Keywords for Chapter 2, Inflammation

Keywords: Chapter 2, Inflammation

Abscess

One of the possible outcomes of acute inflammation, which is especially likely if the inciting agent is a pyogenic (pus-forming) organism. An abscess is a circumscribed cavity filled with pus (purulent exudate) that is associated with liquefactive necrosis of related solid tissue. Although its initiation is usually acute, an abscess can persist, becoming chronic. Under such circumstances, the inflammatory stimulus continues, resulting in a continuing influx of neutrophils. Abscesses can be particularly difficult therapeutic problems, because their interiors have little or no vascularization, making it difficult to deliver therapeutic agents effectively.

Activated oxygen (nitrogen) intermediates or species

Molecules of oxygen and nitrogen that are in altered chemical states, thereby making them capable of injuring cells, tissues, and, in some instances, DNA. The latter kind of injury can cause carcinogenic mutations.

Activation

This is a concept that can be applied either to cells or to plasma proteins. The inflammatory process is potentially dangerous, because it can produce indiscriminate damage to tissues. To minimize this danger, cells and plasma proteins that are potentially the source of injury normally exist in a quiescent, non-active state. Until they are needed, they are harmless. The inflammatory process is designed to marshal its forces locally, i.e., at the site of an inciting stimulus, rather than systemically. This is achieved, in part, through the phenomenon of local activation of inflammatory cells and plasma proteins that can produce proinflammatory mediators. Thus, for example, increased vascular permeability allows plasma proteins that are precursors of inflammatory mediators to leak out into the tissues, where they become activated locally by proteolytic cleavage. Loss of such localization can lead to exceptionally dangerous systemic processes, such as disseminated intravascular coagulation. By the same token, leukocytes are quiescent until they encounter mediators at a site of inflammation that then prime and/or activate them for a variety of functions, such as enhanced phagocytic activity and killing.

Acute phase proteins (reactants)

Also referred to in some species as "heat shock proteins," because of the way in which they were discovered and first studied. These proteins are made early in inflammation, usually by hepatocytes that have been stimulated by the proinflammatory cytokine, interleukin-6 (IL-6). Changes in the levels of acute phase proteins can be measured as a means of monitoring the inflammatory process clinically, e.g., either worsening or progress toward resolution.

Acute phase responses

These are phenomena that are associated with infection or injury. They include fever, increased tendency to sleep, release of neutrophils into the circulation from storage reservoirs, the release of ACTH and corticosteroids into the circulation, and vascular changes that can produce profound hypotension and shock.

Adhesion molecules

Adhesion molecules (see text pp. 49-52; Fig. 2-15) are molecules on the surfaces of cells that assist leukocytes in interacting with their environments through adherence. They are qualitatively and quantitatively changed on the surfaces of endothelial cells and leukocytes during inflammation. Leukocytes in the circulation are "swimming" in the axial zone (central stream) of flowing blood, rarely interacting with the walls of the vessels through which they pass. In inflammatory settings, they peripheralize, i.e., move out of the axial stream, toward the wall, where they begin to become activated and their surfaces have the opportunity to interact with the surfaces of endothelial cells. Such interactions are perpetuated by a variety of adhesion molecules, allowing the leukocytes to attach, tightly adhere, and then to begin crawling on the surfaces of endothelial cells and, subsequently, other substrata (such as collagen, once they have transmigrated into the extravascular tissues). Members of the lectin-like group referred to as selectins (GMP-140, a.k.a. P-selectin; ELAM-1; and LAM-1) tend to initiate leukocyte attachment. The integrins, which are a group of glycoproteins expressed on both leukocytes and endothelial cells, then intensify adherence. Adherence is promoted further by endothelial adherence molecules, such as ICAM-1. Adhesion molecules also assist phagocytic leukocytes in adhering to particles that they want to ingest. The kinds and numbers of adhesion molecules can be changed on the surfaces of cells by the pharmacologic effects of proinflammatory mediators, during the process of activating leukocytes for inflammatory functions. Some inducible genes, which are key to augmentation and amplification of the initial inflammatory response, cannot be expressed until leukocytes become adherent -- another part of the fail-safe check and balance system that serves to constrain the inflammatory process until it is needed.

Alternative pathway (of complement activation)

The "non-classical" pathway of triggering the complement cascade, without the need for participating antibody molecules to produce activation. Bacterial products, such as endotoxin, can activate the alternative pathway, which results in production of the same proinflammatory and membrane-injuring mediators that activation of the classical pathway does (see Fig. 2-16, p. 47 in your text). Note that the name of this pathway is alternative (i.e., other), not alternate (which means to go back-and-forth), as Fig. 2-16 incorrectly suggests.

Amplification

The inflammatory process is dependent upon a number of different processes to rapidly amplify an initial inflammatory response into one that is sufficient to eliminate the inciting stimulus. Some of the main means of amplification are: local activation of precursors of rapidly expanding proinflammatory cascades of plasma proteins (e.g., the complement or Hageman factor-related cascades); autocatalytic feedback loops (e.g., activated Hageman factor leading to the production of kallikrein, which is an activator of more Hageman factor, etc.); rapid, leukocyte-selective, quantitatively dramatic expression of inducible genes, the products of which are proinflammatory (e.g., cyclooxygenase-2, a.k.a. prostaglandin G/H synthase-2); up-regulation by early inflammatory mediators of cell surface molecules that promote the recruitment of leukocytes (e.g., adhesion molecules); local production of precursor proinflammatory molecules by recruited leukocytes (e.g., proinflammatory complement proteins by macrophages); and synergistic augmentation by one cytokine of the proinflammatory effects or production of another (chief among these is interferon-gamma).

Anaphylatoxin

Proinflammatory mediators produced by activation of the complement cascade, either through the classical or alternative pathway. The anaphylatoxins include C3a, C4a, and C5a (Note that C4a can only be produced through the classical pathway, because alternative pathway activation of the complement cascade bypasses activation of C4. There is an apparent inconsistency in your text, p.48, where, under the heading "anaphylatoxins", it implies that they are products of the classical pathway, only. This is incorrect, a fact that is attested to in the paragraph above, wherein it is clearly stated that C3a and C5a can be produced via the alternative pathway.). Anaphylatoxins have several activities, including inducement of smooth-muscle contraction, increased vascular permeability, and degranulation of mast cells and basophils. C5a is one of the most potent chemotactic agents known, for a wide variety of inflammatory cell types. C5a also "primes" or readies neutrophils for various antibacterial functions, e.g., phagocytosis, as they move along the chemotactic gradient, toward higher concentrations of the mediator. This has the effect of increasing their effectiveness when they reach the inciting stimulus.

