid or N-acetylgalactosamine. Therefore, the mannose receptor recognizes microbes and not host cells. Scavenger receptors bind and ingest low-density lipoprotein (LDL) particles as well as a variety of microbes. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized (coated) by specific proteins (opsonins) for which the phagocytes express high-affinity receptors. The major opsonins are immunoglobulin (Ig)G antibodies, the C3b breakdown product of complement activation, and certain plasma lectins, notably mannose-binding lectin, all of which are recognized


Pathology_Robbins

Pathology_Robbins. The major opsonins are immunoglobulin (Ig)G antibodies, the C3b breakdown product of complement activation, and certain plasma lectins, notably mannose-binding lectin, all of which are recognized by specific receptors on leukocytes.


Pathology_Robbins

Pathology_Robbins. Engulfment. After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a cytosolic vesicle (phagosome) that encloses the particle. The phagosome then fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome ( Fig. 3.7 ). During this process the phagocyte also may release some granule contents into the extracellular space, thereby damaging innocent bystander normal cells. http://ebooksmedicine.net Intracellular Destruction of Microbes and Debris The killing of microbes and the destruction of ingested materials are accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates), reactive nitrogen species, mainly derived from nitric oxide (NO), and lysosomal enzymes (


Pathology_Robbins

Pathology_Robbins. Fig. 3.7 ). This is the final step in the elimination of infectious agents and necrotic cells. The killing and degradation of microbes and elimination of dead-cell debris within neutrophils and macrophages occur most efficiently after their activation. All these killing mechanisms are normally sequestered in lysosomes, to which phagocytosed materials are brought. Thus, potentially harmful substances are segregated from the cell’s cytoplasm and nucleus to avoid damage to the phagocyte while it is performing its normal function. Reactive Oxygen Species. ROS are produced by the rapid assembly and activation of a multicomponent enzyme, phagocyte oxidase (also called NADPH oxidase), which oxidizes NADPH (reduced nicotinamide-adenine dinucleotide phosphate) and, in the process, reduces oxygen to the superoxide anion (O2 • ) (


Pathology_Robbins

Pathology_Robbins. Fig. 3.7B ). In neutrophils, this oxidative reaction is tightly linked to phagocytosis, and is called the respiratory burst. Phagocyte oxidase is an enzyme complex consisting of at least seven proteins. In resting neutrophils, different components of the enzyme are located in the plasma membrane and the cytoplasm. In response to activating stimuli, the cytosolic protein components translocate to the phagosomal membrane, where they assemble and form the functional enzyme complex. Thus, the ROS are produced within the phagolysosome, where they can act on ingested particles without damaging the host cell. O2 • so produced is then converted into hydrogen peroxide (H2O2), mostly by spontaneous dis-mutation, a process of simultaneous oxidation and reduction. H2O2 is not able to kill microbes efficiently by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl−, converts H2O2 to hypochlorite (OCl2 − ,


Pathology_Robbins

Pathology_Robbins. by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl−, converts H2O2 to hypochlorite (OCl2 − , the active ingredient in household bleach). The latter is a potent anti-microbial agent that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid peroxidation). The H2O2-MPO-halide system is the most efficient bactericidal system of neutrophils. Nevertheless, inherited deficiency of MPO only causes a modest increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H2O2 also is converted to hydroxyl radical (OH•), another powerful destructive agent. As discussed in Chapter 2, these oxygen-derived free radicals bind to and modify cellular lipids, proteins, and nucleic acids, and thus destroy cells such as microbes.


Pathology_Robbins

Pathology_Robbins. Oxygen-derived radicals may be released extracellularly from leukocytes after exposure to microbes, chemokines, and antigen–antibody complexes, or following a phagocytic challenge. These ROS are implicated in tissue damage accompanying inflammation. Serum, tissue fluids, and host cells possess anti-oxidant mechanisms that protect against these potentially harmful oxygen-derived radicals. These anti-oxidants are discussed in Chapter 2; they include (1) the enzyme superoxide dismutase, which is found in or can be activated in a variety of cell types; (2) catalase, which detoxifies H2O2; and (3) glutathione peroxidase, another powerful H2O2 detoxifier. The role of oxygen-derived free radicals in any given inflammatory reaction depends on the balance between production and inactivation of these metabolites by cells and tissues. Genetic defects in the generation of ROS are the cause of an immunodeficiency disease called chronic granulomatous disease, described in Chapter 5.