Immunology Flashcards

Question

multivalent antigens

Answer 1

Most real-life antigens, and all immunogens, are bigger than epitopes, and in fact have multiple, usually different, antigenic determinants or epitopes (a bacterium or a cell has hundreds). These antigens are therefore multivalent.

Answer 2

f you take a layer of agar gel in a dish, cut two holes in it, and put antibody in one and antigen in the other, they will begin diffusing radially out of their wells. In the area between the two wells, the situation is similar to a quantitative precipitin test; there is antigen excess near the antigen well, and antibody excess near the antibody well, so somewhere in between, eventually, equivalence must be reached. But: what happens at equivalence? The complex precipitates. We go back next day and look at our agar gel, and see a line of precipitate between the wells

Answer 3

also called C1-inh, an inhibitor of the complement activity. If you don’t have it you are at risk for (hereditary or acquired) angioedema, giant hives (urticaria) that can swell up your face like a balloon or, if you’re very unlucky, can swell your larynx shut and kill you.

Answer 4

Cells express receptors in the plasma membrane (for extracellular microbes), the endosomes (for ingested microbes), and the cytosol (for intracellular microbes) that enable the cells to sense the presence of foreign invaders in any cellular com- partment. The best defined of these receptors belong to the family of Toll-like receptors (TLRs) ; these and other cellular receptors of innate immunity. The receptors are expressed on many cell types, including epithelial cells (through which microbes enter from the external environment), dendritic cells, macrophages, and other leukocytes (which may encounter microbes in various tissues). Engagement of these receptors triggers production of molecules involved in inflammation, including adhesion molecules on endothelial cells, cytokines, and other mediators.

Answer 5

All cells have cytosolic receptors that recognize a diverse set of molecules that are liberated or altered as a consequence of cell damage. 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), even DNA when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally, and many others. These 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 (see later). Gain-of-function mutations in the sensor 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 has also been implicated in inflammatory reactions to urate crystals (the cause of gout ), lipids (in metabolic syndrome), cholesterol crystals (in atherosclerosis), and even amyloid deposits in the brain (in Alzheimer disease). These disorders are discussed later in this and other chapters.

Answer 6

Inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it may also 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. 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 damage. 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.

Answer 7

The complement system reacts against microbes and produces mediators of inflammation. A circulating protein called mannose-binding lectin recognizes microbial sugars and promotes ingestion of the microbes and the activation of the complement system. Other proteins called collectins also bind to and combat microbes.

Answer 8

denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate.

Answer 9

a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.

Answer 10

Increased transport of fluids and proteins through the endothelial cell. This process may involve intracellular channels that may be stimulated by certain factors, such as vascular endothelial growth factor (VEGF), that promote vascular leakage. However, the contribution of this process to the vascular permeability of acute inflammation is uncertain

Answer 11

There are three types of selectins: one expressed on leukocytes (L-selectin), one on endothelium (E-selectin), and one in platelets and on endothelium (P-selectin). The ligands for selectins are sialylated oligosaccharides bound to mucin-like glycoprotein backbones. The expression of selectins and their ligands is regulated by cytokines produced in response to infection and injury. Tissue macrophages, mast cells, and endothelial cells that encounter microbes and dead tissues respond by secreting several cytokines, including tumor necrosis factor (TNF), IL-1, and chemokines ( chemo attractant cyto kines ). TNF and IL-1 act on the endothelial cells of postcapillary venules adjacent to the infection and induce the coordinate expression of numerous adhesion molecules. Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands for L-selectin. Other mediators such as histamine and thrombin, described later, stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (called Weibel-Palade bodies ) to the cell surface. Leukocytes express L-selectin at the tips of their microvilli and also express ligands for E- and 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.

Answer 12

TNF and IL-1 induce endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1 (VCAM-1, the ligand for the β1 integrin VLA-4) and intercellular adhesion molecule-1 (ICAM-1, the ligand for the β2 integrins LFA-1 and Mac-1). Leukocytes normally express integrins in a low-affinity state. Chemokines that were produced at the site of injury bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. These chemokines bind to and activate the rolling leukocytes. One of the consequences of activation is the conversion of VLA-4 and LFA-1 integrins on the leukocytes to a high-affinity state. The combination of cytokine- induced expression of integrin ligands on the endothelium and increased integrin affinity on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, their cytoskeleton is reorganized, and they spread out on the endothelial surface.

Answer 13

locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants. The most common exogenous agents are bacterial products , including peptides that possess an N -formylmethionine terminal amino acid and some lipids. Endogenous chemoattractants include several chemical mediator: (1) cytokines , particularly those of the chemokine family (e.g., IL-8); (2) components of the complement system, particularly C5a ; and (3) arachidonic acid (AA) metabolites, mainly leukotriene B (LTB ) . All these chemotactic agents bind to specific seven- transmembrane G protein-coupled receptors on the surface of leukocytes. Signals initiated from these receptors result in activation of second messengers that increase cytosolic calcium and activate small guanosine triphosphatases of the Rac/Rho/cdc42 family as well as numerous kinases. These signals induce polymerization of actin, resulting in increased amounts of polymerized actin 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 as an automobile with front-wheel drive is pulled by the wheels in front. The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.

Answer 14

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. Monocytes not only survive longer but may also 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 infections—for example, those produced by Pseudomonas bacteria—the cellular infiltrate is dominated by continuously recruited 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 the main cell type.

Answer 15

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 or 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.

Answer 16

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 were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoprotein (LDL) particles that can no longer interact with the conventional LDL receptor. Macrophage scavenger receptors bind a variety of microbes in addition to modified LDL particles. Macrophage integrins, notably Mac-1 (CD11b/CD18), may also bind microbes for phagocytosis. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by specific proteins (opsonins) for which the phagocytes express high-affinity receptors. The major opsonins are IgG antibodies, the C3b breakdown product of complement, and certain plasma lectins, notably mannose-binding lectin, all of which are recognized by specific receptors on leukocytes.

Answer 17

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 vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosome. During this process the phagocyte may also release granule contents into the extracellular space. The process of phagocytosis is complex and involves the integration of many receptor-initiated signals that lead to membrane remodeling and cytoskeletal changes. Phagocytosis is dependent on polymerization of actin filaments; it is, therefore, not surprising that the signals that trigger phagocytosis are many of the same that are involved in chemotaxis.

Answer 18

Killing of microbes is accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates) and reactive nitrogen species, mainly derived from nitric oxide (NO), and these as well as lysosomal enzymes destroy phagocytosed debris. This is the final step in the elimination of infectious agents and necrotic cells. The killing and degradation of microbes and dead cell debris within neutrophils and macrophages occur most efficiently after activation of the phagocytes. 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.

Answer 19

oxygen is then converted into hydrogen peroxide (H 2 O 2 ), mostly by spontaneous dismutation. H 2 O 2 is not able to efficiently kill microbes by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl − , converts H 2 O 2 to hypochlorite ( , the active ingredient in household bleach). The latter is a potent antimicrobial 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 H 2 O 2 -MPO-halide system is the most efficient bactericidal system of neutrophils. Nevertheless, inherited deficiency of MPO by itself leads to minimal increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H 2 O 2 is also converted to hydroxyl radical ( − OH), another powerful destructive agent. These oxygen-derived free radicals bind to and modify cellular lipids, proteins, and nucleic acids, and thus destroy cells such as microbes.

Answer 20

Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues. These harmful proteases, however, are normally controlled by a system of antiproteases in the serum and tissue fluids. Foremost among these is α 1 -antitrypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α 1 -antitrypsin deficiency. α 2 -Macroglobulin is another antiprotease found in serum and various secretions.

Answer 21

are extracellular fibrillar networks that provide a high concentration of antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS). The extracellular traps consist of a viscous meshwork of of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes. In the process of NET formation, the nuclei of the neutrophils are lost, leading to death of the cells. NETs have also been detected in the blood during sepsis, and it is believed that their formation in the circulation is dependent on platelet activation. The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins.

Answer 22

some T lymphocytes, which are cells of adaptive immunity, also contribute to acute inflammation. The most important of these cells are those that produce the cytokine IL-17 (so-called T H 17 cells). IL-17 induces the secretion of chemokines that recruit other leukocytes. In the absence of effective T H 17 responses, individuals are susceptible to fungal and bacterial infections, and the skin abscesses that develop are “cold abscesses,” lacking the classic features of acute inflammation, such as warmth and redness.

Answer 23

The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.Mediators are either secreted by cells or generated from plasma proteins. Cell- derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Active mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signaling pathways, described earlier, but we still do not know how other stimuli induce the secretion of mediators (e.g., from mast cells in response to cell injury or mechanical irritation). The usual requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed. Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. One mediator can stimulate the release of other mediators. For instance, products of complement activation stimulate the release of histamine, and the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.

Answer 24

produced by mast cells, basophils, and platelets. Produces vasodilation, increased vascular permeability, and endothelial activation

Answer 25

a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes (neutrophils, basophils and eosinophils) and mast cells. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

Answer 26

A type of protaglandins, platelets contain the enzyme thromboxane synthase, and hence TxA 2 is the major product in these cells. TxA 2 , a potent platelet-aggregating agent and vasoconstrictor, is itself unstable and rapidly converted to its inactive form TxB 2 .

Answer 27

Vascular endothelium lacks thromboxane synthase but possesses prostacyclin synthase, which is responsible for the formation of prostacyclin (PGI 2 ) and its stable end product PGF 1a . Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation, and also markedly potentiates the permeability-increasing and chemotactic effects of other mediators. A thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels.

Answer 28

PGD 2 is the major prostaglandin made by mast cells; along with PGE 2 (which is more widely distributed), it causes vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation. PGF 2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles, and PGD 2 is a chemoattractant for neutrophils.PGE 2 is hyperalgesic and makes the skin hypersensitive to painful stimuli, such as intradermal injection of suboptimal concentrations of histamine and bradykinin. It is involved in cytokine-induced fever during infections

Answer 29

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

Answer 30

include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen. They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis (hence their efficacy in treating pain and fever); aspirin does this by irreversibly acetylating and inactivating cyclooxygenases. Selective COX-2 inhibitors are a newer class of these drugs; they are 200-300 fold more potent in blocking COX-2 than COX-1. There has been great interest in COX-2 as a therapeutic target because of the possibility that COX-1 is responsible for the production of prostaglandins that are involved in both inflammation and homeostatic functions (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract), whereas COX-2 generates prostaglandins that are involved only in inflammatory reactions. If this idea is correct, the selective COX-2 inhibitors should be anti- inflammatory without having the toxicities of the nonselective inhibitors, such as gastric ulceration. However, these distinctions are not absolute, as COX-2 also seems to play a role in normal homeostasis. Furthermore, selective COX-2 inhibitors may increase the risk of cardiovascular and cerebrovascular events, possibly because they impair endothelial cell production of prostacyclin (PGI 2 ), a vasodilator and inhibitor of platelet aggregation, but leave intact the COX-1-mediated production by platelets of thromboxane A 2 (TxA 2 ), an important mediator of platelet aggregation and vasoconstriction. Thus, selective COX-2 inhibition may tilt the balance towards thromboxane and promote vascular thrombosis, especially in individuals with other factors that increase the risk of thrombosis. Nevertheless, these drugs are still used in individuals who do not have risk factors for cardiovascular disease when their benefits outweigh their risks.

Answer 31

5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production (e.g., Zileuton) are useful in the treatment of asthma.

Answer 32

are broad-spectrum antiinflammatory agents that reduce the transcription of genes encoding COX-2, phospholipase A 2 , proinflammatory cytokines (e.g., IL-1 and TNF), and iNOS.

Answer 33

block leukotriene receptors and prevent the actions of the leukotrienes. These drugs (e.g., Montelukast) are useful in the treatment of asthma.

Answer 34

have been remarkably effective in the treatment of chronic inflammatory diseases, particularly rheumatoid arthritis and also psoriasis and some types of inflammatory bowel disease. One of the complications of this therapy is that patients become susceptible to mycobacterial infection, reflecting the reduced ability of macrophages to kill intracellular microbes. Although many of the actions of TNF and IL-1 seem overlapping, IL-1 antagonists are not as effective, for reasons that remain obscure. Also, blocking either cytokine has no effect on the outcome of sepsis, perhaps because other cytokines contribute to this serious systemic inflammatory reaction.