Antihistamine

A drug that counteracts the proinflammatory effects of the vasoactive amine, histamine. Such common drugs as Benadryl, Dramamine, Chlortrimeton, Tagamet (cimetidine), and Zantac (ranitidine) are all antihistaminic in their pharmacologic effects, but can have different mechanisms of action. Depending on the receptors with which they interact, antagonists of histamine are currently classified as either H1 or H2 blockers.

Arachidonic acid

The substrate from which eicosanoids, e.g., prostaglandins, leukotrienes, and numerous other mediators, are produced. AA is produced from membrane phospholipids and fatty acids through the effects of various phospholipases. AA is not stored in cells; however, it can be produced and metabolized into mediators very rapidly.

Aspirin

An antiinflammatory drug that has as its target the critical enzyme, cyclooxygenase. Inhibition of the activity of this enzyme greatly reduces or eliminates production of prostaglandins and thromboxanes from arachidonic acid.

Autocoids

Inflammatory mediators or other chemical substances that have local, hormone-like effects. An example of an autocoid would be prostaglandin E₂.

Autocrine feedback

The product of a cell feeding back on the same cell that produced it. See, in contrast, paracrine feedback.

B cell (lymphocyte)

A major class of lymphocytes, that bear immunoglobulin molecules on their surface. This kind of lymphocyte is the precursor of the plasma cell. As such, B lymphocytes are key to development of humoral (antibody) immune responses. The name of this kind of lymphocyte derives from the bursa of Fabricius, which directs the maturation of B lymphocytes in birds. Functionally, there is a bursa-like organ in mammals that serves the same function. It is likely that this bursa-like organ is the bone marrow.

Bactericidal permeability increasing protein (BPI)

A highly cationic protein that is bactericidal, because of its ability to increase the permeability of bacteria through the activation of phospholipases. It is contained in the primary granules of neutrophils, along with other bactericidal cationic proteins.

Basophil

The least common leukocyte, which has many intracytoplasmic granules that stain intensely basophilic in routine hematologic preparations. They are very similar to mast cells, both in terms of their appearance and functions; however, they are a completely distinct cell type. One distinguishing feature of both basophils and mast cells is their complement of IgE receptors, potentially making them important contributors to allergic responses. They are a rich source of vasoactive mediators, such as histamine, leukotrienes, and platelet activating factor. Additionally, they produce chemotactic factors for neutrophils and eosinophils.

Bradykinin

One of the most important kinins. It is derived by cleavage of precursor plasma proteins, through the kallikrein/kinin system. It is a potent vasodilator, a contractor of a variety of different kinds of extravascular smooth muscle (e.g., bronchial), and an inducer of increased vascular permeability. It also causes pain, another cardinal sign of inflammation.

C3b

One of the split products of the activated form of the complement protein, C3. It binds to and, thereby, opsonizes bacteria, making them easier for neutrophils and macrophages to ingest (phagocytose). Ingestion is enhanced, because both neutrophils and macrophages have receptors for C3b on their surfaces. When a particle becomes bound to the surface of a phagocytic cell, it is easier for the phagocyte to ingest it.

C5a

A split product of the complement protein, C5. It is an exceptionally important and potent proinflammatory mediator, because it has both anaphylatoxic and chemotactic effects. Therefore, it is active in engendering both the vascular and cellular phases of the inflammatory response. Because it is a plasma protein and, therefore, almost instantly available at the site of an inciting stimulus, it is probably the most important mediator in terms of initiating the complex series of events that results in augmentation and amplification of the initial inflammatory stimulus.

Cardinal signs of inflammation

Rubor (redness); dolor (pain); calor (heat - but only of skin and extremities, because the underlying cause is movement of blood at the body's core temperature to areas that are environmentally cooled); tumor (swelling); and functio laesa (loss of function). Redness is caused by increased blood flow to the site, due to the action of mediators, axon reflex, and local increase in the hydrogen ion concentration. Heat is also due to increased blood flow and greater local cellular metabolism. Swelling is the result of increased blood flow, edema, infiltration of cells, and the proliferation of connective tissue in subacute-to-chronic lesions. Pain is due to the direct effects of mediators, such as prostaglandin, and the stretching of sensory nerves due to swelling. Loss of function is due to replacement of parenchymal tissue (e.g., damaged myocardium); reflexive disuse, due to pain; and mechanical, as when a joint either swells during acute inflammation or scar tissue that bridges it contracts as it matures in a chronic lesion.

Cationic proteins

Many of the proteins that are contained in the lysosomes of neutrophils and other leukocytes are bactericidal cationic proteins. They constitute a means of killing that is not dependent on either activated oxygen or nitrogen species. Some of the proteins are: BPI (bactericidal permeability increasing protein), major basic protein, and defensins.

Chediak-Higashi syndrome

A simple recessive, composite abnormality of granule formation that can occur in many species, including human beings, that affects cells ranging from leukocytes to melanocytes (where the partial albinism produced leads to the most highly sought-after "blue" coat colors in mink). Affected individuals are highly susceptible to infection. Phagocytosis is normal, but lysosomes are impaired in their ability to fuse with phagosomes, and there is a deficiency in cathepsin G. Degranulation of leukocytes is impaired. Leukocytes are also poorly chemotactic.

Chemotactic factor

A compound that produces positive directed migration of one or more kinds of leukocytes. The cells follow a chemical gradient. Chemotactic factors are of three general sources: bacterial (N-formylated peptides, which are unique to the initiation of bacterial protein), plasma proteins synthesis (e.g., C5a, one of the activated products of either the classical or alternative pathways of complement activation), and cells (e.g., the cytokine, TGF-beta).

Chemotaxis

Directed positive migration of a cell along a chemotactic chemical gradient. Chemotaxis is to be distinguished from chemokinesis, which refers to accentuated random migration following application of a stimulus.

Chronic granulomatous disease

A group of congenital disorders that can be traced back to defects in the genes that encode the several components of NADPH oxidase, which is critical to the generation of superoxide anion and, therefore, the generation of oxygen-dependent bactericidal mechanisms. Children with this defect are highly susceptible to persistent bacterial infection (especially Gram-positive cocci), because, without benefit of oxygen-dependent killing mechanisms, neutrophils (especially) and other leukocytes are poorly bactericidal. To compensate, the inflammatory response becomes chronic and, finally, granulomatous inflammation. (see separately, H₂O₂-MPO-halide system)

Classical pathway (of complement activation)

The first pathway of complement activation that was discovered. It requires antibody fixation, after which the cascade of complement proteins is sequentially activated, beginning with C1, to produce a variety of proinflammatory mediators, chemotactic factors, and the constellation of activated complement proteins that, together, form the "membrane attack complex". The latter, as the name implies, injures and increases the permeability of cell membranes.

