Williams Hematology



General Characteristics of Inflammation
Acute Inflammation

Hemodynamic Changes

Leukocyte Recruitment

Regulation of the Inflammatory Response
Chronic Inflammation and Repair
Chapter References

The inflammatory response is characterized by a series of events that encompass a rapid and relatively short-lived increase in local blood flow, an increase in microvascular permeability, and the sequential recruitment of different types of leukocytes. Superimposed upon the inflammatory response is a series of reparative processes (e.g., parenchymal regeneration, angiogenesis, production of extracellular matrix material, and scar formation). Early hemodynamic changes at a site of an inflammation establish conditions that enable marginated leukocytes to engage in low-affinity selectin-mediated rolling interactions with endothelial cells. In response to locally produced soluble and cell surface mediators, endothelial cells and rolling leukocytes become activated and sequentially express several sets of complementary adhesion molecules which include b2 integrins, members of the selectin family, and members of the immunoglobulin superfamily. Leukocyte and endothelial cell adhesion molecules mediate the high-affinity adhesive interactions necessary for leukocyte emigration from the vascular space and across specific chemotactic gradients. Analogous, temporally regulated soluble mediators and cellular adhesion molecules also orchestrate the monocyte- and lymphocyte-rich chronic inflammatory response. This basic paradigm is modulated by a large number of surface-active and soluble inflammatory mediators which include vasoactive amines and lipids, reactive oxygen and nitrogen intermediates, cytokines, chemokines, and many plasma proteins (e.g., complement system, kinins, and coagulation cascade).

Acronyms and abbreviations that appear in this chapter include: cGMP, cyclic guanosine 3,5-monophosphate; EDRF, endothelium-derived relaxing factor; ELAM-1, endothelial cell leukocyte adhesion molecule-1; GMP-140, granule membrane protein-140; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; ICAM-1, intercellular adhesion molecule-1; ICAM-2, intercellular adhesion molecule-2; ICAM-3, intercellular adhesion molecule-3; IFN-g, interferon-g; IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8; IL-b, interleukin-b; g-IP-10, g-interferon-inducible protein; LAM-1, leukocyte adhesion molecule-1; LTB4, leukotriene B4; LTC4, leukotriene C4; LTD4, leukotriene D4; LDE4, leukotriene E4; LFA-1, lymphocyte function-associated antigen-1; MCP-1, monocyte chemoattractant protein-1; MGSA (or GROa), melanocyte growth-stimulatory activity; MIP-1a, macrophage inflammatory protein-1a; MIP-1b, macrophage inflammatory protein-1b; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NAP-2, neutrophil-activating peptide; NOS, nitric oxide synthase; PAF, platelet-activating factor; PECAM-1, platelet endothelial cell adhesion molecule; PF4, platelet factor 4; RANTES, regulated upon activation, normal T cell expressed and presumably secreted; RGD; TNF-a, tumor necrosis factor-a; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late antigen 4.