Answer 35

have one amino acid residue separating the first two of the four conserved cysteine residues. These chemokines act primarily on neutrophils. IL-8 is typical of this group. It is secreted by activated macrophages, endothelial cells, and other cell types, and causes activation and chemotaxis of neutrophils, with limited activity on monocytes and eosinophils. Its most important inducers are microbial products and other cytokines, mainly IL-1 and TNF.

Answer 36

have the first two conserved cysteine residues adjacent. The C-C chemokines, which include monocyte chemoattractant protein (MCP-1), eotaxin , macrophage inflammatory protein-1α (MIP-1α), and RANTES (regulated and normal T-cell expressed and secreted), generally attract monocytes, eosinophils, basophils and lymphocytes, but are not as potent chemoattractants for neutrophils. Although most of the chemokines in this class have overlapping actions, eotaxin selectively recruits eosinophils.

Answer 37

lack the first and third of the four conserved cysteines. The C chemokines (e.g., lymphotactin) are relatively specific for lymphocytes.

Answer 38

contain three amino acids between the two cysteines. The only known member of this class is called fractalkine. This chemokine exists in two forms: a cell surface- bound protein induced on endothelial cells by inflammatory cytokines that promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane- bound protein, that has potent chemoattractant activity for the same cells.

Answer 39

blocks the activation of C1, the first protein of the classical complement pathway. Inherited deficiency of this inhibitor is the cause of hereditary angioedema .

Answer 40

are two proteins that are linked to plasma membranes by a glycophosphatidyl (GPI) anchor. DAF prevents formation of C3 convertases and CD59 inhibits formation of the membrane attack complex. An acquired deficiency of the enzyme that creates GPI anchors leads to deficiency of these regulators and excessive complement activation and lysis of red cells (which are sensitive to complement-mediated cell lysis) in the disease called paroxysmal nocturnal hemoglobinuria (PNH).

Answer 41

may be induced by microbial products such as endotoxin, which engage TLRs and other sensors; by T cell–derived signals, importantly the cytokine IFN-γ, in immune responses; or by foreign substances including crystals and particulate matter. Classically activated (also called M1) macrophages produce NO and ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory reactions. As discussed earlier in the context of acute inflammation and leukocyte activation, the same activated cells are capable of injuring normal tissues.

Answer 42

is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal and the cytokines may actually inhibit the classical activation pathway; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis. It seems plausible that in response to most injurious stimuli, the first activation pathway is the classical one, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions.

Answer 43

In some chronic inflammatory reactions, the accumulated lymphocytes, antigen-presenting cells, and plasma cells cluster together to form lymphoid tissues resembling lymph nodes. These are called tertiary lymphoid organs ; this type of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis and in the thyroid in Hashimoto thyroiditis. It has been postulated that the local formation of lymphoid organs may perpetuate the immune reaction, but the significance of these structures is not established.

Answer 44

are incited by relatively inert foreign bodies, in the absence of T cell–mediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage and do not incite any specific inflammatory or immune response. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it appears refractile.

Answer 45

are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response produces granulomas usually when the inciting agent is difficult to eradicate, such as a persistent microbe or a self antigen. In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages. It is not established which macrophage-activating cytokines (IL-4 or IFN-γ) transform the cells into epithelioid cells and multinucleate giant cells.

Answer 46

In severe bacterial infections (sepsis), the large amounts of bacteria and their products in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL- 1. High blood levels of cytokines cause various widespread clinical manifestations such as disseminated intravascular coagulation, hypotensive shock, and metabolic disturbances including insulin resistance and hyperglycemia. This clinical triad is known as septic shock

Answer 47

is most often used to describe the extensive deposition of collagen that occurs in the lungs, liver, kidney, and other organs as a consequence of chronic inflammation, or in the myocardium after extensive ischemic necrosis (infarction). If fibrosis develops in a tissue space occupied by an inflammatory exudate, it is called organization (as in organizing pneumonia affecting the lung).

Answer 48

mainly FGF-2, stimulates the proliferation of endothelial cells. It also promotes the migration of macrophages and fibroblasts to the damaged area, and stimulates epithelial cell migration to cover epidermal wounds.

Answer 49

are growth factors that play a role in angiogenesis and the structural maturation of new vessels. Newly formed vessels need to be stabilized by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue. Ang1 interacts with a tyrosine kinase receptor on endothelial cells called Tie2. The growth factors PDGF and TGF-β also participate in the stabilization process: PDGF recruits smooth muscle cells and TGF-β suppresses endothelial proliferation and migration, and enhances the production of ECM proteins.

Answer 50

After its deposition, the connective tissue in the scar continues to be modified and remodeled. The degradation of collagens and other ECM components is accomplished by a family of matrix metalloproteinases (MMPs). MMPs are produced by a variety of cell types (fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells), and their synthesis and secretion are regulated by growth factors, cytokines, and other agents. The activity of the MMPs is tightly controlled. They are produced as inactive precursors (zymogens) that must be first activated; this is accomplished by proteases (e.g., plasmin) likely to be present only at sites of injury. In addition, activated collagenases can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells. Thus, during scar formation, MMPs are activated to remodel the deposited ECM and then their activity is shut down by the TIMPs.

Answer 51

defect in chemotaxis and lysosomal degranulation into phagosomes

Answer 52

pus, composed of neutrophils, infecions (bacteria and fungal)

Answer 53

contained within parenchyma/ confined space the cavity that exists is newly formed. Contains neutrophils, caused by infections.

Answer 54

located within an anatomic space or cavity (pleural, subdural space, within appendix. Gallbladder) composed of neutrophils, later on macrophages and lymphocytes. Caused by infection

Answer 55

located within skin, fascia, or deep connective tissue. Caused by infections or inflammatory. Often occurs in setting of cut.

Answer 56

usually within parenchyma, rounded/nodular appearance. Composed of macrophages, lymphocytes, and plasma cells. Caused by infections or inflammatory.

Answer 57

gallstone within the gallbladder

Answer 58

gall stone within the common bile duct.

Answer 59

the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.

Answer 60

the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, excessive amount of apoptosis of cells, and disuse or lack of exercise or disease intrinsic to the tissue itself.

Answer 61

the reversible replacement of one differentiated cell type with another mature differentiated cell type. The change from one type of cell to another may generally be a part of normal maturation process or caused by some sort of abnormal stimulus. In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change into another type more suited to the new environment. If the stimulus that caused metaplasia is removed or ceases, tissues return to their normal pattern of differentiation. Metaplasia is not synonymous with dysplasia and is not directly considered carcinogenic.

Answer 62

an increase in the amount of organic tissue that results from cell proliferation. It may lead to the gross enlargement of an organ and the term is sometimes confused with benign neoplasia or benign tumor.

Answer 63

the destructive fragmentation of the nucleus of a dying cell

Answer 64

the irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.

Answer 65

the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonucleases. The whole cell will eventually stain uniformly with eosin after karyolysis. It is usually preceded by karyorrhexis and occurs mainly as a result of necrosis, while in apoptosis after karyorrhexis the nucleus usually dissolves into apoptotic bodies.

Answer 66

a type of accidental cell death typically caused by ischemia or infarction.

Answer 67

a type of necrosis which results in a transformation of the tissue into a liquid viscous mass. Often it is associated with focal bacterial or fungal infections. In liquefactive necrosis, the affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus and the fluid remains of necrotic tissue. Dead leukocytes will remain as a creamy yellow pus. After the removal of cell debris by white blood cells, a fluid filled space is left. It is generally associated with abscess formation and is commonly found in the central nervous system.

Answer 68

a form of cell death in which the tissue maintains a cheese-like appearance. The dead tissue appears as a soft and white proteinaceous dead cell mass. Frequently, caseous necrosis is encountered in the foci of tuberculous infections. It can also be caused by syphilis and certain fungi. A similar appearance can be associated with histoplasmosis, cryptococcosis, and coccidioidomycosis.[

Answer 69

a form of necrosis characterized by the action upon fat by digestive enzymes. It is usually associated with trauma of the pancreas or acute pancreatitis.

Answer 70

a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive).

Answer 71

a condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.

Answer 72

are enzymes that alternately catalyze the dismutation (or partitioning) of the toxic superoxide (O2−) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Can protect against ROS

Answer 73

It catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS).

Answer 74

the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

Answer 75

a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans

Answer 76

a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include hypotension and use of nephrotoxic drugs.

Answer 77

a pathological process characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body. This leads to compromise of tissue blood flow and can ultimately lead to multiple organ damage. In addition, as the coagulation process consumes clotting factors and platelets, normal clotting is disrupted and severe bleeding can occur from various sites. DIC does not occur by itself but only as a complicating factor from another underlying condition, usually in those with a critical illness. The combination of widespread tissue ischemia and simultaneous bleeding carry an increased risk of death in addition to that posed by the underlying disease.

Answer 78

Hydrostatic pressure “pushes” fluid from the capillary into the interstitial space on the arterial end. This loss of fluid then increases the plasma protein concentration (oncotic pressure), so fluid is “pulled” back into the capillary on the venous end to balance the protein concentration. Increased hydrostatic pressure and decreased plasma oncotic pressure each can lead to fluid movement out of the capillaries and into the adjacent tissue (edema) or body cavity (effusion). Damage to capillary walls allows non-regulated movement of fluid and proteins into tissue. Inadequate drainage of fluid from the tissues via the lymphatic system can also lead to fluid accumulation.

Answer 79

heart failure, fluid overload (infusion, renal failure), venous obstruction or compression, arteriolar dilation

Answer 80

due to liver disease: protein loss (kidney, GI tract), low protein production (liver disease, malnutrition)

Answer 81

inflammation infection, neoplasm, post surgery irradiation

Answer 82

Increased blood volume in a tissue may or may not lead to edema and effusions. Hyperemia is an active increase in blood flow due to arteriolar dilation. It serves normal physiologic purposes such as bringing inflammatory and repair mediators into areas of tissue damage or infection, and it provides increased oxygen to exercising skeletal muscle. Hyperemia causes a red coloration (erythema) to the tissue due to the increased mass of oxygenated red blood cells. Congestion is a pathologic accumulation of blood due impaired outflow of venous blood. Congested tissue has a red-blue color due to accumulation of deoxygenated blood, and may have increased hydrostatic pressure.

Answer 83

Physiologic: Active, Arteriolar dilation, Oxygenated blood: red

Answer 84

Pathologic: Passive, Impaired venous outflow, Deoxygenated blood: pale or red/blue

Answer 85

Immobility, recent surgery, Above the age of 40, Estrogen, Pregnancy or post-partum, Previous or current cancer, Limb trauma and/or orthopedic procedures, Coagulation abnormalities, Obesity. All of these effect vircho triad (endothelial injury, hypercoagulability, abnormal blood flow)

Answer 86

athersclerotic plaque of aorta, iliac, or carotid arteries, effects legs, brain, GI tract, and kidney causing stroke, tissue necrosis in the leg, GI pain and bleeding, acute kidney injury.

Answer 87

caused by Torn placental membranes, uterine vein rupture. Affects Lungs, brain, vasculature causing During labor or immediately postpartum onset of respiratory insufficiency, shock, seizures, DIC. 10% of maternal deaths

Answer 88

caused by Heart (vegetations or mural thrombi), aorta, carotid artery, affecting Legs (75%), brain (10%), causing stroke, tissu necrosis in the legs.

Answer 89

adenoma, papilloma

Answer 90

osteoma, chondroma, fibroma

Answer 91

epithelial, Adenocarcinoma (carcinoma with formation of glandular structures)

Answer 92

mesenchymal: Eg: osteosarcoma, chondrosarcoma, fibrosarcoma

Answer 93

mesechymal, Lymphoma (lymph node origin) and Leukemia (bone marrow origin)

Answer 94

Since childhood neoplasms arise in context of developing tissues/organs, they tend to be quite different from adult neoplasms. Origin in developmental precursors. Tendency to recapitulate aspects of developmental program of tissue of origin. Short latency and early metastasis. Fewer mutations; prominent role for oncogenic fusions and epigenetic dysregulation. Relative chemosensitivity (at a price)

Answer 95

the human body contains >200 different cell types. These arise by differentiation from totipotent/multipotent stem cells during embryogenesis. The different types of cells are organized into four basic tissues: epithelium (surface/internal), muscle (cardiac, smooth, skeletal), nerve (CNS, PNS), and connective tissue (bone, joint, fat, blood, bone marrow, lymph glands, etc).