Clotting/fibrinolytic system

One of the three "cascades" of plasma proteins that result in the production of proinflammatory mediators. The initiating protein in the clotting/fibrinolytic system is Hageman factor (clotting factor XII). One product of the cascade, kallikrein, is a strong activator of Hageman factor, resulting in the development of an autocatalytic amplification loop (i.e., activation of Hageman factor leads to the production of kallikrein, which causes the activation of more Hageman factor, etc.). This is also the cascade that leads to the production of fibrin from plasma fibrinogen. Another of the products is plasmin, which is a proteinase that cleaves fibrin (and produces fibrin-split products in the process). However, plasmin is also important as an activator of other proinflammatory systems, such as the complement cascade (where it cleaves C3 to C3a and C5 to C5a).

Colony-stimulating factors (CSF)

These are growth and differentiation factors, produced by macrophages and lymphocytes, that induce pluripotent stem cells to proliferate and to begin maturation within specific lineages. For example, GM-CSF causes stem cells to differentiate into granulocytes and macrophages.

Complement system

A group of 20 plasma proteins that exist, under normal conditions, in inactive forms. When the complement "cascade" is initiated, the enzymatic activation of one component triggers activation of the next. There are two means of activation, the "classical" and "alternative" pathways. The former requires antibody, while the latter does not. For example, endotoxin, a product of Gram negative bacteria, will suffice to activate the alternative pathway. The alternative pathway is particularly valuable, therefore, in instances where the immune system has not yet had time to produce antibody that will activate the cascade by the classical route.

Consolidation

Conversion of an inflamed tissue, especially the lung, into one that is more dense and firm than normal. The cause is infiltration of the tissue by leukocytes.

Corticosteroids

Hormones produced by the adrenal cortex that have, among other things, antiinflammatory properties. For example, corticosteroids interfere both with the activity of phospholipases (thereby compromising the production of arachidonic acid and, subsequently, of the eicosanoids) and the expression of inducible genes that are quantitatively key to the production of certain kinds of proinflammatory mediators. For example, corticosteroids interfere with the expression of the gene that encodes cyclooxygenase-2, without which the production of prostaglandins by inflammatory cells is greatly reduced.

Cyclooxygenase (prostaglandin G/H synthase)

This enzyme is rate-limiting in the production of thromboxanes and prostaglandins (i.e., the prostanoids) from arachidonic acid (see Fig. 2-10, text). There are both constitutive and inducible isoforms of this enzyme, due to the existence of two different genes. The constitutive form (PGHS-1) is critical to the low-level production of arachidonic acid metabolites that are essential to the maintenance of homeostasis, e.g., maintenance of the integrity of the gastric mucosa. The gene that encodes PGHS-2, the inducible isoform, is selectively expressed in certain cell types, such as leukocytes. It allows them to produce large quantities of prostanoids at the site of an inflammatory stimulus. PGHS-2 is an excellent example of how selective expression of an inducible gene can be used to augment and amplify the initial response to an inflammatory stimulus. Aspirin and indomethacin interfere with the activity of cyclooxygenases, and corticosteroids, such as dexamethasone, interfere with expression of the gene that encodes PGHS-2.

Cytokine

A vast array of relatively low molecular weight, pharmacologically active proteins that are secreted by one cell for the purpose of altering either its own functions (autocrine effect) or those of adjacent cells (paracrine effect). In many instances, individual cytokines have multiple biological activities. Different cytokines can also have the same activity, which provides for functional redundancy within the inflammatory and immune systems. As a result, it is infrequent that loss or neutralization of one cytokine will markedly interfere with the overall function of either of these two systems. This fact has great significance in the development of therapeutic strategies. Among the cytokine group are the interleukins (see separately), as well as growth and Colony-stimulating factors.

Cytokine network

The biological effect of one cytokine is often modified or augmented by another. Because an interdigitating, redundant network of cytokines is involved in the production of most biological effects, it usually requires more than a single defect in the network to alter drastically the outcome of the process.

Defensins

A family of abundant, modestly potent cationic proteins that is found in the primary granules of neutrophils and in the lysosomes of some mononuclear phagocytes. In addition to being bactericidal, defensins can kill fungi and viruses. One of these proteins is chemotactic for monocytes, suggesting that its release may be a way in which neutrophils, also the first cells to reach a site of inflammation, help to attract the "second wave" of leukocytes, i.e., mononuclear phagocytes.

Degranulation

The process by which cells eject the contents of their cytoplasmic granules, either into a phagosome, or to the exterior of the cell through the process of exocytosis.

Diapedesis

The transmigration of formed elements of the blood across the wall of a vessel into the extravascular space. For leukocytes, a number of steps are involved, including adherence to the endothelium, extension of a pseudopod between endothelial cells, and digestion of the vessel's basement membrane.

Edema, inflammatory

Edema is an early component of a developing inflammatory lesion. It occurs due to increased vascular permeability that allows plasma proteins to escape from the circulation locally. Their presence increases oncotic (osmotic) pressure extravascularly, which tends to increase the loss of fluid from the leaky vessels. Because of these facts, inflammatory edema fluid will almost always have a specific gravity >1.015. Increased vascular permeability, coupled with egress of plasma proteins into the extravascular space, collectively are very important in the earliest phases of an inflammatory reaction: increased flow of fluid through the lesion into the lymphatics may help to flush away the inciting stimulus and, more important, the plasma protein precursors of inflammatory mediators are almost immediately made available to begin expanding and augmenting the inflammatory response.

Edema, noninflammatory

Noninflammatory edema can be understood, in all its pathogenetic forms, by understanding Starling's hypothesis or law: hydrostatic outflow of fluid from the circulation is nearly balanced by the osmotic attraction of (oncotic pressure created by) circulating plasma proteins, which cannot leave the circulation under normal conditions. Knowing only this principle, it is possible, for example, to deduce the pathogenesis of pulmonary edema secondary to left ventricular cardiac failure (increased hydrostatic pressure), or why ascites commonly develops in nephrotic syndrome, where large amounts of albumin are being lost through the glomerular basement membranes of the kidneys (hypoalbuminemia, resulting in decreased oncotic pressure).

Effusion

Excess fluid in a tissue or, more frequently, a body cavity. Clinicopathologic analysis of fluid tapped from cavities often yields important diagnostic clues as to its origin(s).

Eicosanoid

Any product of the metabolism of arachidonic acid, e.g., the prostaglandins, thromboxanes, HETEs, and leukotrienes. (NOTE: this is not the definition given in your text, which suggests that eicosanoids are the HETEs. This is a rare mistake that will undoubtedly be corrected in later editions.) The eicosanoids can collectively mediate almost every aspect of the inflammatory response.

Endocytosis

A general term that denotes a kind of vesicular engulfment of extracellular material by a cell. It includes both phagocytosis (ingestion of particles) and pinocytosis (ingestion of fluid phase material, i.e., "cell drinking").