The sentinel clinical features of acute inflammation, rubor, calor, tumor, and dolor, have been recognized for at least five thousand years. Dr. John Hunter, the renowned late eighteenth century Scottish surgeon, observed that the inflammatory response is not a disease per se but rather a nonspecific and salutary response to a variety of insults. Through his microscopic examinations of transparent vital membrane preparations, Julius Cohnheim concluded that the inflammatory response is fundamentally a vascular phenomenon. Leukocytic phagocytosis was discovered late in the nineteenth century by Eli Metchnikoff and his colleagues. Morphologic studies, using both live animals and fixed histologic preparations, transformed our understanding of inflammation and led to the currently held concepts of inflammation-associated hemodynamic alterations, “acute” inflammation, and “chronic” inflammation.1 It has been during the past thirty to forty years that the modern techniques of biochemistry (e.g., protein and lipid purification and the measurements of reactive oxygen and nitrogen species), tissue culture, monoclonal antibody production, recombinant DNA technology, and the genetic manipulation of isolated cells and whole animals, have enabled a more detailed understanding of the cellular and molecular mechanisms which characterize the inflammatory response. These studies, in concert with “experiments of nature” such as chronic granulomatous disease (see Chap. 67 and Chap. 72) and the leukocyte adhesion deficiency disorders (see Chap. 72), have provided for the formulation of complex, yet elegant, models of acute and chronic inflammation and the development of incisive therapeutic approaches that promise to exploit this knowledge. A vast array of human diseases is marked by either defects in the development of the inflammatory response or the deleterious effects of the inflammatory response itself.
While necessarily contrived, it remains useful to consider inflammation as an acute or chronic process. “Acute” inflammation lasts from minutes to several days and is characterized by local hemodynamic and microvascular changes and leukocyte accumulation.2 The acute inflammatory response is consistently marked by microvascular leakage and the accumulation of neutrophils. The four cardinal signs of inflammation, alluded to above, can be accounted for within the physiologic terms of acute inflammation.
In contrast, the chronic inflammatory response lasts much longer and is more varied in its effects.2 Cellular infiltrates are composed primarily of lymphocytes and monocytes but there are many variations in the cellular composition, anatomic distribution, and tempo of development of chronic inflammatory lesions. The chronic inflammatory response is also marked by the proliferation of resident fibroblasts and the growth of new capillaries. Chronic inflammatory processes are classified according to these variations. For example, granulomatous inflammation is a chronic process marked by nodular aggregates of mononuclear phagocytes that have become “transformed” into so-called epithelioid histiocytes because of their similar appearance to epithelial cells. In many cases there are accompanying multinucleate giant cells. Granulomas may be distributed along blood vessels (e.g., angiocentric), along airways (e.g., bronchocentric), or randomly throughout the interstitium or parenchyma of an organ. Some chronic inflammatory processes are marked by the appearance of plasma cells or eosinophils.
Superimposed upon the acute and chronic inflammatory response is repair.2 Repair may entail the regeneration of parenchymal cells damaged as the result of an insult per se or damaged secondary to the inflammatory response to the insult. Repair is characterized by the growth of new capillaries (angiogenesis) and the activation of fibroblasts which produce extracellular matrix molecules (e.g., scar tissue). In some circumstances an acute inflammatory response is self-contained and nonprogressive. In other situations the response progresses to a chronic process which can persist for years (e.g., tuberculous granulomas).
This chapter will first address acute inflammation, which encompasses localized changes in blood flow, alterations in microvascular permeability, and neutrophil exudation. There has been a rapid advance in understanding of the processes of endothelial cell activation, leukocyte-endothelial cell rolling and adhesive interactions, leukocyte emigration, and leukocyte activation. The second section of this chapter will introduce the vast array of soluble and surface-active mediators that orchestrate both acute and chronic inflammatory responses. These mediators include substances that range from short-lived reactive oxygen and nitrogen intermediates to entire regulatory systems (e.g., complement system and coagulation cascade). Finally, a brief overview of chronic inflammation and tissue repair will be provided. The goal of this chapter is to provide a framework for understanding the basic processes of inflammation while gaining an appreciation for the highly complex and integrated nature of the regulated inflammatory response.