Answer 96

a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include hypotension and use of nephrotoxic drugs. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN (e.g. hydration and cessation of the offending drug). Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the cause is corrected, and recovery is likely within 7 to 21 days. ATN may be classified as either toxic or ischemic. Toxic ATN occurs when the tubular cells are exposed to a toxic substance (nephrotoxic ATN). Ischemic ATN occurs when the tubular cells do not get enough oxygen, a condition that they are highly sensitive and susceptible to, due to their very high metabolism.

Answer 97

Physical agents - trauma, extreme temperatures (burns, hyperthermia, hypothermia, Humans must maintain a temperature no lower  than about 30°C, nor higher than about 42°C), etc. Chemical and drugs - drug toxicity, poisoning, etc. Infection - pathogenic bacteria, virus, fungi, protozoa, etc. Immunologic insults - anaphylaxis, autoimmunity, etc. Genetic derangement-phenylketonuria, cystic fibrosis, etc. Nutritional imbalance - atherosclerosis, protein and vitamin deficiency, etc. Hypoxia - cells receive too little 02. Multiple causes - primary lung disease, heart failure, shock, arterial or venous thrombosis, etc.

Answer 98

different cells vary in the ability to tolerate hypoxia. Neurons can tolerate only 3 to 5 min while fat cells and skeletal muscle cells survive for many hours. There is a second type of injury that stems from the production of oxygen radicals that follow 02 therapy, acute inflammation and reperfusion of hypoxic tissues.

Answer 99

Burns cause about 5000 deaths annually in the U.S. Mortality and morbidity from a burn injury depend upon: total surface area affected; depth of burn injury. (In a “partial thickness” burn, the dermis and  dermal appendages survive. Partial thickness burns typically show blistering. In a “full thickness” burn, there is total destruction of the epidermis and dermis.); whether there is thermal injury to the lungs; and effective treatment. Complications of serious burns include: neurogenic shock and large losses of fluid; infection-especially with Pseudomonas aeruginosa and Staph. (Infection of the burn can lead to endocarditis,  sepsis, septic shock, and renal failure.); hypermetabolic state - the metabolic rate may double with  severe burn injury; anemia-bone marrow production is suppressed.

Answer 100

elevated body temperature. Exertional heat stroke - (i.e. marathon runners): hot, dry skin, usually  (not always) there is cessation of sweating. Usually lactic acidosis. May lead to rhabdomyolysis (breakdown of skeletal muscle fibers), necrosis of renal tubules (ATN), widespread intravascular coagulation (DIC), multi organ failure. Classic heat stroke - young, elderly, obese in hot humid weather. Hot, dry skin. No lactic acidosis, but respiratory alkalosis. Hypotension, coma. ATN and DIC are very uncommon.

Answer 101

Injury from prolonged exposure to the cold. Slowing of metabolic processes, especially in the brain, may lead to coma and death. Freezing of cells and tissues - results in an increase in local  concentrations of salt as intracellular water crystallizes. Proteins may denature, cell organelles may be injured. May cause a decrease in blood flow form vasoconstriction and from an increase in blood viscosity. Organ damage, loss of digits, toes, etc. become evident once blood flow is restored.

Answer 102

In addition to burn injury, the exposure to electric current may cause sudden disruption of neural impulses and lead to cardiac arrest. Outcome is a function of tissue conductance, the amount of heat generated, and the intensity of the current. Dry skin is fairly resistant. However, wet skin is a good conductor. Exposure of wet skin to even household levels of current (120 or 220 Volts) can trigger ventricular fibrillation. Exposure to AC (alternating current, which is used in the US) can cause tetany and prolong the contact with the electrical source. Spasm of chest wall muscles can cause asphyxia.

Answer 103

All human disease stems from some form of cell and tissue injury. Injury is non lethal, physical damage or alteration from normal of one or more components of the structure of the cell. Injured cells cannot perform at full capacity and illness results. Injury can occur “acutely”-producing effects in cells within seconds or minutes, or “chronically”-resulting in cell stress and damage that can persist days, months, or even years. [In practice, pathologists classify diseases as acute or chronic based on the type of inflammatory cells (PMNs, acute; lymphocytes/macrophages, chronic) identified in the injured tissue.] Although any cell and tissue in the body can be injured, most human disease occurs from injury to epithelium. The epithelium is the tissue that first encounters injurious agents and stimuli from the environment, and it is not surprising that many important human diseases occur from epithelial injury-the major killer of adults, atherosclerosis occurs from injury to the epithelial cells (the so-called endothelium) that line arteries and >90% of all adult cancers, as another example, arise from epithelia). The outcome following an injurious insult depends upon several obvious factors, including the type, severity, and duration of the injury, and the type of cell being injured (a skeletal muscle cell can survive many hours without oxygen, while a cardiac myocyte and neuron die after only a few minutes). The ability of a tissue to survive also is a function of the tissue’s ability to undergo repair/replacement. Some tissues undergo continual proliferation (eg GI/bone). This facilitates replacement of irreversibly damaged cells. Others can be induced to undergo new cell proliferation when necessary (eg liver). Yet other tissues (eg heart/brain) contain cells that are “post-mitotic” and presumably “never” divide. This prevents replacement of irreversibly damaged cells and such cells are effectively lost forever. In addition, it follows that the ability of the cell/tissue to survive injury also depends upon whether the blood supply to the tissue is compromised, and whether the population of stem cells present in the tissue had survived.

Answer 104

The cell swelling, and mitochondrial and ER swelling and dysfunction are all potentially reversible, if the injurious stimulus is removed. Damaged organelles can be degraded via autophagosomes, damaged membranes replenished and repaired via new membrane and lipid synthesis, denatured proteins removed via ubiquitination and proteasome degradation, and damage to DNA chromatin repaired via a large assortment of DNA repair enzymes. Once membranes are restored, intracellular ion concentrations return to normal and cell and organelle swelling abates.

Answer 105

Cell membrane injury: it is the first to be damaged because it interacts with the outside environment. Also, lipids are easily oxidized and supports an oxidative chain reaction called lipid peroxidation. Damage to the membrane may physically break it or inactivate the ion pumps that control the ionic concentration in the cytoplasm, leading to the cell swelling (this is commonly seen in nearly all types of injury). Recall that in the normal cell there are impressive Na+, K+ and Ca++ concentration gradients across the membrane that the cell requires. Outside the cell, the Ca++ is approximately 10-3M while within the cytoplasm, the Ca++ is approximately 10-7M. In the injured cell, the accumulation of Na+ leads to an increase in H20 and cell swelling.

Answer 106

Morphologic changes in affected tissue allows the pathologist to diagnose the disease process.

Answer 107

02 therapy - high levels of 02 are needed acutely to keep the patient alive. However, high levels of 02 radicals are also produced and have toxic effects on cells - especially in the lung. Acute inflammation - PMNs have enzymes such as myeloperoxidase which produce oxygen radicals. Many hypoxic tissues are infiltrated with PMNs. Reperfusion. In hypoxia, xanthine dehydrogenase is proteolytically converted to xanthine oxidase. Once the hypoxia is corrected, the xanthine oxidase produces activated oxygen species.

Answer 108

can remove super oxide e.g. 2O2- + 2H-> H2O2 + O2-. However if catalase is not sufficiently active the H2O2 can be converted to highly reactive hydroxyl radical via ionizing radiation: 1) H202 -> 0H− +0H 2) Fe++ + H202 -> Fe+++ + 0H + 0H− (Fenton reaction) 3) H202 + 02 -> 0H + 0H− + 02 (Haber-Weiss reaction). Fortunately, antioxidants (uric acid, vitamin E, etc.) catalase, and glutathione peroxidase serve to eliminate these radicals: a) 2H202 -(catalase)-> 02+2H20 b) 2 0H + 2 GSH –(glutathione peroxidase)-> 2 H20 + GSSG

Answer 109

Important species include 02(radical), and (radical)0H. These free radicals can chemically damage proteins, DNA, RNA and trigger lipid peroxidation in cell membranes. Free radicals are generated by intrinsic oxidases (present in the ER of all cells and in PMNs; eg. O2-> O2- (superoxide)) and radiation especially in the setting of high p02.

Answer 110

usually occurs due to ischemia, which is a hypoxic injury (too little oxygen) caused by a problem with vascular blood flow to the tissue. In ischemic necrosis (also called coagulative), a large portion of tissue dies all at once. Irreversible hypoxic injury most likely occurs when there is an elevation in intracellular concentration of Ca2+, causing a shut down of mitochondrial ATP synthesis and release of lysosomal hyrolases. Ca+2 leaks across the plasma membrane into the cell and is released internally from storage depots of Ca+2 in the ER and mitochondria. Once this occurs, Ca+2-dependent proteases and lipases become activated; the mitochondrial membrane permeability transition pore (MTP) is opened, with a loss in the ability to make ATP. In this “classic” type of cell necrosis, the cytoplasm of the dead cell is swollen, the mitochondria and ER appear dilated, there is prominent blebbing of the plasma membrane, and loss of membrane integrity. This type of cell necrosis occurs from ischemia/anoxia and from exposure to toxins/chemicals. Analysis of the chromosomal DNA from the necrotic cell by agarose gel electrophoresis reveals a nonspecific degradative smear of DNA fragments.

Answer 111

unlike necrosis, it tends to affect scattered individual cells, rather than a large area of tissue. It is also highly regulated, switched on by the binding of extracellular ligands to specific cell surface receptors (eg Fas ligand and its receptor). Also important are signals coming from the mitochondrion-(cytochrome c/apoptosis inducing factor AIF) that activate caspases (a class of protease) and an apoptotic-specific nuclear DNA endonuclease, etc. In the apoptotic type of dead cell, the cytoplasm is not swollen but shrunken, there are large plasma membrane blebs, and the nuclear DNA appear uniformly compacted and very dense. Eventually, the cell breaks up into small membrane bound vesicles. These are taken up by macrophages. Analysis of the chromosomal DNA by agarose gel electrophoresis reveals a degradative pattern that reflects internucleosomal (nucleosomal ladder) breakage of the DNA.

Answer 112

an increase in the size of the cell secondary to an increase in cell function. There is typically an increase in the number of mitochondria and ER, etc. Example: enlargement (hypertrophy) of the left ventricle secondary to severe, longstanding hypertension. With hypertension, each myocyte works harder and this causes the cell to produce more organelles.

Answer 113

decrease in the size and functional capacity of the cell. Example: shrinkage (atrophy) of skeletal muscles following motor neuron loss from infection by poliovirus.

Answer 114

replacement of one type of tissue with another in response to an injury. Example: chronic reflux esophagitis leads to replacement of the stratified squamous epithelium along the distal esophagus by a columnar type of intestinal epithelium. Or replacement of the pseudostratified columnar epithelium of the bronchus by stratified squamous epithelium in response to thermal injury from tobacco smoke.

Answer 115

an increase in the number of cells of a tissue in response to a stimulus or injury. Example: increase in the number of adrenal cortical cells secondary to a tumor that produces an ACTH- like polypeptide.

Answer 116

Mitochondrial swelling, due to the accumulation of H20 in the matrix compartment, is a morphologic change that occurs very soon after many types of cell injury, especially in those cases where the supply of oxygen to the cell is interrupted. This swelling results from a decrease in the 02- dependent synthesis of ATP required to fuel the ion pumps of the mitochondrial membrane.

Answer 117

In many types of acute injury, the cisternae of the endoplasmic reticulum are also distended and the polyribosomes detached from the rough ER. This causes a decrease in the ability of the cell to synthesize new protein.

Answer 118

In most types of reversible injury, there are alterations in the appearance of the nucleolus. These changes are not well characterized but there is probably some effect on the synthesis of rRNAs, again causing a decrease in protein synthesis.