Enzyme cascade

Enzyme cascades are key to the amplification of initial inflammatory responses. There are three: the complement system; the clotting/fibrinolytic system; and the kallikrein/kinin cascade. Under normal conditions, all of the proteins in each of the cascades are in a non-active, noninflammatory form. Each of the cascades (see each seperately) is dependent on activation of a protein in the cascade, which then enzymatically activates the next, and so on, until numerous active products and proinflammatory mediators result. In addition, products of one cascade can cause further amplification by activating proteins in the other cascades. For example, plasmin (from the clotting/fibrinolysis cascade) can activate both C3 and C5 in the complement cascade, to produce the anaphylatoxins, C3a and C5a, respectively. C5a additionally has potent chemotactic activity.

Eosinophil

These cells are easily distinguished by their relatively large granules that take up red dye in routine stains. Eosinophils are particularly prevalent in allergic reactions and parasitic infections, where their numbers can be increased in both the circulation and at the site of inflammation. The granules of eosinophils, which are characterized by electron-dense bar-like bodies ultrastructurally, contain unique basic proteins that are toxic to certain parasites. They also contain peroxidase, acid phosphatase, and cationic major basic protein. Eosinophils respond chemotactically to a cytokine produced by stimulated mast cells (eosinophil chemotactic factor).

Eosinophil cationic protein

A cationic protein that is found in the granules of eosinophils. It is relatively ineffective against bacteria, but it has a potent antiparasitic effect.

Eosinophilia

The condition of having an absolute (compared to a relative) increase in the number of eosinophils in the circulating blood. The absolute number is obtained by multiplying the percentage of eosinophils times the white blood cell count.

Epithelioid cell

A specialized form of mononuclear phagocyte that is derived from macrophages. It is the cell type that is uniquely found in granulomatous inflammation. The name derives from the fact that macrophages are converted into cells that have an epithelial-like appearance, i.e., have abundant, pale cytoplasm. The epithelioid histiogle is a pathognomonic hallmark of granulomatous inflammation.

Exocytosis

The extrusion of granule contents to the exterior of a cell. The event requires fusion of the granule's membrane with that of the cell's plasma membrane. The result is that the contents of the granule are opened to the extracellular space. Leukocytes can concentrate the process of exocytosis onto a surface to which they have become adherent. Damage caused by the contents of the granules is, therefore, concentrated on that surface. The process is referred to as "frustrated phagocytosis". This is the mechanism by which glomerular basement membranes that are either coated with antibody or that contain antigen/antibody complexes are damaged by leukocytes in antibody dependent autoimmune glomerular diseases.

Extracellular matrix

Most kinds of cells must grow adherent to a substratum, i.e., they must have a scaffolding to which to attach. The extracellular matrix is that scaffolding. The extracellular matrix also modulates the functions of cells. For example, some inducible genes that are important in the inflammatory response cannot be expressed unless leukocytes are adherent to a matrix component. There are five major components: collagens, basement membranes, structural glycoproteins, elastic fibers, and proteoglycans. The extracellular matrix is susceptible to digestion by the lysosomal enzymes produced by leukocytes during exocytosis.

Exudate

Edema fluid with a high protein concentration (specific gravity >1.015) that often contains inflammatory components, such as leukocytes, fibrin, etc. Exudates are named, depending on their predominant characteristics: see p 39 of text. It is possible to make combinations of descriptive terms to describe exudates that contain more than one component. For example, an exudate that is both fibrinous and purulent can be described as fibrinopurulent. One that is serous and sanguinous can best be described as serosanguinous.

Fibrin

Fibrin is the product of an activated coagulation system. It forms in the extravascular space by cleavage of fibrinogen. It is an important component of a blood clot, as well as a thrombus. However, in the context of this section, it is important to understand that fibrin can be a prominent part of exudates that develop when vascular permeability/injury has been sufficiently great to allow a large molecule like fibrinogen to cross into the extravascular space. Fibrinogen is cleaved in the extravascular space to form fibrin.

Fibrin-split products

As the name implies, these are produced when fibrin is degraded by (plasmin). Their presence in the circulation can have diagnostic significance, because they indicate that fibrin (which is normally not found) is being cleaved. They also have proinflammatory properties.

Fibrinogen

An acute phase protein that is part of the coagulation cascade of proteins (see fibrin). The amount of fibrinogen in the plasma can be measured as a nonspecific indicator of whether or not an inflammatory process is present in the body. Elevated fibrinogen levels also contribute to an accelerated erythrocyte sedimentation rate (ESR), which can be used as another nonspecific indicator of inflammation. The ESR can be used, as the level of fibrinogen can be, to monitor the course of a chronic inflammatory process: decreases suggest improvement, while increases suggest worsening of the process.

Fibrinolysis

Proteolytic cleavage of fibrin by plasmin to produce fibrinopeptides. This is an important process in the final resolution of a fibrinous inflammatory process. It is also key in the recanalization of thrombi.

Fibrinous

An adjective that denotes the presence of fibrin, as in a fibrinous exudate.

Fibrosis

The production of fibrous connective tissue as a consequence of chronic inflammation or healing. Fibrosis is the process that replaces lost parenchymal tissue, resulting in scar formation.

Formylated peptides

N-formylated peptides are uniquely used by bacteria to initiate protein synthesis. Leukocytes seem to be aware of the fact that they signal the presence of invading bacteria, because N-formylated peptides are chemotactic for leukocytes.

Giant cell

A syncytium of macrophages to form a giant, multinucleated cell. These are commonly found in association with granulomatous inflammation. Fusion of the macrophages is directed by cytokines that are produced at the site of the lesion. One of the most potent of these is interferon-gamma; another is interleukin-4. A foreign body giant cell is a particular subtype, in that it contains visible (and often indigestible) foreign material that the cell has engulfed. Another special subtype is the Langhans giant cell. This type has its multiple nuclei arranged at the periphery of the cell in either a complete circle or, more commonly, a horseshoe configuration.

Gradient, chemotactic

Leukocytes are attracted along a chemical gradient. They have the ability to distinguish between the concentration of a chemotactic agent at the front, compared to the back, of the cell body. Therefore, they can orient themselves toward the source of the gradient and follow the increasingly strengthening chemical gradient until they encounter what is causing its production. There are three general sources of chemotactic factors: bacterial products (e.g., N-formylated peptides) activated plasma proteins and secretory products of cells.

Granulation tissue

This has nothing to do with either granulomas or granulomatous inflammation. Granulation tissue is formed as part of the healing and repair process, which will be covered as a separate subject (see that section for details). Granulation tissue is so named, because it has a granular appearance when viewed grossly.

Granulocyte

Leukocytes that contain intracytoplasmic granules, e.g., neutrophils, eosinophils and basophils. Thus, granulocytic leukemia would be a leukemia that derives from a member of the granulocytic series. Granulocyte is sometimes used (incorrectly) as a synonym for neutrophil.