The hemodynamic changes that occur early in the acute phase of inflammation include arteriolar vasodilatation and localized increases in microvascular permeability. In many but not all circumstances arteriolar vasodilatation follows a rapidly developing (within seconds) and brief (seconds) period of vasoconstriction.3 Arteriolar vasodilation results in increased blood flow, thus explaining the familiar redness and warmth which characterize a site of acute inflammation. The increase in blood flow, coupled with increases in microvascular permeability, results in hemoconcentration and increased local viscosity. These localized hemodynamic changes are critical to subsequent leukocyte emigration because selectin-mediated low-affinity rolling leukocyte-endothelial adhesive interactions can efficiently occur only under such conditions of low shear force (see below). Experimental studies using in vitro flow chambers and live animals indicate that selectin-mediated leukocyte-endothelial rolling adhesive interactions cannot occur in the face of the shear forces exerted by normal blood flow. Increased microvascular permeability leads to the exudation of protein-rich plasma which is a fundamental characteristic of acute inflammation. Microvascular leakage occurs through a variety of mechanisms that include venular endothelial cell contraction, which is accompanied by widening of intercellular junctions; so-called endothelial cell retraction, which is not well understood but involves cytosketetal changes; leukocyte-mediated endothelial cell injury; direct endothelial injury; and leakage via new capillaries which do not yet possess fully “closed” intercellular junctions.4,5 Increases in rate of transcytosis in which plasma constituents cross endothelial cells in vesicles or vacuoles have a role in neoplastic blood vessels and may play a role in inflammation.6 Alterations in local blood flow occur at the level of arterioles which are regulated largely by the autonomic nervous system, vasoactive peptides, and eicosanoids. A variety of soluble mediators [e.g., histamine, leukotrienes, complement components C3a and C5a, interleukin-1, tumor necrosis factor-a (TNF-a), and interferon-g (IFN-g)] can induce increases in microvascular permeability through several of the above-mentioned mechanisms.
The orchestrated recruitment of leukocytes into a site of inflammation is a fundamental characteristic of the inflammatory response.6 The importance of white blood cells in host defense is highlighted in patients with genetic defects in white blood cell function [e.g., absence respiratory burst in patients with chronic granulomatous disease (Chap. 67) and diminished leukocyte emigration in patients with leukocyte adhesion deficiency (Chap. 72)]. Leukocytes are critical because of their central role in the phagocytosis and containment or killing of microbes and in the digestion of necrotic tissue debris. Leukocyte-derived products such as proteolytic enzymes and reactive oxygen intermediates contribute to tissue injury.
Leukocyte Adhesion and Transmigration
When vascular stasis occurs as the result of the hemodynamic changes of early acute inflammation, leukocytes are pushed from the central axial column of blood cells to a position along the endothelial surface. This process, called margination, occurs under conditions of slow blood flow.2 Individual leukocytes adhere transiently and weakly to the endothelial surface. Studies using vital membrane preparations and flow chamber studies using endothelial cell monolayers and suspensions of purified leukocytes have revealed that cells roll along the endothelial surface.6,7,8,9,10,11,12 and 13 Rolling neutrophil-endothelial adhesive interactions occur early (minutes) after the initiation of an acute inflammatory response and can, depending upon the time within the evolution of an inflammatory response, involve neutrophils, lymphocytes, monocytes, basophils, or eosinophils. The leukocyte-endothelial cell rolling adhesive interaction is a specific and necessary step that precedes tight adhesion and emigration.10 Studies indicate that early rolling adhesive interactions are mediated largely by selectins.11 In turn, the cell surface expression of selectins (and other intercellular adhesion molecules, see below) is regulated by a number of locally produced proinflammatory mediators.6,8,9,10,11,12 and 13
Selectins contain a C-terminal cytoplasmic tail, a lipophilic transmembrane domain, a series of complement regulatory domains, an epidermal growth factor–like domain, and an extracellular N-terminal carbohydrate-binding region which is homologous to mammalian lectins (Table 6-1).9,10,11,12 and 13 P-selectin (previously known as GMP-140) is expressed by endothelial cells and platelets, E-selectin (formerly ELAM-1) by endothelial cells, and L-selectin (also known as LAM-1) by most white blood cells. P-selectin is stored in endothelial intracytoplasmic granules called Weibel-Palade bodies.14,15 When endothelial cells are exposed to histamine, thrombin, or platelet-activating factor, P-selectin is rapidly (minutes) translocated to the endothelial surface where it engages marginated leukocytes via carbohydrate moieties that contain sialic acid residues (e.g., sialyl LewisX glycoprotein).9,10,11,12 and 13 This transient, low-affinity binding interaction which can withstand only the low-flow shear force conditions found in stasis, accounts in part for the early rolling leukocyte-endothelial cell adhesive interactions (Fig. 6-1). Exposure of endothelial cells to TNF-a or IL-b results in protein synthesis–dependent expression of E-selectin, a response that occurs within 1–2 hours and peaks at 4–6 hours.16,17 As in the case of P-selectin–mediated leukocyte adhesion, E-selectin–mediated adhesion occurs via a series of sialylated and fucosylated carbohydrate moieties related to the sialyl LewisX (SLeX) and sialyl LewisA (SLeA) blood group antigens on leukocytes (Table 6-1).13,18 L-selectin is constitutively expressed by leukocytes, participates in white blood cell-endothelial cell adhesive interactions via mucin-like glycoproteins (e.g., CD34, GlyCAM), and is shed when the leukocyte is activated (Table 6-1).9,19 It is believed that L-selectin shedding facilitates leukocyte emigration by allowing the white blood cell to detach from the endothelium. Low-affinity rolling adhesive interactions set the stage for b-integrin and immunoglobulin superfamily-mediated high-affinity adhesive interactions and leukocyte transmigration.10