Answer 119

dead cell remains a ghost-like remnant of its former self. Classically seen in the heart following a myocardial infarction ("infarction" means "necrosis" secondary to vascular insufficiency). The necrotic myocyte has a cytoplasm which is more eosinophilic than normal. The nucleus shrinks and the chromatin becomes deeply basophilic as it clumps. This pattern of chromatin staining is called "pyknosis". The pyknotic nucleus may then fragment, an appearance known as "karyorrhexis". Eventually, the pyknotic clumps are broken down and disappear - a process called "karyolysis".

Answer 120

dead cell dissolves away as lysosomal hydrolases digest cellular components. Commonly seen in the brain and spleen, and with acute infection.

Answer 121

seen only in tuberculosis. The central portion of an infected lymph node is necrotic (attributed to toxic affects of mycobacteria) and has a chalky white appearance, not unlike the milk protein casein.

Answer 122

refers to necrotic adipose tissue typically following acute pancreatitis or trauma. In fat necrosis, fats are hydrolyzed into free fatty acids, which precipitate with Ca++ producing a peculiar chalky gray material characteristic of "fat necrosis".

Answer 123

Reversible changes include: decrease of ATP, Na pumps (cell swelling), pH and protein synthesis; increase in glycolysis. Irreversible changes include: activation of lysosomal enzymes, DNA and protein degradation, and increase of Ca 2+ influx. Some of the injury simply stems from the cells inability to make sufficient ATP.

Answer 124

The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, by destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes. Macrophages are professional phagocytes that act as filters for particulate matter, microbes, and senescent cells. They also function as effector cells that eliminate microbes in cellular and humoral immune responses. Committed progenitors in the bone marrow give rise to monocytes, which enter the blood, migrate into various tissues and differentiate into macrophages. It is typical of macrophages to be at sites of inflammation and in some tissues such as the skin and intestinal tract. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. Most tissue resident macrophages, such as microglia, Kupffer cells, alveolar macrophages and macrophages in the spleen and connective tissues, may arise from yolk sac or fetal liver very early in embryogenesis, populate the tissues, stay for long periods in the steady state, and are replenished mainly by proliferation of resident cells. In inflammatory reactions, monocytes begin to emigrate into extravascular tissues quite early, and within 48 hours they may constitute the predominant cell type. Extravasation of monocytes is governed by the same factors that are involved in neutrophil emigration, that is, adhesion molecules and chemical mediators with chemotactic and activating properties.

Answer 125

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

Answer 126

they can be activated by the classical and alternative pathways.

Answer 127

Macrophages, like the other type of phagocyte, the neutrophils, ingest and eliminate microbes and dead tissues. Macrophages initiate the process of tissue repair and are involved in scar formation and fibrosis. Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanoids. Thus, macrophages are central to the initiation and propagation of inflammatory reactions. Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell- mediated immune responses.

Answer 128

Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation. Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens, these cells are often present in chronic inflammation and when they are activated, the inflammation tends to be persistent and severe. Some of the strongest chronic inflammatory reactions, such as granulomatous inflammation, are dependent on lymphocyte responses. Lymphocytes may be the dominant population in the chronic inflammation seen in autoimmune and other hypersensitivity diseases. Antigen-stimulated (effector and memory) T and B lymphocytes use various adhesion molecule pairs (selectins, integrins and their ligands) and chemokines to migrate into inflammatory sites. Cytokines from activated macrophages, mainly TNF, IL-1, and chemokines, promote leukocyte recruitment, setting the stage for persistence of the inflammatory response.

Answer 129

promote inflammation and influence the nature of the inflammatory reaction through the secretion of cytokines. They greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of innate immunity. There are three types: T H 1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway. T H 2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation. T H 17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils (and monocytes) into the reaction. Both T H 1 and T H 17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseases. T H 2 cells are important in defense against helminthic parasites and in allergic inflammation. Macro phages display antigens to T cells, express membrane molecules (called costimulators), and produce cytokines (IL- 12 and others) that stimulate T-cell responses. Activated T lymphocytes, in turn, produce cytokines, which recruit and activate macrophages, promoting more antigen presentation and cytokine secretion. The result is a cycle of cellular reactions that fuel and sustain chronic inflammation.

Answer 130

Activated B lymphocytes and antibody-producing plasma cells are often present at sites of chronic inflammation. The antibodies may be specific for persistent foreign or self antigens in the inflammatory site or against altered tissue components.

Answer 131

are abundant in immune reactions mediated by IgE and in parasitic infections. Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections, yet they also contribute to tissue damage in immune reactions such as allergies.

Answer 132

are widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions. Mast cells express on their surface the receptor (FcεRI) that binds the Fc portion of IgE antibody. In immediate hypersensitivity reactions, IgE antibodies bound to the cells' Fc receptors specifically recognize antigen, and the cells degranulate and release mediators, such as histamine and prostaglandins. This type of response occurs during allergic reactions to foods, insect venom, or drugs, sometimes with catastrophic results (e.g., anaphylactic shock). Mast cells are also present in chronic inflammatory reactions, and because they secrete a plethora of cytokines, they may promote inflammatory reactions in different situations.

Answer 133

Although neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for months, continue to show large numbers of neutrophils, induced either by persistent microbes or by mediators produced by activated macrophages and T lymphocytes. In chronic bacterial infection of bone (osteomyelitis), a neutrophilic exudate can persist for many months. Neutrophils are also important in the chronic damage induced in lungs by smoking and other irritant stimuli. This pattern of inflammation has been called acute on chronic.

Answer 134

The initial, rapid response to infections and tissue damage. 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, but if the response fails to clear the stimulus, the reaction can progress to chronic inflammation. Acute inflammation is one of the reactions of the type of host defense known as innate immunity.

Answer 135

(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

Answer 136

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. Vasodilation is mainly induced by histamine, which acts on smooth muscles, resulting in increased blood flow, which causes heat and redness (erythema). Vasodilation is quickly followed by increased permeability of the microvasculature releasing exudate. The loss of fluid and increased vessel diameter leads to slower blood flow and RBC get concentrated in small vessels leading to stasis (the engorgement of small vessels with slowly moving RBCs). As stasis develops, blood leukocytes (mainly neutrophils) accumulate in the vascular endothelium. Endothelial cells are also activated by mediators produced at the site of infection/ tissue damage and express adhesion molecules. This allows leukocytes to adhere to the endothelial cells and migrate through the vascular wall into interstitial tissue. Increased vascular permeability can occur through retraction of endothelial cells (induced by histamine, bradykinin, leukotrienes or others, is rapid and short lived) or endothelial injury (caused by burns or microbial toxins, is rapid and long-lived, neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells thus amplify the reaction). Transcytosis also increases fluid and proteins in interstitial tissue.

Answer 137

the process by which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Examples of macromolecules transported include IgA, transferrin, and insulin. While transcytosis is most commonly observed in cells of an epithelium, the process is also present elsewhere. Blood capillaries are a well-known site for transcytosis, though it occurs in other cells, including neurons, osteoclasts and M cells of the intestine.

Answer 138

vascular changes are quickly followed by an influx of leukocytes into the tissue where they eliminate the offending agents. The most important leukocytes are the ones capable of phagocytosis, mainly neutrophils and macrophages. Along with ingesting and destroying bacteria, other microbes, necrotic tissue, and foreign substances, they also produce growth factors to aid in repair. Leukocytes, when strongly activated, may induce tissue damage and prolong inflammation by injuring innocent bystanders.

Answer 139

is mediated by adhesion molecules and chemokines (a type of cytokine) and occurs in three steps: 1) first they roll and become activated and adhere to the endothelium. When statis occurs more white cells can move to the peripheral position along the endothelial surface (migration). Leukocytes then adhere transiently to endothelium, detach and bind again (rolling). the initial rolling is mediated by selectins. These weak rolling interactions slow down the leukocytes and give them the opportunity to bind more firmly to the endothelium. Firm adhesion is mediated by a family of heterodimeric leukocyte surface proteins called integrins 2) then they migrate across the endothelium vessel wall (transmigration or diapedesis). This occus mainly in postcapillary venules. Chemokines act on the adherent leukocytes and stimulate the cells to migrate toward the chemical concentration gradient. Adhesion molecules, including CD31 (a member of the immunoglobulin superfamily) or PECAM-1 (platelet endothelial cell adhesion molecule). After traversing the endothelium, leukocytes pass through the basement membrane by secreting collagenases. 3) and migrate in the tissues toward a chemotactic stimulus, along a chemical gradient. In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours. Once leukocytes (particularly neutrophils and monocytes) have been recruited to a site of infection or cell death, they must be activated to perform their functions.

Answer 140

consist of (1) recognition of the offending agents by TLRs and other receptors, described earlier, which deliver signals that (2) activate the leukocytes to phagocytose and destroy the offending agents.

Answer 141

leukocyte activation occurs with recognition of microbes or dead cells, which result in signaling pathways, resulting in increased cytosolic Ca and activation of protein kinase C and phospholipase A leading to a three step process: 1) recognition and attachment of the paticle to be ingested, 2) englument with formation of phagocytic vacuole, and 3) killing or degradation.

Answer 142

is of longer duration (weeks or months) and is associated with more tissue destruction, the presence of lymphocytes and macrophages, the proliferation of blood vessels, and the deposition of connective tissue. It is more prominent in the reactions of adaptive immunity. It may follow acute inflammation, as described earlier, or chronic inflammation may begin insidiously, as a low-grade, smoldering response without any manifestations of a preceding acute reaction.

Answer 143

persistent infections by microorganisms that are difficult to eradicate such as mycobacteria and certain viruses, fungi and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity. The inflammatory response sometimes takes a specific pattern called a granulomatous reaction. In other cases, an unresolved acute inflammation may evolve into chronic inflammation, as may occur in acute bacterial infection of the lung that progresses to a chronic lung abscess. Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not conventionally thought of as inflammatory disorders. These include neurodegenerative diseases such as Alzheimer disease, metabolic syndrome and the associated type 2 diabetes, and certain cancers in which inflammatory reactions promote tumor development.

Answer 144

Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions immune reactions develop against the individual's own tissues, leading to autoimmune diseases. In these diseases, autoantigens evoke a self-perpetuating immune reaction that results in chronic tissue damage and inflammation; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In other cases, chronic inflammation is the result of unregulated immune responses against microbes, as in inflammatory bowel disease. Immune responses against common environmental substances are the cause of allergic diseases , such as bronchial asthma. Because these autoimmune and allergic reactions are inappropriately triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages. Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis.

Answer 145

a chronic inflammatory process of the arterial wall induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids.

Answer 146

The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities. 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 triggered by some sort of tissue injury and an ongoing inflammatory reaction.

Answer 147

is a fluid with low protein content (most of which is albumin), 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 the vessel wall without an increase in vascular permeability.

Answer 148

In acute inflammation polymorphonuclear neutrophils usually predominate, whereas macrophages and lymphocytes predominate in chronic inflammation.

Answer 149

dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissue.

Answer 150

is marked by the exudation of cell-poor fluid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura or pericardium. It is typically not infected by destructive organisms and does not contain large numbers of leukocytes. The fluid may be derived from plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation). The accumulation of fluid in these cavities is called effusion. (Effusions also occur in noninflammatory conditions, such as reduced blood outflow in heart failure, or reduced plasma protein levels in some kidney and liver diseases.) The skin blister resulting from a burn or viral infection represents accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin.

Answer 151

With greater increase in vascular permeability, large molecules such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus (e.g., cancer cells). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium and pleura. Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages. If the fibrin is not removed, over time it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac leads to opaque fibrous thickening of the pericardium and epicardium in the area of exudation and, if the fibrosis is extensive, obliteration of the pericardial space.

Answer 152

is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells and edema fluid. The most frequent cause of this is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci. These pathogens are referred to as pyogenic (pus-producing) bacteria. A common example is acute appendicitis. Abscesses are localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, organ, or confined space. Abscesses have a central region that appears as a mass of necrotic leukocytes and tissue cells. There is usually a zone of preserved neutrophils around this necrotic focus, and outside this region there may be vascular dilation and parenchymal and fibroblastic proliferation, indicating chronic inflammation and repair. In time the abscess may become walled off and ultimately replaced by connective tissue.