Granuloma

A special form of chronic inflammation. It is formed most often when either a foreign body or persistent microorganism, such as the tubercle bacillus, evades destruction by the unmodified chronic inflammatory response. In its most classical form, a granuloma consists of concentric layers of cells that, together, form the distinctive lesion. At the center, there often is a focus of caseous necrosis, although this need not be the case. This central focus is surrounded by a layer of specialized macrophages, called epithelioid cells, and multinucleated giant cells. The latter form as the result of cytoplasmic fusion of macrophages, due to stimulation by a cytokine. The next layer is predominantly lymphocytes, and the outer layer is most often fibroblasts, which are attempting to wall off the inciting stimulus with fibrous connective tissue. Granulocytes, plasma cells, and other cells types may also be present. If the agent is an inert foreign body, the granuloma will be of the nonimmune type. However, if the inciting agent is antigenic, the lesion will be an immune type of granuloma, in which the antigen-stimulated lymphocytes are producing cytokines, such as interferon-gamma, to activate the macrophages and their specialized forms (epithelioid and multinucleated giant cells to heightened levels of microbicidal activity.

Granulomatous inflammation

This form of inflammation contains the distinguishing components of a granuloma, i.e., epithelioid cells and multinucleated giant cells. While it can contain discrete, nodular granulomas, it does not usually have to. The process can be more diffuse, without the formation of actual granulomas. This diffuse form of granulomatous inflammation is most often seen when an individual's immune system is either innately hyporesponsive to a pathogen or compromised to the extent that it is difficult for the inflammatory process to form discrete granulomas. An example of innate hyporesponsiveness is the lepromatous, compared to the tuberculoid, form of leprosy. An even better example of acquired hyporesponsiveness is tuberculosis as it is seen in persons with AIDS, compared to those with a healthy immune system.

H₂O₂-MPO-halide system

This is an absolutely critical oxygen-dependent killing system, without which leukocytes have great difficulty killing bacteria in phagolysosomal vacuoles by halogenation. It is dependent on the oxidative burst that follows ingestion of a bacterium. Superoxide anion is formed as a result, which is converted to hydrogen peroxide by the superoxide dismutase reaction. Meanwhile, the lysosomal enzyme, myeloperoxidase (MPO), has entered the phagolysosome when lysosomal contents are emptied into the phagocytic vacuole (phagosome). In the presence of a halide ion, MPO catalyzes the formation of an hypohalous (usually hypochlorous) acid, which kills the bacterium, either by binding the halide ion to intracellular constituents (a process called halogenation) or by oxidation of bacterial lipids and proteins (hypohalous acids are more potent oxidants than hydrogen peroxide).

Hageman factor

Also known as clotting factor XII. It was discovered, because of its deficiency in a person with the surname, Hageman. This is a very important plasma protein, which can cause the production of inflammatory mediators and products from several different plasma protein cascades. Thus, to understand why this protein is important, you must think of it in terms of Hageman factor-related systems. For example, it is the protein that initiates the intrinsic (in contrast to the extrinsic) clotting process and fibrinolysis. As a result of Hageman factor's activation, fibrin is produced. Fibrinolysis develops after Hageman factor's activation, because the fibrinolytic proteinase, plasmin, is subsequently produced. Plasmin can also activate C3 and C5 in the complement cascade, producing C3a and C5a, respectively. Both of these activated products are anaphylatoxins, with C5a additionally having powerful chemotactic activity. Hageman factor's activation also leads to kinin production, because the kallikrein/kinin cascade is subsequently triggered.

Hepatization, gray

Consolidation (see separately) of the lung, to the extent that it develops the firmness and consistency of liver. The modifier, "gray", is appended to reflect the color that the consolidated tissue has when examined grossly. In gray hepatization, the inflammatory process has continued long enough for hyperemia to subside, leaving primarily leukocytes. Thus, the color. See red hepatization as a contrast.

Hepatization, red

Consolidation (see separately) of the lung, to the extent that it develops the firmness and consistency of liver. The modifier, "red", denotes that the inflammatory process is still in an acute phase, with sufficient hyperemia to cause the organ to be predominantly red. As the inflammatory process becomes less acute, the amount of hyperemia subsides, leading to gray hepatization.

HETEs

A group of eicosanoids, meaning that they are derived from arachidonic acid metabolism, that is produced by the catalytic activity of lipoxygenases. The abbreviated name, HETE, derives from hydroxyeicosatetraenoic acid. Each member of the group is designated by a number, e.g., 5-HETE or 12-HETE. Some of them are chemotactic for neutrophils and eosinophils.

Histamine

Beta-aminoethylimidazole. A vasoactive amine that acts by interacting with two kinds of receptors, H1 or H2. The former receptors appear to be most important in the induction of increased vascular permeability, which is largely due to contraction of endothelial cells in postcapillary venules. Both kinds of receptors are involved in causing vasodilitation. Histamine is the principal cause of the acute-transient vascular phenomena that are responsible for producing the triple response reaction (see separately).

Histiocyte

For the purpose of this course (and most other venues), histiocytes is a synonym for macrophage (see separately). The text makes the distinction that histiocytes are cells derived from monocytes and have not yet phagocytosed particulate material, while macrophages, which have the same origin, have. This is not a widely used means of distinguishing between the two.

Hormone

In the context of this section, a hormone is a biologically active product of one cell that has its pharmacologic effect on another cell, which is located at a great distance from the producer cell. To have such a distant effect, hormones must enter and travel via one or more of the body fluids. An example of a group of hormones that influence the inflammatory response would be the corticosteroids. An exception to the definition given above is a group of chemical substances that primarily have potent local hormonal effects. They are called, "autocoids" (see separately). For example, the prostaglandins are members of the autocoid group.

Hydrogen peroxide (H₂O₂)

Hydrogen peroxide is an important product of oxidative metabolism that is key to the killing of microorganisms. It is formed from superoxide anion and can be converted into a highly bactericidal hypohalous (usually hypochlorous) acid by the lysosomal enzyme, myeloperoxidase (see H₂O₂-MPO-halide system). Hydrogen peroxide can also be reduced further, to form the potent oxidant, hydroxyl radical. Hydrogen peroxide is broken down by catalase if it is not utilized as described above.

Hydroxyl radical (OH)

OH is a highly reactive oxygen species that can be formed from hydrogen peroxide in several different ways. One of these pathways is facilitated by the presence of ferrous iron.

Hypochlorous acid

This potent oxidant is the most common hypohalous acid that is produced by the H₂O₂-MPO-halide system (see separately). It is an essential component of oxygen-dependent killing of bacteria phagocytosed by leukocytes, especially neutrophils. It kills either by oxidizing bacterial lipids and proteins or by chlorinating bacterial cellular constituents.