FIGURE 6-1 Leukocyte-endothelial adhesive interactions. Early in the acute inflammatory response, marginated leukocytes engage in transient, low-affinity, selectin-mediated adhesive interactions with endothelial cells. As the response evolves, activated leukocytes and endothelial cells engage in high-affinity b2-integrin and immunoglobulin superfamily-mediated adhesive interactions. A variety of chemotactic factors can provide the motive force for leukocyte emigration. [Modified and redrawn from multiple references (7,8,9,10 and 11)].

Relatively weak selectin-mediated and high-affinity adhesive interactions are not temporally or mechanistically discrete. For example, TNF-a and IL-b induce both E-selectin, which is not expressed by quiescent cells, and increases in endothelial expression of ICAM-1 and VCAM-1, which are constitutively expressed in low concentrations and are involved in the recruitment of all types of leukocytes in the case of ICAM-1, and chronic inflammatory leukocytes (lymphocytes, monocytes, eosinophils, and basophils) in the case of VCAM-1.6,8,9,10,11 and 12,20 Intercellular adhesion molecule-1 binds to b2 (leukocyte) integrins (e.g., CD11a/CD18, CD11b/CD18) and VCAM-1 binds to b1 integrins (e.g., VLA-4/a4b1) (Table 6-1).21 It is believed that activated endothelial cells secrete such mediators as platelet-activating factor and IL-8 which in turn activate overlying leukocytes.6 Leukocyte CD11a/CD18 (LFA-1) undergoes a conformational change by which there is an increase in its binding affinity for endothelial ICAM-1. The b2 integrins are heterodimeric structures which contain varied alpha chains (CD11a, CD11b, CD11c) and a common beta chain (CD18).21 The role of CD11c/CD18 is less clearcut than those of CD11a/CD18 and CD11b/CD18. Intercellular adhesion molecules (ICAM-1, ICAM-2, ICAM-3) are found on a variety of cell types aside from endothelial cells.22,23 and 24 CD11a/CD18 interacts with both ICAM-1 and ICAM-2 while CD11b/CD18 binds to ICAM-2 and the complement activation product, iC3b (see below). The role of ICAM-3 in leukocyte-endothelial adhesion is less well established. b1 integrins, notably VLA-4, are found primarily on chronic inflammatory leukocytes (e.g., lymphocytes, monocytes, basophils, and eosinophils) and mediate leukocyte binding via VCAM-1.25,26 and 27 b1-integrin–mediated adhesive interactions occur via RGD amino acid sequences within VCAM-1 as well as other molecules (e.g., fibronectin). b2 integrin-ICAM and b1-VCAM-1–mediated adhesive interactions occur later (hours-days) in the inflammatory response than do selectin-mediated interactions. Studies indicate that additional adhesive interactions are also involved in leukocyte transmigration [e.g., CD31 or PECAM-1 (platelet endothelial cell adhesion molecule)].28 The functional importance of the various complementary leukocyte-endothelial adhesive interactions has been clarified by in vitro leukocyte-endothelial binding studies and in vivo studies that have employed neutralizing antibodies directed against adhesion molecules, pharmacologic antagonists of adhesion molecules, and knockout mice.29,30 and 31 The functional importance of leukocyte integrins (CD11a/CD18, CD11b/CD18, CD11c/CD18) has also been highlighted by clinical and experimental observations in patients with leukocyte adhesion deficiencies (see Chap. 72).32
Leukocytes that are tightly bound to endothelium emigrate from the vascular space into the interstitium by extending pseudopods between intercellular junctions (Fig. 6-1). Secreted specific granule proteases play a role in the passage or “invasion” of leukocytes through subendothelial extracellular matrix material (e.g., basement membrane). Leukocyte emigration and movement through the interstitium is facilitated by binding interactions between leukocyte integrins and complementary sites on extracellular matrix molecules (e.g., fibronectin).33 A wide variety of soluble mediators can provide the motive force (chemotaxis) for this process.34 Chemotactic factors for neurophils include peptides derived from bacteria (e.g., N-formyl-methionyl peptides), complement-derived peptides (e.g., C5a, see below), chemotactic lipids [e.g., leukotriene B4 (LTB4) and others, see below], and locally produced cytokines (e.g., TNF-a and IL-1b) and chemokines (e.g., IL-8, see below). Chemotactic factors vary with respect to their specificity for different types of leukocytes. For example, C5a and N-formyl peptides both induce neutrophil and monocyte