Answer 153

is a local defect or excavation of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in (1) the mucosa of the mouth, stomach, intestines, or genitourinary tract, and (2) the skin and subcutaneous tissue of the lower extremities in older persons who have circulatory disturbances that predispose to extensive ischemic necrosis. Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist. During the acute stage there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. With chronicity, the margins and base of the ulcer develop fibroblastic proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells.

Answer 154

Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells. Tissue destruction, induced by the persistent offending agent or by the inflammatory cells. Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis.

Answer 155

a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate. In this attempt there is often strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells . In the usual hematoxylin and eosin preparations, the activated macrophages in granulomas have pink granular cytoplasm with indistinct cell boundaries and are called epithelioid cells because of their resemblance to epithelia. The aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes. Older granulomas may have a rim of fibroblasts and connective tissue. Frequently, but not invariably, multinucleated giant cells 40 to 50 μm in diameter are found in granulomas; these are called Langhans giant cells. They consist of a large mass of cytoplasm and many nuclei, and they derive from the fusion of multiple activated macrophages. Granulomas may also develop in some immune- mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease. Tuber culosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified. In this disease the granuloma is referred to as a tubercle. The morphologic patterns in the various granulomatous diseases may be sufficiently different to allow reasonably accurate diagnosis by an experienced pathologist; however, there are so many atypical presentations that it is always necessary to identify the specific etiologic agent by special stains for organisms (e.g., acid-fast stains for tubercle bacilli), by culture methods (e.g., in tuberculosis and fungal diseases), by molecular techniques (e.g., the polymerase chain reaction in tuberculosis), and by serologic studies (e.g., in syphilis).

Answer 156

In granulomas associated with certain infectious organisms (most classically Mycobacterium tuberculosis ), a combination of hypoxia and free radical– mediated injury leads to a central zone of necrosis. Grossly, this has a granular, cheesy appearance and is therefore called caseous necrosis. Microscopically, this necrotic material appears as amorphous, structureless, eosinophilic, granular debris, with complete loss of cellular details. The granulomas in Crohn disease, sarcoidosis, and foreign body reactions tend to not have necrotic centers and are said to be noncaseating.

Answer 157

is accompanied by fibrosis that may be extensive. Granulomas are encountered in certain pathologic states. In the setting of persistent T-cell responses to certain microbes (e.g., M. tuberculosis , Treponema pallidum , or fungi), T cell–derived cytokines are responsible for chronic macrophage activation and granuloma formation.

Answer 158

cytokine induced systemic reactions associated with inflammation in response to bacterial or viral products such as LPS. The cytokines TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction; other cytokines, notably type I interferons, also contribute to the reaction. It consist of fever, leukocytosis, acute phase proteins, and other manifestations such as increased pulse and blood pressure, decreased sweating, rigors (shivering), chills, anorexia, somnolence, and malaise.

Answer 159

substances that induce fever. The increase in body temperature is caused by prostaglandins that are produced in the vascular and perivascular cells of the hypothalamus. Bacterial products, such as LPS (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the enzymes (cyclooxy genases) that convert AA into prostaglandins. In the hypothalamus, the prostaglandins, especially PGE 2 , stimulate the production of neurotransmitters that reset the temperature set point at a higher level. NSAIDs, including aspirin, reduce fever by inhibiting prostaglandin synthesis.

Answer 160

are plasma proteins, mostly synthesized in the liver whose plasma concentrations may increase several hundred fold in response to inflammation including C-reactive protein (CRP), fibrinogen and serum amyloid A (SAA) protein. Synthesis is stimulated by cytokines. These proteins bind to microbial cell wall and act as opsonins. They also bind to chromatin. Fibrinogen binds to RBC causing them to form stacks that sediment faster then other RBC (erythrocyte sedimentation rate). Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease. It is postulated that inflammation involving atherosclerotic plaques in the coronary arteries may predispose to thrombosis and subsequent infarction. Another pep tide whose production is increased in the acute-phase response is the iron-regulating peptide hepcidin . Chronically elevated plasma concentrations of hepcidin reduce the availability of iron and are responsible for the anemia associated with chronic inflammation

Answer 161

The leukocyte count usually climbs to 15,000 or 20,000 cells/mL, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/mL. These extreme elevations are referred to as leukemoid reactions , because they are similar to the white cell counts observed in leukemia and have to be distinguished from leukemia. The leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood, referred to as a left shift . Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased production of colony-stimulating factors. Thus, the bone marrow output of leukocytes is increased to compensate for the loss of these cells in the inflammatory reaction. Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis) . In some allergies and parasitic infestations, there is an increase in the absolute number of eosinophils, creating an eosinophilia . Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia).

Answer 162

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.

Answer 163

A low white blood cell count (leukopenia) may be caused by a medical condition, such as an autoimmune disorder that destroys white blood cells, bone marrow problems or cancer. Certain medications also can cause white blood cell counts to drop. If your white blood cell count is higher than normal, you may have an infection or inflammation. Or, it could indicate that you have an immune system disorder or a bone marrow disease. A high white blood cell count can also be a reaction to medication.

Answer 164

a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrin protein. D-dimer concentration may be determined by a blood test to help diagnose thrombosis.

Answer 165

are components of the blood produced by clot degeneration. Clotting, also called coagulation, at the wound site produces a mass of fibrin threads called a net that remains in place until the cut is healed. As a cut heals, the clotting slows down. Eventually the clot is broken down and dissolved by plasmin. When the clot and fibrin net dissolve, fragments of protein are released into the body. These fragments are fibrin degradation products or FDPs. If your body is unable to dissolve a clot, you may have abnormal levels of FDPs. The most notable subtype of fibrin degradation products is D-dimer

Answer 166

The terms thrombocytopenia and thrombopenia refer to a disorder in which there is a relative decrease of thrombocytes, commonly known as platelets, present in the blood. Thrombocytosis (or thrombocythemia) is the presence of high platelet counts in the blood, and can be either primary (also termed essential and caused by a myeloproliferative disease) or reactive (also termed secondary). Although often symptomless (particularly when it is a secondary reaction), it can predispose to thrombosis in some patients.

Answer 167

Lymphatic vessels also participate in acute inflammation. In inflammation, lymph flow is increased and helps drain edema fluid. 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 hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This constellation of pathologic changes is termed reactive , or inflammatory , lymphadenitis. 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 is diagnostic of lymphangitis; it may be accompanied by painful enlargement of the draining lymph nodes, indicating lymphadenitis.

Answer 168

The vascular and cellular reactions account for the signs and symptoms of the inflammatory response. The increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins, known as edema . The redness (rubor) , warmth (calor) , and swelling (tumor) of acute inflammation are caused by the increased blood flow and edema. Circulating leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules, traverse the endothelium, and migrate to the site of injury under the influence of chemotactic agents. Leukocytes that are activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage. During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor).

Answer 169

Skin / Respiratory System / Gut: Epithelial cells: Ability to Regenerate- Ectodermal Derived: Skin; Endoderm-Derived: Gut, Respiratory, Urinary. Epithelial defense mechanism- Squamous Epithelium: Skin and Esophagus (Surface cells slough with passage of foreign objects (e.g. in esophagus: food); Epithelial cells turn over; Mucus / Sebaceous / sweat lubricant secretion by specialized glands. Columnar Epithelium: Mucus secretion by epithelium; Epithelial cells turn over.

Answer 170

alveolar allow free diffusion of gases, there are inflammatory cells monitoring the environment.

Answer 171

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

Answer 172

1) complete resolution- eliminating the offending agent and resolution. 2) Healing by connective tissue replacement (scarring or fibrosis). This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue, a process also called organization. 3) Progression of the response to chronic inflammation. Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing.

Answer 173

Infectious, inflammatory, degenerative, trauma, toxic metabolic

Answer 174

a type of vasoactive amine, released by mast cells, basophils, platelets. Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation and increased venous permeability.

Answer 175

a type of chemokine released primarily of macrophages. Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.

Answer 176

a type of cytokine, released by t-cells and natural killer cells. Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.

Answer 177

a type of eicosanoid, released by leukocytes. Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosome enzymes by these cells.

Answer 178

a soluble gas, released by macrophages, endothelial cells and some neurons. Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.

Answer 179

a type of econsanoid, released by mass cells. A group of lipids that can cause vasodilation, fever, and pain.

Answer 180

a type of cytokine, released by macrophages. Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation of fibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF-α inhibits osteoblast differentiation.

Answer 181

histamine and serotonin are the two major ones. They are stored as pre-formed molecules and are therefore among the first mediators. Mast cells are the main source of histamine, but are also found in blood basophils and platelets. Histamine are released by mast cells degranulation in response to physical injury, binding of antibodes to mast cells (cause of allergies) and in response to anaphylatoxins (C3a and C5a). Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) may also trigger release of histamine. histamine causes dilation of arterioles and increases the permability of venules, producing interendothelial gaps. Its vasoactive effects are mediated mainly via binding to receptors, called H 1 receptors, on microvascular endothelial cells. The antihistamine drugs that are commonly used to treat some inflammatory reactions, such as allergies, are H 1 receptor antagonists that bind to and block the receptor. Histamine also causes contraction of some smooth muscles.

Answer 182

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation. AA is a 20-carbon polyunsaturated fatty acid (5,8,11,14- eicosatetraenoic acid) that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid . It does not occur free in the cell but is normally esterified in membrane phos- pholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A 2 . The biochemical signals involved in the activation of phospholipase A 2 include an increase in cytoplasmic Ca 2+ and activation of various kinases in response to external stimuli. AA-derived mediators, also called eicosanoids (because they are derived from 20-carbon fatty acids; Greek eicosa = 20) , are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and lipoxins). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation

Answer 183

produced by mast cells , macrophages, and endothelial cells. Produces vasodilation, pain, and fever. They are generated by the actions of two cyclooxgenases , called COX-1 and COX- 2. COX-1 is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX-2 is induced by inflammatory stimuli and thus generates the prostaglandins that are involved in inflammatory reactions, but it is low or absent in most normal tissues. Prostaglandins are divided into series based on structural features as coded by a letter (PGD, PGE, PGF, PGG, and PGH) and a subscript numeral (e.g., 1, 2), which indicates the number of double bonds in the compound. The most important ones in inflammation are PGE 2 , PGD 2 , PGF 2a , PGI2 (prostacyclin), and TxA 2 (thromboxane A2), each of which is derived by the action of a specific enzyme on an intermediate in the pathway. Some of these enzymes have restricted tissue distribution.

Answer 184

Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. There are three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme converts AA to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is the precursor of the leukotrienes. LTB 4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, gen eration of ROS, and release of lysosomal enzymes. The cysteinyl-containing leukotrienes LTC 4 , LTD 4 , and LTE 4 cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Leukotrienes are more potent than is histamine in increasing vascular permeability and causing bronchospasm.

Answer 185

a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation.

Answer 186

Causes vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, and oxidative burst. PAF is a phospholipid- derived mediator that was discovered as a factor that caused platelet aggregation. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endo thelial cells, can elaborate PAF, in both secreted and cell-bound forms. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased venular permeability.

Answer 187

Includes TNF, IL-1, IL-6, interferons, and chemokines. Produced by macrophages, endothelial cells and mast cells. Causes local endothelial activation (expression of adhesion molecules) and systematic fever, metabolic abnormalities, and hypotension (shock). By convention, growth factors that act on epithelial and mesenchymal cells are not grouped under cytokines.

Answer 188

TNF and IL-1 serve critical roles in leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels. These cytokines are produced mainly by activated macrophages and dendritic cells; TNF is also produced by T lymphocytes and mast cells, and IL-1 is produced by some epithelial cells as well. The secretion of TNF and IL-1 can be stimulated by microbial products, immune complexes, foreign bodies, physical injury, and a variety of other inflammatory stimuli. The production of TNF is induced by signals through TLRs and other microbial sensors, and the synthesis of IL-1 is stimulated by the same signals but the generation of the biologically active form of this cytokine is dependent on the inflammasome, described earlier. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly E- and P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and chemokines, growth factors, and eicosanoids; and increased procoagulant activity of the endothelium. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages, in part by inducing production of NO. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial and other mesenchymal cells. IL-1 also stimulates T H 17 responses, which in turn induce acute inflammation. IL-1 and TNF (as well as IL-6) induce the systemic acute- phase responses associated with infection or injury, including fever (described later in the chapter). They are also implicated in the syndrome of sepsis, resulting from disseminated bacterial infection. TNF regulates energy balance by promoting lipid and protein mobilization and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia , a pathologic state characterized by weight loss and anorexia that accompanies some chronic infections and neoplastic diseases.