ICAM-1

Intercellular adhesion molecule-1 is a member of the adhesion molecules (see separately) family that is related to the immunoglobulins. It is up-regulated on the surfaces of mediator-stimulated endothelial cells. It, therefore, is important in the process of recruiting leukocytes, which have receptors for ICAM-1 on their surfaces, to sites of inflammation.

IgE (immunoglobulin E)

IgE is the immunoglobulin class that is associated with type I (immediate) hypersensitivity reactions (allergy, asthma, and anaphylaxis). This class of immunoglobulin binds to and "sensitizes" mast cells and basophils. Thus primed, when they encounter the relevant antigen, these cells are triggered to degranulate, thereby releasing proinflammatory mediators.

Indomethacin

A nonsteroidal antiinflammatory drug that interferes with the enzymatic activity of cyclooxygenase, thereby preventing/reducing the production of products of the cyclooxygenase pathway of arachidonic acid metabolism (e.g., thromboxanes and prostaglandins).

Integrins

This class of adhesion molecules (see separately) is key to cell-cell and cell-matrix interactions that are important in genesis of the cellular phase of the inflammatory response. They are particularly important as the molecules that increase adherence of leukocytes to the surfaces of endothelial cells, thereby allowing the leukocytes to crawl to the gaps between endothelial cells and transmigrate to the extravascular space.

Interferons

Interferon-alpha and -beta are so-called type I interferons. They are secreted by a wide variety of cell types and have a wide range of functions. They are best known for their antiviral properties. They mediate their effects through the same receptor, which is present on the surfaces of virtually all nucleated cell types. Interferon-gamma (immune or type II interferon) is distinct in several ways from both interferon-alpha and -beta. It mediates its effects through a separate receptor from the one used by the type I interferons. In addition to having antiviral properties, it is especially noteworthy as a potent modulator of the functions of a wide range of cell types. Many of these functions are critical to the immune and inflammatory responses.

Interleukins

Interleukin is the generic name for a group of well-characterized cytokines that are produced by leukocytes and other cell types. They have a broad spectrum of functional activities that regulate the activities and capabilities of a wide variety of cell types. They are particularly important as members of the cytokine networks (see separately) that regulate inflammatory and immune responses.

Kallikrein

The serine proteinase that is generated by activated Hageman factor from the inactive plasma protein, prekallikrein. It cleaves the precursor plasma proteins, called kininogens, to form the proinflammatory kinins, e.g., bradykinin. It also can activate plasminogen to yield plasmin. Kallikrein has direct chemotactic activity and also has the capacity to cleave C5 to C5a, which is an exceptionally potent chemotactic agent.

Kininogen

A group of inactive plasma proteins that, when proteolytically cleaved by kallikrein, give rise to kinins (bradykinin and kallidin).

Lactoferrin

A bactericidal protein that is found in the secondary granules of neutrophils. It kills by chelating iron, which is key to the metabolism and, therefore, survival of bacteria.

Left shift

A change in the leukogram that denotes an absolute increase in the number of immature neutrophils that are found in the circulation. The nuclei of such cells have fewer lobes, because lobation develops as the cells mature. A left shift indicates that neutrophils are being called forth from the bone marrow faster than they can mature. This usually signifies a serious inflammatory drain on their production. A degenerative left shift is similar, except that the absolute number of neutrophils in the circulation is decreased, indicating inability of the bone marrow to keep up with the demand. This is a seriously negative laboratory finding. A right shift, a term that is rarely used, denotes hypersegmentation of the neutrophil population, possibly indicating that circulationg neutrophils are remaining in the circulation longer than normal.

Leukemoid reaction

A change in the leukogram, often in response to an infectious agent, that can closely mimic true leukemia. The changes include elevation of the absolute number of leukocytes of a specific lineage, sometimes to an extreme degree, together with an increased number of circulating immature forms in that same series.

Leukotriene

A group of eicosanoids that is produced by the catalytic effect of lipoxygenases on arachidonic acid. They have a wide range of proinflammatory activities.

Lymphocyte

A class of leukocyte produced in a variety of lymphoid organs throughout the body that is responsible for cellular and humoral immune responses. Lymphocytes can be divided into two main classes, T lymphocytes and B lymphocytes (see separately). Lymphocytes are often seen at sites of chronic inflammation. They produce many secretory products (lymphokines) that modulate the functional activities of a wide variety of cell types.

Lymphocytosis

The condition of having an absolute increase in the number of circulating lymphocytes.

Lymphokine

Cytokines that are produced by lymphocytes.

Lymphopenic

The condition of having an absolute decrease in the number of circulating lymphocytes.

Lysosomal enzymes (hydrolases)

Hydrolytic enzymes that are stored by, and released from, lysosomes.

Lysosome

Intracytoplasmic organelles that are found within leukocytes, but most prominently in the granulocytes (neutrophils, basophils and eosinophils). These structures can fuse with the membranes of other organelles (e.g., phagocytic vacuoles) and the plasma membrane. When they fuse with a phagocytic vacuole, a phagolysosome is formed. When they fuse with the plasma membrane, (called exocytosis - see seperately)the contents of these storage granules are ejected into the extracellular environment. Lysosomal products can also be lost to the extracellular compartment when lysosomes fuse with phagocytic vacuoles before the latter are completely closed (regurgitation while feeding).

Lysozyme

One of the bactericidal hydrolytic enzymes found in the granules of leukocytes. Its activity is not dependent on the generation of oxygen or nitrogen intermediates. Instead, its mechanism of effect is through the hydrolysis of a component of the glycopeptide coat of susceptible bacteria.

Macrophage (synonym: histiocyte)

The most mature form of the mononuclear phagocyte lineage. Its immediate precursor is the monocyte, which is found in the circulation. Macrophages have a wide variety of functions, ranging from the scavenging and degradation of dead tissue and effete cells, through antigen presentation for lymphocytes, to activation for host defense against bacteria, parasites, and tumor cells. The functions of mature macrophages are directed by microenvironmental signals that are encountered by monocytes when they emerge from vessels and begin maturing into macrophages. Your text distinguishes between macrophages and histiocytes, based on prior phagocytic activity (macrophage) of lack thereof (histiocyte). This is an artificial distinction that should not (and is not)usedby most. Macrophages are characteristically found at sites of chronic inflammation and can become specialized in granulomatous inflammation to form epithelioid cells and multinucleated giant cells.

Major basic protein

A bactericidal cationic protein that is found in the granules of eosinophils.

Margination

The process by which leukocytes move out of the central, axial stream in blood vessels to the peripheral zone, where they can interact with the surfaces of endothelial cells. The inflammatory events that foster margination are vasodilatation, attendant slowing of blood flow, and increased turbulence.

Mast cell

These cells are found in the tissues. They look like basophils, because their large granules stain in the same way. They are also similar to basophils with respect to their surfaces having receptors for IgE, and in regard to the complement of proinflammatory mediators that they are capable of producing. Despite these similarities, however, mast cells are produced through a completely separate lineage than the one that is responsible for basophils.