chemotaxis, IL-8 induces neutrophil chemotaxis, and monocyte chemoattractant protein-1 (MCP-1) induces chemotactic responses in monocytes and a specific subset of memory T lymphocytes. Each of these chemotactic factors activates “target” cells by engaging specific, cell surface receptors which in turn are linked to the contractile cell motility apparatus (e.g., microfilament proteins such as myosin and actin, and actin-regulating proteins such as gelsolin, filamen, profilin, and calmodulin) via complex signal-transduction pathways.33,34 In addition to chemotaxis, soluble and cell surface mediators induce leukocyte activation which is manifested by a wide array of changes in cellular function (e.g., adhesion molecule upregulation and increased adhesion molecule binding avidity (e.g., CD11a/CD18), selectin shedding (e.g., L-selectin), lysosome degranulation, and initiation of the respiratory burst). There have been great advances in understanding of the biochemical pathways involved in chemotaxis and cell activation. While there are many nuances in the signal-transduction pathways involved in these processes, several themes have emerged. Cell surface receptors are activated by specific ligands (e.g., C5a, LTB4, IL-8, etc.) and receptor activation is transduced via specific G proteins and membrane-associated phospholipases which in turn leads to mobilization of intracellular calcium, influx of extracellular calcium, and protein phosphorylation. Genetic defects in the regulation of many of these processes have been described and are detailed elsewhere throughout this text.
The principal result of neutrophil and monocyte recruitment are to provide 1) high concentrations of activated leukocytes that can release lytic substances and reactive oxygen and nitrogen intermediates needed to destroy foreign invaders, and 2) a vehicle to contain foreign particulates through phagocytosis. The products and functions of activated inflammatory cells are at once salutary because they contain and destroy invaders and deleterious because they cause tissue damage.
Leukocyte activation, especially that of neutrophils and mononuclear phagocytes, induced either by soluble mediators or by the process of phagocytosis, results in the secretion of many lysosomal substances (e.g., myeloperoxidase by neutrophils), the generation of reactive oxygen and nitrogen intermediates (e.g.,
, H2O2, NO), the generation of arachidonate metabolites (e.g., leukotrienes and prostaglandins), and the production of other mediators (see below).35,36 In some circumstances these materials are released into phagolysosomes where they contribute to the destruction of engulfed microbes while in other circumstances they are secreted into the extracellular milieu where they may amplify the inflammatory response and cause tissue damage.
Phagocytosis involves three distinct steps: recognition and attachment, engulfment, and degradation (killing) of the ingested material.37,38 Phagocytosis is enhanced greatly when particles (e.g., bacteria) are coated with opsonins which in turn function as ligands for leukocyte surface receptors. The major opsonins include the Fc domain of IgG and IgM immunoglobulins and the complement-derived fragments, C3b and iC3b, which covalently link to the surfaces of particles and large molecules. There are a variety of Fc receptors (FcgRI, FcgRII. FcgRIII, etc.) and complement receptors (e.g., CR1, CR2, CR3) which specifically engage their respective opsonins when the latter coat foreign particulates. As noted in Table 6-1, some enhanced phagocytic reactions occur independently of opsonins (e.g., CR3, the b2 integrin Mac-1, binds lipopolysaccharide directly). Engulfment is triggered as the result of engagement of FcgR and is enhanced by the concurrent engagement of complement receptors. In some circumstances, engulfment is enhanced by the simultaneous binding of the leukocyte to specific extracellular matrix molecules (e.g., fibronectin) or soluble cytokines. Engulfment results in the formation of phagosomes which fuse with lysosomes to form phagolysosomes in which the foreign particle is degraded. Numerous mechanisms for killing and/or degradation of microbes have been elucidated (Table 6-2). Although these mechanisms are classified as either oxygen-dependent or oxygen-independent, both types of processes may be involved in the destruction of a given microorganism, and a given microorganism may vary greatly in its susceptibility to various mechanisms of destruction.35,39