Answer 189

IFNs belong to the large class of proteins known as cytokines, molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens. Interferons are named for their ability to "interfere" with viral replication by protecting cells from virus infection. IFNs also have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase host defenses by up-regulating antigen presentation by virtue of increasing the expression of major histocompatibility complex (MHC) antigens. Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are also caused by the production of IFNs and other cytokines.

Answer 190

produced by leukocytes and activated macrophages. Causes chemotaxis and leukocyte activation. Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. They are classified into four major groups, according to the arrangement of cysteine (C) residues in the proteins: C-X-C, C-C, C, CX C chemokines. Chemokines mediate their activities by binding to seven-transmembrane G protein–coupled receptors. These receptors (called CXCR or CCR , for C-X-C or C-C chemokine receptors) usually exhibit overlapping ligand specificities, and leukocytes generally express more than one receptor type. Certain chemokine receptors (CXCR-4, CCR-5) act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV), the cause of AIDS, and are thus involved in binding and entry of the virus into cells. Chemokines may be displayed at high concentrations attached to proteoglycans on the surface of endothelial cells and in the extracellular matrix and have two main functions: in acute inflammation, chemokines are the ones whose production is induced by microbes and other stimuli, which stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins and they stimulate migration of leukocytes in tissues to the site of infection or tissue damage. Chemokines are also produced constitutively in tissues called homeostatic chemokines, which organize cell types in different anatomic regions of the tissues (eg. T and B lymphocytes in discrete areas of the spleen and lymph nodes). Two other important cytokines are IL-6, made by macrophages and is involved in local and systemic reactions and IL-7, produced mainly by T lymphocytes, which promotes neutrophil recruitment

Answer 191

Neutrophils and monocytes contain lysosomal granules that contribute to microbial killing and, when released, may contribute to tissue damage. Neutrophils have two main types of granules. The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. The larger azurophil (or primary) granules contain myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Both types of granules can fuse with phagocytic vacuoles containing engulfed material, or the granule contents can be released into the extracellular space. Different granule enzymes serve different functions. Acid proteases degrade bacteria and debris within the phagolysosomes , which are acidified by membrane-bound proton pumps. Neutral proteases are capable of degrading various extracellular components, such as collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes. Neutral proteases can also cleave C3 and C5 complement proteins directly, yielding anaphylatoxins, and release a kinin-like peptide from kininogen. Neutrophil elastase has been shown to degrade virulence factors of bacteria and thus combat bacterial infections. Macrophages also contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator. Other microbicidal granule contents include defensins , cationic arginine-rich granule peptides that are toxic to microbes; cathelicidins , antimicrobial proteins found in neutrophils and other cells; lysozyme , which hydrolyzes the muramic acid- N -acetylglucosamine bond, found in the glycopeptide coat of all bacteria; lactoferrin , an iron-binding protein present in specific granules; and major basic protein , a cationic protein of eosinophils, which has limited bactericidal activity but is cytotoxic to many parasites.

Answer 192

Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, such as substance P and neurokinin A, are produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and increasing vascular permeability.

Answer 193

ROS are produced by the rapid assembly and activation of NADPH oxidase (also called phagocyte oxidase, a multicomponent oxidase), which oxidizes NAPDH and in the process reduces oxygen to superoxide anion. In neutrophils, this oxidative reaction is triggered by the respiratory burst (the activating signals that accompanies phagocytosis). Phagocyte oxidase consists of at least 7 proteins. In a resting neutrophil, the different compents are located in the plasma membrane and cytoplasm. When activated, the cytosolic protein components translocate to the phagosomal membrane where they assemble. ROS are therefore produced within the lysosome and phagolysosome, where they act without damaging the host. The superoxide anion is then converted to hydrogen peroxide (H2O2). The acurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which in the presence of Cl-, converts H2O2 to hypochlorite (this has antimicrobial abilities). ROS released extracellularly from leukocytes can create tissue damage.

Answer 194

a soluble gas produced from arginine by the action of nitric oxide synthase (NOS). There are three types: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). eNOS and nNOS are constitutively expressed at low levels and the NO they generate functions to maintain vascular tone and as a neurotransmitter, respectively. iNOS, the type that is involved in microbial killing, is induced when macrophages and neutrophils are activated by cytokines (e.g., IFN-γ) or microbial products. In macrophages, NO reacts with superoxide ( ) to generate the highly reactive free radical peroxynitrite (ONOO − ). These nitrogen derived act similarly to ROS and damage the lipids, proteins, and nucleic acids of the microbes. NO also relaxes vascular smooth muscle and promotes vasodilation.

Answer 195

protease-activated receptors (PARs), which are activated by thrombin (the protease that cleaves fibrinogen to produce fibrin, which forms the clot), and are expressed on platelets and leukocytes. It is, however, likely that the major role of the PARs is in platelet activation during clotting. In fact, it is difficult to dissociate clotting and inflammation, since virtually all forms of tissue injury that lead to clotting also induce inflammation, and inflammation causes changes in endothelial cells that increase the likelihood of abnormal clotting (thrombosis).

Answer 196

are produced in liver and circulate in plasma. Causes leukocyte chemotaxis and activation, direct target killing (membrane attack complex), vasodilation (mast cell stimulation). The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions. This system functions in both innate and adaptive immunity. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonication. Complement proteins are present in inactive forms in the plasa and they are activated to become proteolytic enzymes, forming an enzymatic cascade with amplification. The critical step is cleavage of C3.

Answer 197

the classical alternative, and lectin pathway activate C3 convertase, which splits C3 into two functionally distinct fragments, C3a and C3b. C3a is released and C3b becomes covalently attached to the cell or molecule where complement is being activated and eventually binds to form c5 convertase.

Answer 198

C5 convertase , which cleaves C5 to release C5a and leave C5b attached to the cell surface. C5b binds the late components (C6-C9), culminating in the formation of the membrane attack complex (MAC, composed of multiple C9 molecules).

Answer 199

1) C3a, C5a and to a lesser extent C4a are cleavage products that stimulate histamine release from mast cells and thereby increase vascular permeability and vasodilation. They are called anaphlatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis. C5a is also a chemotactic agent for neutrophils, monocytes, eosinophils, and basophils. C5a also activates the lipoxygenase pathway of AA metabolism in neutrophils and monocytes, causing the release of further release of inflammatory mediators. 2) opsonization and phagocytosis. C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for the complement fragments. 3) Cell lysis. The deposition of the MAC on cells makes these cells permeable to water and ions and results in death (lysis) of the cells. This role of complement is important mainly for the killing of microbes with thin cell walls, such as Neisseria bacteria, and deficiency of the terminal components of complement predisposes to Neisseria infections.

Answer 200

it is tightly controlled by cell-associated and circulating regulatory proteins. Different regulatory proteins inhibit the production of active complement fragments or remove fragments that deposit of cells. These regulators are expressed on normal host cells and are thus designed to prevent healthy tissues from being injured at sites of complement activation. Regulatory proteins can be overwhelmed when large amounts of complement are deposited on host cells and in tissues (as with autoimmune diseases).

Answer 201

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

Answer 202

principal mediators are prostaglandins, histamine, C3a and C5a, and leukotrines.

Answer 203

TNF, IL-1, chemokines, C3a, C5a, Leukotriene.

Answer 204

prostaglandins and bradykinin.

Answer 205

IL-1, TNF, and prostaglandins

Answer 206

lysosomal enzymes of leukocytes and ROS

Answer 207

a protein synthesized by the liver that circulates in an inactive form until it encounters collagen, basement membrane, or activated platelets (e.g., at a site of endothelial injury). Activated Hageman factor (factor XIIa) initiates four systems that may contribute to the inflammatory response: (1) the kinin system, producing vasoactive kinins; (2) the clotting system, inducing the activation of thrombin, fibrinopeptides, and factor X, all with inflammatory properties; (3) the fibrinolytic system, producing plasmin and inactivating thrombin; and (4) the complement system, producing the anaphylatoxins C3a and C5a.

Answer 208

activation leads ultimately to the formation of bradykinin from its circulating precursor, high-molecular-weight kininogen (HMWK). Like histamine, bradykinin causes increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction. It also causes pain when injected into the skin. The actions of bradykinin are short-lived because it is rapidly degraded by kininases present in plasma and tissues. Kallikrein, an intermediate in the kinin cascade with chemotactic activity, also is a potent activator of Hageman factor and thus constitutes another link between the kinin and clotting systems.

Answer 209

the proteolytic cascade leads to activation of thrombin, which then cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot. Factor Xa, an intermediate in the clotting cascade, causes increased vascular permeability and leukocyte emigration. Thrombin participates in inflammation by binding to protease-activated receptors that are expressed on platelets, endothelial cells, and many other cell types. Binding of thrombin to these receptors on endothelial cells leads to their activation and enhanced leukocyte adhesion. In addition, thrombin generates fibrinopeptides (during fibrinogen cleavage) that increase vascular permeability and are chemotactic for leukocytes. Thrombin also cleaves C5 to generate C5a, thus linking coagulation with complement activation.

Answer 210

activated concurrently whenever clotting is initiated by Hageman factor. This mechanism serves to limit clotting by cleaving fibrin, thereby solubilizing the fibrin clot. Plasminogen activator (released from endothelium, leukocytes, and other tissues) and kallikrein cleave plasminogen, a plasma protein bound up in the evolving fibrin clot. The resulting product, plasmin, is a multifunctional protease that cleaves fibrin and is therefore important in lysing clots. However, fibrinolysis also participates in multiple steps in the vascular phenomena of inflammation. For example, fibrin degradation products increase vascular permeability, and plasmin cleaves the C3 complement protein, resulting in production of C3a and vasodilation and increased vascular permeability. Plasmin can also activate Hageman factor, thereby amplifying the entire set of responses.

Answer 211

prostaglandins, NO, Histamin, serotonin, C3a, C5a, bradykinin, leukotrienes, PAF, substance P, TNF, IL-1, chemokines, bacterial products, ROS, lysosomal enzymes of leukocytes

Answer 212

IL-1, TNF, prostaglandins, bradykinin

Answer 213

collagen synthesis by fibroblasts begins early in wound healing (days 3 to 5) and continues for several weeks, depending on the size of the wound. Net collagen accumulation, however, depends not only on increased synthesis but also on diminished collagen degradation

Answer 214

when the injury involves only the epithelial layer. Wounding causes the rapid activation of coagulation pathways, which results in the formation of a blood clot on the wound surface. The clot serves to stop bleeding and acts as a scaffold for migrating cells, which are attracted by growth factors, cytokines, and chemokines released into the area. Release of VEGF leads to increased vessel permeability and edema. As dehydration occurs at the external surface of the clot, a scab covering the wound is formed. Within 24 hours, neutrophils are seen at the incision margin, migrating toward the fibrin clot. They release proteolytic enzymes that begin to clear the debris. Basal cells at the cut edge of the epidermis begin to show increased mitotic activity. Within 24 to 48 hours, epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane components as they progress. By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space. As mentioned earlier, macrophages are key cellular constituents of tissue repair, clearing extracellular debris, fibrin, and other foreign material, and promoting angiogenesis and ECM deposition. Collagen fibers are now evident at the incision margins. Epithelial cell proliferation continues, forming a covering approaching the normal thickness of the epidermis. By day 5, neovascularization reaches its peak as granulation tissue fills the incisional space. During the second week, there is continued collagen accumulation and fibroblast proliferation. The leukocyte infiltrate, edema, and increased vascularity are substantially diminished. By the end of the first month, the scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an essentially normal epidermis.