Mediator, inflammatory (pro-inflammatory)

Any one of many chemical substances that contribute to the initiation, augmentation, or termination of inflammatory responses. Generally speaking, there are two main sources: plasma proteins and cellular secretion. Proinflammatory mediators, which are the ones that encourage inflammation, overlap widely with respect to their pharmacologic activities.

Membrane attack complex (of complement system)

The terminal proteins in the complement cascade (C5b,6,7,8, and 9) form a lipid-soluble macromolecular protein channel that permeabilizes cell membranes. It can affect the membranes of both bacterial and mammalian cells. When the permeability of the cell under attack is lost, osmotic control is lost, the consequence of which is rapid cell lysis.

Monocyte

The member of the mononuclear phagocyte lineage that is found in the circulation. It is the immediate precursor of the macrophage, into which it differentiates when it emigrates into the extravascular space.

Monokine

Cytokines that are produced by members of the mononuclear phagocyte series, mainly monocytes and macrophages.

Mononuclear phagocyte

This is the generic term that is used to include all members of the differentiation pathway that leads to the formation of macrophages.

Myeloperoxidase (MPO)

A lysosomal enzyme that is critical to the oxygen-dependent killing of bacteria by phagocytic leukocytes. (see H₂O₂-MPO-halide system)

NADPH oxidase

A critical enzyme needed to generate superoxide anion and, therefore, oxygen-dependent killing mechanisms. It is this enzyme that is defective in the congenital condition, chronic granulomatous disease.

Neutropenia

The condition of an absolute deficiency in the number of circulating neutrophils.

Neutrophil

This is the most numerous granulocyte (the other two being the basophil and the eosinophil). The name stems from the relatively neutral color that its granules have (compared to those of basophils and eosinophils) when routinely stained. The neutrophil arises from the bone marrow and is fully mature when it is released into the circulation. It is, therefore, fully prepared to function in its role as the first line of cellular defense. It becomes activated, i.e., augmented in its ability to perform many of its functions, by exposing it to certain proinflammatory mediators and the chemotactic factors that attract it to the site of an inciting stimulus. It is voraciously phagocytic to the extent that it, along with the macrophage, has been termed a "professional" phagocyte, thereby distinguishing these cell types from others that are capable of ingesting things, but not to the same extent.

Neutrophilia

The condition of an absolute increase in the number of circulating neutrophils.

Nitric oxide (EDRF [endothelium-derived relaxing factor])

This is a potent regulatory and cytotoxic molecule. In inflammation, its production is catalyzed by inducible nitric oxide synthase, which is the product of an inducible gene that is selectively expressed under inflammatory conditions. It allows leukocytes, especially macrophages and neutrophils, to produce large amounts of a reactive nitrogen intermediate, NO (nitric oxide), during inflammatory responses. NO, like its reactive oxygen counterparts (see also reactive oxygen intermediates), can kill microorganisms, tumor cells, and damage tissues. The earlier name, EDRF, comes from the fact that a second gene, which encodes a constitutively expressed isoform of nitric oxide synthase, produces small amounts of NO that are involved in the regulation of vascular smooth muscle tone. Nitric oxide is also preduced in the brain by a neuronal isoform of nitric oxide synthase, where it functions in intercellular signaling between nerve cells.

Oncotic pressure

The osmotic pressure created by colloids (mainly plasma proteins) that are normally retained within the vascular system. Oncotic pressure nearly offsets the hydrostatic pressure that acts to drive fluid out of vessels into the extravascular space. The result is that small amounts of fluid cross the vascular barrier, which are then transported back to the blood via the lymphatics. A decrease in oncotic pressure can be a cause of non-inflammatory edema (see separately).

Opsonization

The coating of a particle with a substance that helps it to attach to a phagocytic leukocyte. The two most important are C3b, of the complement system, and antibody. The former binds through receptors on leukocytes for C3b, while the latter opsonins interact with cells through receptors for the Fc portion of the antibody molecule.

Paracrine stimulation or feedback

The product of one cell that acts on adjacent cells.

Peripheral zone (in blood vessels)

Cellular elements normally remain in the central or axial stream of blood vessels. There is, therefore, a peripheral zone of plasma that is free of cells. Thus, under normal conditions, it is uncommon for cellular elements of the blood to come into contact with endothelial cell surfaces.

Phagocytosis

The process by which particulate material is ingested by cells. All cells are phagocytic to a certain degree. However, neutrophils and monocytes/macrophages are quantitatively much more able to ingest particulates. Therefore, they are sometimes referred to as "professional" phagocytes. The process consists of recognition of the particle, ingestion of the particle, and digestion of the particle. Phagocytic vacuoles (phagosomes) are formed by invagination of the plasma membrane. Phagosomes fuse with lysosomes, to produce phagolysosomes in which the killing (if applicable) and digestion of particulate material are accomplished.

Phagocytosis, frustrated

Imagine a phagocytic cell undertaking the ingestion of something so large that it cannot be internalized. Under such conditions, especially if the surface has been opsonized, phagocytic cells will attach and eject lysosomal contents onto the surface. This has been referred to as "frustrated phagocytosis". It is the cause of tissue injury in many different autoimmune diseases.

Plasma cell

This cell type is derived from B lymphocytes and is the main producer of antibody. These cells are filled by rough surfaced endoplasmic reticulum, to the extent that their ultrastructural appearance is that of a "protein factory". This cell type is often found in association with chronic inflammatory processes.

Plasmin

The serene proteinase that is responsible for digesting fibrin, i.e., for fibrinolysis. It also has the capacity to activate precursor proteins in other mediator cascades. For example, it can activate both C3 and C5, resulting in mediators that have both analphylatoxic (C3a and C5a)) and chemotactic (C5a) properties.

Plasminogen

The inactive plasma protein precursor of plasmin.

Platelet

Platelets circulate in the blood and are derived from megakaryocytes in the marrow. Like erythrocytes, they are anucleate. However, unlike erythrocytes, they contain numerous intracytoplasmic granules and are the source of numerous proinflammatory mediators. In fact, they are quantitatively the greatest single source of vasoactive amines in the body. They also are a rich source of thromboxane A2. It is their activation that, in part, initiates the vascular phase of the acute inflammatory response (see Fig. 2-13 in text). To have them play this role makes imminently good sense, because they are present in large numbers throughout the circulation, i.e., some are always in close proximity to an inciting stimulus.

Platelet activating factor

PAF is produced by many different kinds of stimulated cells (e.g., basophils, neutrophils, monocytes, macrophages, endothelial cells) from phospholipids mobilized from cell membranes by phospholipase A₂, i.e., PAF is not preformed in storage granules. Unlike the eicosanoids, which are also not stored in cells, PAF is not made from arachidonic acid. Chemically, it is an acetyl glycerol ether phosphocholine. It is 100-to-10,000 times more potent than histamine with respect to its vasoactive properties. As one of its smooth muscle effects, it is a strong bronchoconstrictor. It also stimulates other cells to increase their functional and metabolic activities, i.e., primes or activates them for more effective function.