The foregoing sections provide a conceptual framework for the inflammatory response, specifically, the hemodynamic alterations, mechanisms of specific leukocyte-endothelial adhesive interactions, chemotaxis, and leukocyte activation and phagocytosis. The many steps that constitute this paradigm are regulated by a variety of soluble mediators that are produced by endothelial cells and leukocytes at a site of inflammation, by other resident cells (e.g., tissue macrophages, fibroblasts, mast cells), and as by-products of blood-borne proteins (e.g., complement system, coagulation cascade). These inflammatory mediator systems are summarized in Table 6-3.


Since the early 1970s it has been recognized that activated phagocytes exhibit a transient but marked increase in oxygen consumption and the generation of reduced oxygen metabolites.35 Although small quantities of reactive oxygen intermediates are produced as by-products of a variety of biochemical pathways, the chief source is the leukocyte membrane-associated NADPH oxidase, an enzyme complex that is defective in patients with chronic granulomatous disease (see Chap. 67). Reactive oxygen intermediates include superoxide anion (
), hydrogen peroxide (H2O2), hydroxyl radical (H
), and singlet oxygen (1O2). These reduced oxygen products play a major role in intraphagolysosomal killing of microorganisms and when released extracellularly are directly or indirectly responsible for a variety of inflammatory processes including endothelial cell lysis, extracellular matrix degradation, activation of latent proteolytic enzymes (collagenase, gelatinase), inactivation of antiproteases, interaction with toxic metabolites of L-arginine, and generation of chemotactic factors from arachidonic acid and the complement component, C5. In addition to their role in endothelial cytotoxicity, reactive oxygen intermediates have been shown to be cytotoxic for fibroblasts, erythrocytes, tumor cells, and various parenchymal cells. The biochemical mechanisms implicated include lipid peroxidation, the formation of carbonyl moieties and nitrosylation products, intracellular enzyme inactivation, protein oxidation, and oxidant-mediated DNA damage. Studies indicate that reactive oxygen intermediates (e.g.,
) can also undergo reactions with reactive nitrogen intermediates (e.g., NO, see below) to generate toxic NO derivatives.
Described in 1980 as endothelium-derived relaxing factor (EDRF), NO is the soluble, short-acting biosynthetic product of L-arginine, O2, NADPH, and nitric oxide synthase (NOS).40,41 As suggested by its original name, NO mediates vascular smooth muscle relaxation. NO binds to the heme moiety of guanylyl cyclase to trigger the generation of intracytoplasmic cGMP and, through the activation of a series of kinases, induces smooth muscle relaxation and vasodilatation. At least three different forms of NOS have been characterized. Nitric oxide can be produced either constitutively or induced in a wide variety of cell types (e.g., endothelial cells, neurons, macrophages). In addition to its activity as a vasodilator, NO plays important roles in the inhibition of smooth muscle proliferation and in inflammation. For instance, NO can react with reactive oxygen intermediates to form both reactive oxygen and nitrogen species (e.g., NO +
® N
+ H
), it can inhibit DNA synthesis, it can directly kill microbes and tumor cells, and it can inactivate cytosolic glutathione and a number of sulfhydryl enzymes. In vivo studies have confirmed that inhibition of NO synthesis with antagonistic L-arginine analogs can reduce tissue injury in models of inflammation.42,43
The activation of neutrophils, monocytes, and macrophages results in the release, either through exocytosis or as the result of cell death, of a wide variety of proinflammatory mediators that have important roles in the inflammatory response.44 Neutrophils contain two major types of granules (see Chap. 64, Chap. 65, and Chap. 67). Large, primary (azurophilic) granules contain lysozyme, a variety of cationic proteins, myeloperoxidase, defensins, phospholipase, acid hydrolases, and neutral proteases (e.g., proteinase 3, collagenases, elastase). Smaller, secondary (specific) granules contain lysozyme, lactoferrin, type IV collagenase, alkaline phosphatase, membrane-associated NADPH oxidase, and the b2 integrins. Acid proteases function most efficiently within phagolysosomes where the pH is low, while neutral proteases can function efficiently within extracellular inflammatory exudates. Lysosomal granule constituents contribute to the inflammatory response and tissue injury through a wide array of mechanisms (e.g., degradation of extracellular matrix, proteolytic generation of chemotactic peptide, catalysis of reactive oxygen metabolite generation).
Cytokines are relatively small (5–20kD) proteins that modulate the function of other cell types. A large number of cytokines and chemokines have been identified and characterized in recent years.45,46 and 47 In addition to their important roles in regulating various aspects of the immune response, many cytokines participate in inflammatory processes. Among the most thoroughly characterized cytokines are IL-1 and TNF-a. Interleukin 1 and TNF-a are structurally dissimilar but share many biologic activities and function as autocrine, paracrine, and endocrine mediators (Table 6-4).


IL-1 is a 17 kD protein that exhibits a wide variety of biological activities. Initially termed “endogenous pyrogen” due to its ability to induce temperature elevation and the acute-phase response, IL-1 is now known to be relevant to acute inflammation because of its ability to induce cytokine production in monocytes, macrophages, fibroblasts, and endothelial cells (TNF-a, IL-1, and IL-6). Interleukin-1 can also induce NOS. As noted in the section that describes endothelial-leukocyte adhesive interactions, IL-1 can activate endothelial cells, resulting in the expression of adhesion molecules.
Tumor necrosis factor-a (TNF-a), or cachectin, is also a 17 kD protein. Like IL-1, TNF-a can induce cytokine production in a variety of cells. TNF-a can induce neutrophil activation and the expression of adhesion molecules on endothelial cells. In contrast to IL-1, TNF-a possesses potent cytotoxic activities for certain types of cells. Both IL-1 and TNF-a are produced in response to endotoxemia and both can initiate a systemic shock-like response.
Chemokines, or “intercrines,” are cytokines which exhibit prominent chemotactic activities.48,49,50 and 51 The two major subfamilies include the alpha, or “-C-X-C-,” chemokines and the beta, or “C-C,” chemokines. “C-X-C” chemokines are so-designated because the first two N-terminal cystine residues are separated by a single amino acid. Alpha chemokines, of which IL-8 is the prototype, consistently exhibit neutrophil chemotactic activity, while the beta, or “-C-C,” chemokines, of which monocyte chemoattractant protein-1 (MCP-1) is the prototype, exhibit monocyte chemotactic activity (Table 6-5). Chemokines activate leukocytes through membrane receptors (serpentines) which contain seven transmembrane domains and are linked to cytosolic surface G proteins.52