Answer 215

When cell or tissue loss is more extensive, such as in large wounds, abscesses, ulceration, and ischemic necrosis (infarction) in parenchymal organs, the repair process involves a combination of regeneration and scarring. In wounds causing large tissue deficits, the fibrin clot is larger, and there is more exudate and necrotic debris in the wounded area. Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. Consequently, large defects have a greater potential for secondary, inflammation-mediated, injury. Much larger amounts of granulation tissue are formed. Larger defects require a greater volume of granulation tissue to fill in the gaps and provide the underlying framework for the regrowth of tissue epithelium. At first a provisional matrix containing fibrin, plasma fibronectin, and type III collagen is formed, but in about 2 weeks this is replaced by a matrix composed primarily of type I collagen. Ultimately, the original granulation tissue scaffold is converted into a pale, avascular scar, composed of spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components. Wound contraction generally occurs in large surface wounds. The contraction helps to close the wound by decreasing the gap between its dermal edges and by reducing the wound surface area. Hence, it is an important feature in healing by secondary union. The initial steps of wound contraction involve the formation, at the edge of the wound, of a network of myofibroblasts , which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.

Answer 216

regeneration by proliferation of residual (uninjured) cells and maturation of tissue stem cells, and the deposition of connective tissue to form a scar. Macrophages play a central role in repair by clearing offending agents and dead tissue, providing growth factors for the proliferation of various cells, and secreting cytokines that stimulate fibroblast proliferation and connective tissue synthesis and deposition.

Answer 217

proliferation of cells that survive the injury and retain the capacity to proliferate, for example, in the rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver. In other cases, tissue stem cells may contribute to the restoration of damaged tissues. Regeneration is driven by growth factors and is dependent on the extracellular matrix.

Answer 218

If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that may result in scar formation. Although the fibrous scar is not normal, it provides enough structural stability that the injured tissue is usually able to function.

Answer 219

Several cell types proliferate during tissue repair. These include the remnants of the injured tissue (which attempt to restore normal structure), vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process), and fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration). Based on their intrinsic proliferative capacity there are three types of tissue: labile- continuously dividing (hematopoitic and surface epithelia). As long as the pool of stem cells is preserved they can regenerate. Stable- are quiescent (G0) but may divide in response to injury (eg liver and kidney). Permanent- are terminally differentiad and non proliferative (eg cardiac muscle and neurons). Scar formation is dominant. Cell proliferation is driven by signals provided by growth factors and from the extracellular matrix. The most important sources of these growth factors are macrophages that are activated by the tissue injury, but epithelial and stromal cells also produce some of these factors. Several growth factors bind to ECM proteins and are displayed at high concentrations. All growth factors activate signaling pathways that ultimately induce the production of proteins that are involved in driving cells through the cell cycle and other proteins that release blocks on the cell cycle (checkpoints). Cells also use integrins to bind to ECM proteins, and signals from the integrins can also stimulate cell proliferation. In the process of regeneration, proliferation of residual cells is supplemented by development of mature cells from stem cells. These stem cells live in specialized niches, and it is believed that injury triggers signals in these niches that activate quiescent stem cells to proliferate and differentiate into mature cells that repopulate the injured tissue.

Answer 220

1) Vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF). 2) Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout. 3) Migration of endothelial cells toward the area of tissue injury. 4) Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells. 5) Remodeling into capillary tubes. 6) Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel, 7) Suppression of endothelial proliferation and migration and deposition of the basement membrane. Through “cross-talk” with VEGF, the Notch signaling pathway regulates the sprouting and branching of new vessels and thus ensures that the new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood. ECM proteins participate in the process of vessel sprouting in angiogenesis, largely through interactions with integrin receptors in endothelial cells and by providing the scaffold for vessel growth. Enzymes in the ECM, notably the matrix metalloproteinases (MMPs), degrade the ECM to permit remodeling and extension of the vascular tube.

Answer 221

Migration and proliferation of fibroblasts and deposition of loose connective tissue, together with the vessels and interspersed leukocytes. Its histologic appearance is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), in a loose extracellular matrix, often with admixed inflammatory cells, mainly macrophages. Granulation tissue progressively invades the site of injury; the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation. The amount of connective tissue increases in the granulation tissue, eventually resulting in the formation of a scar

Answer 222

such as the epithelia of the intestinal tract and skin, injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells provided the underlying basement membrane is intact. The growth factors involved in these processes are not defined. Loss of blood cells is corrected by proliferation of hematopoietic stem cells in the bone marrow and other tissues, driven by growth factors called colony-stimulating factors (CSFs), which are produced in response to the reduced numbers of blood cells.

Answer 223

It is triggered by cytokines and growth factors produced in response to loss of liver mass and inflammation. In different situations, regeneration may occur by proliferation of surviving hepatocytes or repopulation from progenitor cells. In situations where the proliferative capacity of hepatocytes is impaired, such as after chronic liver injury or inflammation, progenitor cells in the liver contribute to repopulation.

Answer 224

Deposition of collagen is part of normal wound healing. The term fibrosis is used to denote the excessive deposition of collagen and other ECM components in a tissue. As already mentioned, the terms scar and fibrosis are used interchangeably, but fibrosis most often refers to the abnormal deposition of collagen that occurs in internal organs in chronic diseases. The basic mechanisms of fibrosis are the same as those of scar formation in the skin during tissue repair. Fibrosis is a pathologic process induced by persistent injurious stimuli such as chronic infections and immunologic reactions, and is typically associated with loss of tissue. It may be responsible for substantial organ dysfunction and even organ failure. the major cytokine involved in fibrosis is TGF-β. cells that produce collagen under TGF-β stimulation may vary depending on the tissue. In most organs, such as in lung and kidney, myofibroblasts are the main source of collagen, but stellate cells are the major collagen producers in liver cirrhosis. Fibrotic disorders include diverse chronic and debilitating diseases such as liver cirrhosis, systemic sclerosis (scleroderma), fibrosing diseases of the lung (idiopathic pulmonary fibrosis, pneumoconioses, and drug-, radiation-induced pulmonary fibrosis), end-stage kidney disease, and constrictive pericarditis .

Answer 225

Scarring may happen if the tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as to the connective tissue framework, or if nondividing cells are injured. VEGF drives angiogenesis. Formation granulation tissue also occurs.

Answer 226

The laying down of connective tissue occurs in two steps: (1) migration and proliferation of fibroblasts into the site of injury and (2) deposition of ECM proteins produced by these cells . These processes are orchestrated by locally produced cytokines and growth factors, including PDGF, FGF-2, and TGF-β (the most important). TGF-β stimulates fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM due to inhibition of metalloproteinases. TGF-β is involved not only in scar formation after injury but also in the development of fibrosis in lung, liver, and kidneys that follows chronic inflammation. TGF-β is also an antiinflammatory cytokine that serves to limit and terminate inflammatory responses. It does this by inhibiting lymphocyte proliferation and the activity of other leukocytes.

Answer 227

The recovery of tensile strength results from the excess of collagen synthesis over collagen degradation during the first 2 months of healing, and, at later times, from structural modifications of collagen fibers (cross-linking, increased fiber size) after collagen synthesis ceases. Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point.

Answer 228

Inadequate formation of granulation tissue or formation of a scar can lead to two types of complications: wound dehiscence and ulceration . Dehiscence or rupture of a wound, although not common, occurs most frequently after abdominal surgery and is due to increased abdominal pressure. Vomiting, coughing, or ileus can generate mechanical stress on the abdominal wound. Wounds can ulcerate because of inadequate vascularization during healing. For example, lower extremity wounds in individuals with atherosclerotic peripheral vascular disease typically ulcerate ( Chapter 11 ). Nonhealing wounds also form in areas devoid of sensation. These neuropathic ulcers are occasionally seen in patients with diabetic peripheral neuropathy.

Answer 229

Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids. The accumulation of excessive amounts of collagen may give rise to a raised scar known as a hypertrophic scar ; if the scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a keloid. Keloid formation seems to be an individual predisposition, and for unknown reasons this aberration is somewhat more common in African Americans. Hypertrophic scars generally develop after thermal or traumatic injury that involves the deep layers of the dermis.

Answer 230

another deviation in wound healing consisting of the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks reepithelialization (this process has been called, with more literary fervor, proud flesh ). Excessive granulation must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium. Fortunately rarely, incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other connective tissue elements that may, in fact, recur after excision. Called desmoids , or aggressive fibromatoses , these neoplasms lie in the interface between benign and malignant (though low-grade) tumors.

Answer 231

Contraction in the size of a wound is an important part of the normal healing process. An exaggeration of this process gives rise to contracture and results in deformities of the wound and the surrounding tissues. Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax. Contractures are commonly seen after serious burns and can compromise the movement of joints.

Answer 232

nfection prolongs inflammation and potentially increases the local tissue injury. Diabetes is one of the most important systemic causes of abnormal wound healing. Nutritional status has profound effects on repair; protein deficiency, for example, and particularly vitamin C deficiency, inhibits collagen synthesis and retards healing. Glucocorticoids (steroids) have antiinflammatory effects, and their administration may result in weakness of the scar due to inhibition of TGF-β production and diminished fibrosis. Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart, or dehisce. Poor perfusion, due either to arteriosclerosis and diabetes or to obstructed venous drainage (e.g., in varicose veins), also impairs healing. Foreign bodies such as fragments of steel, glass, or even bone impede healing. The type and extent of tissue injury affects the subsequent repair. Complete restoration can occur only in tissues composed of stable and labile cells; even then, extensive injury will probably result in incomplete tissue regeneration and at least partial loss of function. Injury to tissues composed of permanent cells must inevitably result in scarring with, at most, attempts at functional compensation by the remaining viable elements. Such is the case with healing of a myocardial infarct. The location of the injury and the character of the tissue in which the injury occurs are also important. For example, inflammation arising in tissue spaces (e.g., pleural, peritoneal, synovial cavities) develops extensive exudates. Subsequent repair may occur by digestion of the exudate, initiated by the proteolytic enzymes of leukocytes and resorption of the liquefied exudate. This is called resolution, and in the absence of cellular necrosis, normal tissue architecture is generally restored. However, in the setting of larger accumulations, the exudate undergoes organization: granulation tissue grows into the exudate, and a fibrous scar ultimately forms.

Answer 233

The fluid of edema or effusions can be classified as either a transudate or an exudate. Transudates typically occur when the vessel wall is intact due to elevated hydrostatic pressure or lowered plasma oncotic pressure (heart failure, fluid overload, liver disease, venous obstruction). Exudates are associated with damage to the vessel wall resulting in abnormal permeability to proteins (inflammation, toxins, and burns). Exudates are often due to inflammation and have high levels of white blood cells, this causes the level of glucose to be lower. Transudate: vessel wall is intake. All that can move is fluids, small electrolates and peptides. Exudate: break down in vessel wall. This happens normaly with inflammation causing endothelial cell contractions creates small gaps. Can also occur due to damage to the endothelial cells.

Answer 234

Normal hemodynamic balance can be significantly disrupted by hemorrhage or thrombosis. In hemorrhagic disorders, excessive bleeding occurs because tissue and vessel damage exceeds the body’s normal hemostatic mechanisms or because diminished hemostatic mechanisms cannot manage and repair normal levels of damage. Impaired integrity of vessel walls, or impaired function and/or low levels of platelets or coagulation factors can result in hemorrhage.

Answer 235

Thrombosis is promoted by three basic factors known as the Virchow triad. Thrombosis can occur because of a single factor or a combination of factors. It is more common in the venous system because of slower blood flow, with the veins of the lower extremities being the most common site. Thrombosis in the arterial system most commonly occurs due to endothelial injury and turbulent blood flow, often associated with atherosclerosis. Arterial thrombi most commonly occur in the coronary, cerebral and femoral arteries. Thrombi are attached to the vessel wall, at least focally. As the thrombus propagates, additional layers of platelets, red cells and fibrin added to the thrombus become less stable and are prone to fragmentation, forming thromboemboli.

Answer 236

fluid build up in lungs. Pulmonary edema and pleural effusion. There will also be a decrease of blood flow forward to body, this is detected by the kidney and will increase your blood volume to counteract decreased renal blood flow. This causes peripheral edema (legs). Fluid back up in lungs can also cause right heart failure.

Answer 237

this causes liver congestion, which causes back up in spleen (splenic congestion), GI tract varices (esophageal varices) this can also lead to ascites.