PMN

The abbreviation for polymorphonuclear leukocyte and, often, neutrophil.

Polymorphonuclear leukocyte

This term refers primarily (and in the minds of some, exclusively) to neutrophils. The name derives from the multiple lobes of the mature neutrophil's nucleus. The eosinophil is bilobate and, to some, therefore, qualifies as a member of the PMN group. The basophil usually has a bean-shaped nucleus, but is characterized by some as being a polymorph.

Postcapillary venule

The blood vessel that joins the capillary bed to a system of increasingly larger venules and, finally, veins. Its significance is that it is the target organ for the transient vasoactive effects of inflammatory mediators, particularly endothelial contraction and the resultant increase in vascular permeability.

Priming

The phenomenon of being readied to perform a particular function at a quantitatively increased level. This is particularly true of leukocytes as they follow chemotactic gradients into a site of inflammation.

Prostacyclin

One of the prostaglandins, also known as PGI₂. It inhibits platelet aggregation, as well as the activation of leukocytes, and is a powerful vasodilator. It is produced by endothelial cells, among other cell types. It is the physiologic antagonist of the thromboxanes, primarily TXA₂. Imbalance between PGI₂ and TXA₂, in favor of the latter, can initiate platelet aggregation and an acute inflammatory response (see fig. 2-13, text).

Prostaglandin

A group of eicosanoids (see separately) that are produced by the enzymatic activity of cyclooxygenase (see separately). Together with the thromboxanes, prostaglandins constitute the prostanoid subgroup of the eicosanoids.

Pruritus

This word is included, only because it is probably one of the most often misspelled words in medicine. The suffix, -itis, means inflammation of. Thus, pruritus, which refers to itching, should not be spelled, pruritis, as it often is.

Purulent

An adjective that is used to describe an exudate or condition that is associated with large numbers of neutrophils.

Pyrogen

Pyrogens are substances that cause fever. The most important endogenous pyrogens, meaning that they are pyrogens that are produced in the body, are the cytokines interleukin-1 and TNF-alpha.

Reactive oxygen (or nitrogen) intermediates

Molecules of oxygen (or nitrogen) that are in altered chemical states, thereby making them capable of oxidatively injuring cells, tissues, and, in some instances, DNA. The latter kind of injury can cause carcinogenic mutations. Also referred to as activated oxygen (or nitrogen) species.

Sanguinous

An adjective that is used to describe an exudate or transudate that contains erythrocytes.

Sarcoidosis

A chronic granulomatous disease of unknown cause that is characterized by the presence of noncaseating granulomas (i.e., ones that do not have a zone of caseous necrosis at their center). The lung is commonly involved, but lesions have been reported in virtually every organ of the body.

Scar

One of the possible outcomes of inflammation. Scars consist of collagenous connective tissue, which can replace parenchyma that is lost due to injury or as a result of the inflammatory process. Scarring, or fibrosis, can be the basis for one of the cardinal signs of inflammation, namely, loss of function. The loss can either be due to replacement of parenchymatous tissue (e.g., contractile heart muscle fibers) or to mechanical problems that scar tissue can produce. For example, as scar tissue matures, it contracts. It can, therefore, constrict organs that it surrounds (so-called napkin ring scarring or fibrosis of the intestine) or impede movement (e.g., when it crosses a joint).

Selectins

Lectin-like adhesion molecules that are important in the intitial interactions between leukocytes and endothelial cells during the margination process.

Serotonin

5-hydroxytryptamine. This preformed vasoactive amine is stored in the cytoplasmic granules of acute inflammatory cellular components, such as platelets. Its actions are similar to those of histamine.

Serous

An adjective used to describe an exudate or effusion that is thin and watery, and which lacks a significant cellular component.

Slow-reacting substances of anaphylaxis

Eicosanoids of the leukotriene group (leukotrienes C4, D4 , and E4 ) that contract smooth muscle and increase vascular permeability. These are very important in the development of the clinical symptomatology of type I (immediate) hypersensitivity reactions. For example, they are potent bronchoconstrictors.

Superoxide anion

An important reactive oxygen intermediate that is formed through the catalytic activity of NADPH oxidase. Superoxide anion is the precursor of hydrogen peroxide (see separately).

Suppurative

An adjective that is used to describe an exudate that contains large numbers of neutrophils, particularly in conjunction with liquefaction necrosis.

T cell (lymphocyte)

This is one of the two major classes of lymphocyte. T cells cannot be distinguished morphologically from B cells (the other major class of lymphocyte), and neither can the subclasses of T cells be differentiated, without special examinations for specific surface marker molecules. The subclasses of T cells have many different functions, from providing "help" with the production of antibodies to mediating cytotoxicity. However, all have in common the fact that they mature by traversing the thymus (which is where the "T" designation comes from).

Thromboxane

A group of eicosanoids that is produced from arachidonic acid by the action of cyclooxygenase. The principal proinflammatory mediator in the group is the highly unstable TXA₂, which is known for its potency as an aggregator of platelets and as a cause of mediator release from their granules. It is also a vasoconstrictor. Thromboxanes are, thus, the physiologic antagonists of prostacyclin (PGI₂; see separately). An imbalance between the two, in the favor of thromboxane, will lead to initiation of platelet aggregation and an acute inflammatory response (fig. 2-13, text). The thromboxanes, together with the prostaglandins, make up the prostanoid subgroup of the eicosanoids.

Tight junction

The kind of intercellular junction that is so "tight" it excludes the passage of liquids between cells. This is the type of junction that normally exists between endothelial cells, and which is disrupted by the events that cause transiently increased vascular permeability during the early stages of acute inflammatory responses.

Transudate

Edema fluid that contains very little protein (specific gravity < 1.015) and, usually, very few cells. Transudates usually suggest a noninflammatory source of the fluid, such as increased hydrostatic pressure that exceeds oncotic pressure. See exudate for the inflammatory counterpart.

Triple response

Also known as the wheal and flare reaction. When the skin is stroked with a blunt object, a dull red line develops almost immediately. This is followed soon by an enlarging red halo (the flare) and elevation of the skin (swelling; the wheal) along the original red line. The original red line is the result of immediate, transient vasodilatation (hyperemia, mainly of precapillary arterioles). The spreading flare is the result of spreading vasodilatation, while the wheal is produced by loss of fluid and plasma proteins from the transiently permeable postcapillary venules (edema).

Vasoactive

Literally translated, this adjective means that a substance has the capacity to alter the physiologic state, especially the tone and caliber, of a vessel.