Arachidonic acid is a 20-carbon polyunsaturated fatty acid (5, 8, 11, 14-eicosatetraenoic acid) derived either from dietary sources or by conversion from linoleic acid. Arachidonic acid is maintained in cell membranes as an esterified phospholipid. The two families of inflammatory mediators derived from arachidonic acid are generated via the cyclooxygenase and lipoxygenase pathways (resulting in the appearance of prostaglandins and leukotrienes, respectively).53 Cell activation or mechanical stress can result in the release of arachidonic acid. Activation of the cyclooxygenase family of phospholipases results in prostaglandins synthesis. Members of this group of mediators exhibit several proinflammatory activities which include vasodilatation, vasoconstriction, increases in permeability, and platelet activation (aggregation). Activation of the lipoxygenase pathway results in the synthesis of 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is a potent chemoattractant of neutrophils and is further modified to yield a series of leukotrienes. Leukotriene B4 (LTB4) induces neutrophil chemotaxis, aggregation, degranulation, and adherence, while LTC4, LTD4, and LTE4 trigger smooth muscle constriction and increases in vascular permeability. Members of both of these families of lipid-derived mediators have been detected in inflammatory exudates. Nonsteroidal anti-inflammatory agents and aspirin, which inhibit cyclooxygenase, emphasize the importance of these mediators in the development of an acute inflammatory response.
Platelet-activating factor (PAF) is a potent proinflammatory lipid produced by a variety of cell types including neutrophils, monocytes, endothelial cells, and IgE-sensitized basophils.54 Derived from the cell membrane constituent, choline phosphoglyceride, PAF is an acetyl glycerol ether phosphocholine which is synthesized following the activation of phospholipase A2. PAF triggers platelet aggregation and degranulation, increases vascular permeability, and promotes leukocyte accumulation and activation. In vivo studies using specific PAF antagonists have suggested a role for PAF in ischemia-reperfusion of the heart and gut and in immune complex–mediated injury in the skin, lung, and kidney.54 In addition, a PAF-like lipid has been measured in the blood of patients with angioedema and cold urticaria.
The kinin system is activated by contact activation of clotting factor XII (Hageman factor) (see Chap. 112).55 Activation of the kinin system results in the generation of the vasoactive nine amino acid peptide, bradykinin. Bradykinin possesses several activities, including the capacity to increase vascular permeability, to induce smooth muscle contraction, to trigger vasodilation, and to cause pain.55 Activated Hageman factor (factor XIIa), also known as the prekallikrein activator, converts plasma prekallikrein to kallikrein. Kallikrein cleaves high-molecular-weight kininogen to produce bradykinin. Models of septic shock have revealed decreases in plasma kininogen that parallel decreases in peripheral arterial resistance.55 The presence of plasma kininases precludes the routine measurement of bradykinin by functional or immunochemical approaches.
Histamine and serotonin (5-hydroxytryptamine) are low molecular weight vasoactive amines. Histamine is contained in mast cell and basophil granules while platelets are the chief source of serotonin.56 Localized release of histamine results in wheal formation due to increases in vascular permeability. Histamine induces the formation of reversible openings in endothelial tight junctions, triggers the formation of prostacyclin in endothelium, and induces NO release from the endothelium. In addition, histamine, like thrombin, can induce the rapid upregulation of endothelial P-selectin.57 Serotonin, which acts through receptors on vascular smooth muscle cells, is responsible for vasoconstriction, whereas interaction with endothelial receptors results in vasodilation (via release of NO) and increased permeability. Release of histamine and serotonin from mast cells and platelets can be triggered by IgE-mediated type I hypersensitivity reactions, directly by C3a or C5a, and directly by neutrophil granule-derived cationic proteins.
The complement system, including its soluble and cell membrane–associated regulators, consists of nearly two dozen plasma proteins that give rise to mediators of chemotaxis, increased vascular permeability, opsonic activity, phagocytic activation, and cytolysis.58 In a manner analogous to coagulation, the complement system is activated through a cascade of proteolytic cleavage reactions. There are two convergent pathways (Figure 6-2). The first of these, the classical pathway, is initiated by complement-fixing immune complexes (IgG and IgM), while the second, the alternative pathway, is triggered by a variety of substances that include IgA aggregates, endotoxin, cobra venom factor, and the polysaccharide components of some bacterial and fungal cell walls. The classical pathway is initiated by the fixation of C1 (C1qr2s2) by the Fc portion of surface-bound IgG or IgM immunoglobulins. Activated C1 (C1qr2s2) cleaves C2 and C4 which leads to the formation of “classical pathway” C3 convertase, C4b2a. Activation of the alternative pathway results in the formation of an “alternative pathway” C3 convertase following direct cleavage of C3 and subsequent interactions of C3b with factors B and D in the presence of Mg2+. The resulting complex, C3bBb is stabilized by properdin, leading to a stable C3 convertase, C3bBbP. C3 convertases generated via either pathway can cleave C3 to form C3a and C3b. C3b can bind to either the classical or alternative pathway C3 convertase to form a C5 convertase, which cleaves C5 into C5a and C5b. C5a is released into the fluid phase, like C3a, whereas C5b combines first with C6 and then C7 to form C5b-7 which in turn binds with C8 and multiple C9 molecules to form C5b-9, the membrane attack complex. In addition to the cell-activating and cytolytic activities of C5b-9, individual complement cleavage products and complexes have a wide variety of specific and potent proinflammatory activities.58 These various functions, combined with the rapid amplification in numbers of complement-derived mediators, emphasize the vital role of complement in acute inflammation. The most important activation products of complement appear to be the major chemotactic factor, C5a, and the anaphylatoxins (C3a, C4a, C5a), of which C3a is the most abundant. C5b-9 appears to be a major cytotoxic product, provided that this complex is assembled on the surface of a susceptible cell (e.g., bacterium). A series of soluble and cell membrane–associated complement proteins play important roles in the regulation of the complement cascade.58