Answer 238

Shock occurs when the circulating blood volume or blood pressure is not adequate to perfuse body tissues. This leads to widespread cellular hypoxia, that if not quickly reversed, leads to global cell death.

Answer 239

results from failure of the heart to pump an adequate amount of blood and/or to generate an adequate blood pressure to perfuse distal tissues.

Answer 240

occurs when there is not enough blood volume to widely perfuse all tissues, and the cardiac output decreases because there is low blood return to the heart. The low blood pressure and low cardiac output initially lead to vasoconstriction, increased heart rate, and renal conservation of fluid, so patients with hypovolemic and cardiogenic shock typically present with coolness and pallor of their skin, tachycardia, and decreased urine output.

Answer 241

is a subtype of shock due to systemic inflammation (SIRS). It occurs when microbial infections cause high levels of inflammatory mediators in the blood leading to widespread arterial vasodilation, vascular leakage and venous blood pooling. This in turn results in hypotension and decreased tissue perfusion. Septic shock typically initially presents with warm, flushed skin and fever.

Answer 242

blood outside the vasculature, due to vessel damage due to: impaired integrity of vessel walls, low level, function of platelets, low level/function of coagulation

Answer 243

is a small (1 - 2 mm) red or purple spot on the skin, caused by a minor hemorrhage (broken capillary blood vessels)

Answer 244

are red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin usually secondary to vasculitis or dietary deficiency of vitamin C (scurvy).

Answer 245

a subcutaneous purpura (extravasation of blood) larger than 1 centimeter or a hematoma, commonly called a bruise

Answer 246

bleeding in a closed space.

Answer 247

Infarcts are areas of tissue death (necrosis) caused by ischemia (a vessel was occluded). Typically coagulate necrosis (myocardial infarction). Liquefactive necrosis in the brain. Infarct will be white if there is no hemorrhage (heart, kidney, spleen) or red if blood supply is resupplied and fills empty space (lung, liver, and intestine).

Answer 248

a unique condition where thrombosis and hemorrhage can occur simultaneously. Generalized activation of clotting leads to widespread thrombosis with subsequent consumption of platelets and clotting factors. This creates a deficiency of platelets and clotting factors that then results in bleeding. This systemic activation of thrombin can be caused by any underlying condition that results in release of procoagulants, such as tissue factor, into the circulation or by widespread endothelial cell injury. DIC often presents clinically with anemia, respiratory insufficiency, convulsions, acute renal failure and shock. Bleeding typically dominates in acute onset of DIC, and thrombosis dominates with chronic DIC.

Answer 249

Symptoms from multiple organ systems: Respiratory insufficiency, MSC, Convulsions, Acute renal failure, Petechiae/Purpura, GI, oral hemorrhage. Shock. Hemolytic anemia (due to RBC trying to get past clots), thrombocytopenia, low fibrinogen (sucked into clots), elevated D-dimer and other fibrin degradation products (trying to overcome clots)

Answer 250

out of control clotting. Deep vein thrombosis can cause pulmonary embolus. Thrombosis and emboli commonly lead to severe tissue ischemia and infarction. The loss of adequate blood flow can be due to obstruction of arterial blood supply or venous drainage. Infarcts can be classified as red (hemorrhagic) or white (anemic). Features associated with white infarcts are an arterial blockage, a single blood supply, and a dense tissue that limits accumulation of blood in necrotic areas. Features favoring formation of a red infarct include venous occlusion, a dual blood supply and loose tissue that permits movement of blood from adjacent areas into the necrotic area. A red infarct can form after an arterial occlusion if blood flow is subsequently reestablished and damaged vessels allow movement of blood into the necrotic area. Most infarcts are roughly wedge-shaped due to arborization of blood vessels from the arterial supply.

Answer 251

A free floating, intravascular mass of a solid, liquid or gas. t can be carried by the blood from its sight of origin to other areas of the body until it becomes lodged in a vessel too small to pass through. Most emboli are detached thrombi, or fragments of thrombi, called thromboemboli. Other types of emboli include fat, atherosclerotic debris, gas bubbles, bone marrow, tumor fragments, amniotic fluid or foreign material. The clinical consequence of vessel blockage depends on the size of the vessel, the organ/tissue involved, and whether complete or partial vessel occlusion occurs. Emboli in the venous/right sided system most commonly lodge in the lungs. Emboli in the arterial/left sided system can affect any organ, but most commonly travel to the legs or brain.

Answer 252

build up of fluid in pleural of lungs. Could be caused by inflammation (exudate), hypovolemic, hypertensive (transudate).

Answer 253

an abnormal accumulation of fluid in the pericardial cavity.

Answer 254

fluid build up in the abdominal cavity.

Answer 255

Once development is fully complete (adulthood), there is an overall diminution of active cell growth. Any cell growth that normally happens is under tight regulatory control. Under conditions of homeostasis, adult tissues include: Non-dividing tissues (little/no proliferation; eg: brain) Quiescent tissues (normally do not proliferate, but can do so in response to stimuli; eg: liver) Continuously dividing tissues (eg: gut) ( the most likely to become neoplastic).

Answer 256

cell reacts with its intrinsic environment (differentiation program, age of cell), extrinsic microenvironment (extracellular matrix/ stroma, growth factors, inflammatory milieu), macroenvironment (circulating factors, hormones), and external envirnonment (physical environment). When homeostatic balance is disturbed, pathology results.

Answer 257

increase in cell size, usually in response to some stimulus; can be physiologic (eg: pregnant uterus) or pathologic (eg: hypertensive cardiac hypertrophy). Does not predispose to neoplasia.

Answer 258

increase in cell number, often in response to some stimulus; can be physiologic (breast during puberty/pregnancy) or pathologic (endometrium, known risk factor for endometrial neoplasia); may predispose to neoplasia 

Answer 259

change from one benign, differentiated cell type to another, usually in response to injury (eg: inflammation); may predispose to neoplasia. Examples: Bronchus( columnar to squamous metaplasia, cause: smoking, known risk factor for bronchopulmonary neoplasia, Esophagus (squamous to columnar metaplasia (“Barrett esophagus”), cause: acid reflux, known risk factor for esophageal neoplasia)

Answer 260

autonomous, progressive cell growth (can be invasive and metastatic), involving clonal cell population. New formation, generally pathologic and irreversible resulting in a tumor.

Answer 261

original meaning from Latin is “swelling”; however, in common usage, generally synonymous with neoplasm.

Answer 262

Neoplasia, or clonal, autonomous and progressive cell growth, begins with the acquisition of non-lethal genetic damage in a cell. This can be inherited or acquired. Acquired mutations can be caused by environmental carcinogens, or may be stochastic. There is still a great deal we don’t understand about the biology of tumor initiation, and this is an area of intense scientific investigation. The principal targets of such mutations are growth promoting proto-oncogenes, growth suppressive tumor suppressor genes, regulators of apoptosis and DNA repair genes themselves. Benign (non-invasive, non-metastatic) neoplasms tend to remain as such, and we know relatively little about their biology. Malignant (invasive, metastatic) neoplasms are synonymous with “cancer”. A common trait of many malignant neoplasms is tumor “progression”, corresponding to the acquisition of more and more genetic mutations and phenotypic traits, including the ability to invade surrounding tissue and vasculature, and “seed” distant organs (metastasis).

Answer 263

altered cell-autonomous mechanism (activation of oncogene, inactivation of tumor suppressor), cell-nonautonomous mechanisms (altered microenvironment (surrounding tissue, including stroma, blood vessels, immune cells), and altered macro environment (circulating cells (e.g. immune cells) and factors (e.g. hormones, cytokines)).

Answer 264

do not invade or metastasize, cause injury largely by compression/interference in function of adjacent structures. Gross pathologic features include circumscribed/ encapsulated, necrosis is uncommon. Microscopic pathological features: generally relatively well differentriated, generally low rate of cell turnover (proliferation and apoptosis), cytrologic uniformity (cells similar to each other), boundary between tumor and adjacent tissue generally maintained (ie: tumor is not invasive). Clinical correlates: Treated by excision/surgical resection alone, May recur (especially if incompletely excised), Generally do not progress to malignancy (important exception: benign, but premalignant, neoplasms; eg: colonic adenoma). Biological correlates -- ie: molecular pathways involved, generally less well understood because less studied

Answer 265

benign neoplasm that could become malignant.

Answer 266

invade and metastasize, cancer, cause injury both by local tissue destruction and distant dissemination and tissue destruction. Gross pathologic features include invasive into adjacent tissue, necrosis is common. Microscopic pathologic features include variable differentiation (generally less than benign tumors), generally have high rate of cell turnover (proliferation and apoptosis), cytologic pleomorphism cells different from each other, often markedly so), generally loss of boundary between tumor and adjacent tissue (tumor invasive).

Answer 267

They include age (the longer you live, the greater the chance for a cancer-initiating event in one of your cells), lifestyle/ environmental exposures (eg: alcohol, tobacco), occupational hazards (eg: asbestos), radiation (eg: sunlight exposure), infectious agents (eg: Human Papilloma Virus), chonic inflammation (eg: inflammatory bowel disease) and genetics (inherited cancer predisposing mutations).

Answer 268

include genetic mutation, gene copy amplification or deletion, promoter methylation (this silences gene expression) and chromosomal translocations that either result in inappropriate expression of normal genes or create “neogenes” with oncogenic activity. Additional important hallmarks of cancer include limitless replicative potential and angiogenesis. By expressing the enzyme telomerase, cancer cells maintain telomeres (ends of chromosomes) and escape the normal replicative senescence that all cells are subjected to. By expressing factors like VEGF (vascular endothelial growth factor), cancer cells stimulate the growth of blood vessels (angiogenesis), thus allowing the delivery of nutrients essential for cell growth. All of these factors contribute to the ability of cancer cells to grow unchecked. Lastly, cancer cells acquire the ability to invade surrounding tissue and spread to distant sites in the body.

Answer 269

self sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, evading apoptosis. Ongoing genetic alterations and selection lead to clonal evolution. Multistep pathway of carcinoma development is observable pathologic changes and molecular correlates. These changes roughly parallel clonal evolution of the tumor cells, including acquisition of additional mutations and selection of phenotypic traits favorable to proliferation and survival.

Answer 270

disordered growth. In epithelia hallmark of early premalignant neoplasia. Characteristic histologic features: loss of cytologic uniformity, loss of normal histologic maturation, loss of architectural orientation. Usually histologic grade (low versus high; marked/extensive dysplasia= “carcinoma in-situ”- haven’t invaded yet but likely to invade).

Answer 271

Degree of tumor histologic differentiation (ie: resemblance of normal tissue counterpart). Low grade: more differentiation/ greater resemblance to normal. High grade: less differentiation/ resemblance to normal. Grading schemes vary by tumor type/ Some schemes also take into account mitotic activity and tumor architectural features (eg: extent of gland formation in an adenocarcinoma). Can be predictive of biologic behavior (tumor dependent), but overall less reliable than disease stage

Answer 272

a cancer staging notation system that gives codes to describe the stage of a person's cancer, when this originates with a solid tumor. T describes the size of the original (primary) tumor and whether it has invaded nearby tissue, N describes nearby (regional) lymph nodes that are involved, M describes distant metastasis (spread of cancer from one part of the body to another).

Answer 273

size or direct extent of the primary tumor. Tx: tumor cannot be evaluated. Tis: carcinoma in situ. T0: no signs of tumor. T1, T2, T3, T4: size and/or extension of the primary tumor

Answer 274

degree of spread to regional lymph nodes. Nx: lymph nodes cannot be evaluated. N0: tumor cells absent from regional lymph nodes. N1: regional lymph node metastasis present; (at some sites: tumor spread to closest or small number of regional lymph nodes). N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites). N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all sites)

Answer 275

presence of distant metastasis. M0: no distant metastasis. M1: metastasis to distant organs (beyond regional lymph nodes)

Answer 276

T1, T2; N0; M0 ; 93% survival rate

Answer 277

T3; N0; M0; 85% survival rate

Answer 278

T4; N0; M0; 72% survival rate

Answer 279

T1, T2; N1; M0

Answer 280

T3, T4; N1; M0

Answer 281

Any T; N2; M0

Answer 282

Any T; Any N; M1; %8 survival rate

Immunology Flashcards

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