FIGURE 6-2 The complement system. The complement system consists of a series of soluble and surface-associated mediators which are functionally organized into the classical and alternative pathways. The classical and alternative pathways of complement converge and lead to the production of the pore-forming membrane attack complex. The classical pathway is most often activated by IgG- and IgM-containing immune complexes while the alternative pathway can be activated by a variety of particulates. In both cases, complex multicomponent enzyme complexes called C3 and C5 convertases are formed. A variety of proinflammatory peptide fragments (e.g., C3a, C5a) are generated as a result of complement activation.

The coagulation system, its disorders, and the clinical management of its disorders, are reviewed in detail in Chap. 112, Chap. 113, Chap. 114, Chap. 115, Chap. 116, Chap. 117, Chap. 118, Chap. 119, Chap. 120, Chap. 121, Chap. 122, Chap. 123, Chap. 124, Chap. 125, Chap. 126, Chap. 127, Chap. 128, Chap. 129, Chap. 130, Chap. 131, Chap. 132, Chap. 133 and Chap. 134. Activation of the clotting cascade results in the generation of fibrinopeptides which increase vascular permeability and are chemotactic for leukocytes. Thrombin has been shown to induce endothelial expression of P-selectin, resulting in increased neutrophil adhesion.59 In addition, plasmin is responsible for the activation of Hageman factor, which then can activate the kinin system, and can cleave C3 into its active components; it can also generate fibrin-split products. The induction of procoagulant activity in endothelial cells exposed to TNF-a and IL-1 further links the coagulation system to the inflammatory response.60
The chronic inflammatory response and repair processes are, like the acute inflammatory response, highly regulated. Chronic inflammation is characterized by the recruitment of lymphocytes, monocytes, and plasma cells as well as by the proliferation of new capillaries (angiogenesis) and increases in the deposition of extracellular matrix molecules.1,2 and 3 The recruitment of this wide variety of cell types is achieved by a complex interaction among cytokines, chemokines, and indigenous cells. Great advances in understanding of angiogenesis and extracellular matrix molecule metabolism have been made in recent years. The characteristics of individual chronic inflammatory responses are dependent upon the location of the injury and the type of injurious agent. For instance, lymphocyte- and monocyte-binding interactions with endothelial cells are mediated by selectins, b1 and b2 integrins, and both ICAM and VCAM-1. Bacterium-derived chemotactic peptides play a role in monocyte recruitment, and members of the b chemokine subfamily induce monocyte and lymphocyte recruitment. These several factors have been observed to play a key role in the development of some models of chronic inflammation (Table 6-5).
The proliferation of fibroblasts and the induction of angiogenesis that accompany chronic inflammation are mediated by a variety of cytokines and growth factors derived from platelets, macrophages, and lymphocytes. For instance, fibroblast chemotaxis has been observed in response to a variety of mediators including TNF-a, C5a, collagen fragments, and growth factors (e.g., transforming growth factor-b, platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor).1,2 and 3 Chronic inflammatory responses can persist for lengthy periods of time and are less stereotypic than acute responses.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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