General Features of Inflammation

Changes in Vascular Flow and Caliber

Increased Vascular Permeability (Vascular Leakage)

The milky white fluid shown here in the peritoneal cavity represents a chylous ascites. This is an uncommon fluid accumulation that can be due to blockage of lymphatic drainage, in this case by a malignant lymphoma involving the mesentery and retroperitoneum.

Release of Leukocyte Products and Leukocyte-Induced Tissue Injury

During activation and phagocytosis, leukocytes release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances ieutrophils and macrophages are lysosomal enzymes, present in the granules; reactive oxygen intermediates; and products of arachidonic acid metabolism, including prostaglandins and leukotrienes. These products are capable of causing endothelial injury and tissue damage and may thus amplify the effects of the initial injurious agent. Products of monocytes/macrophages and other leukocyte types have additional potentially harmful products, which are described in the discussion of chronic inflammation. Thus, if persistent and unchecked, the leukocyte infiltrate itself becomes the offender, and leukocyte-dependent tissue injury underlies many acute and chronic human diseases. This fact becomes evident in the discussion of specific disorders throughout this book.

Regulated secretion of lysosomal proteins is a peculiarity of leukocytes and other hematopoietic cells. (Recall that in most secretory cells, the proteins that are secreted are not stored within lysosomes.) The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by diverse mechanisms. Release may occur if the phagocytic vacuole remains transiently open to the outside before complete closure of the phagolysosome (regurgitation during feeding). If cells are exposed to potentially ingestible materials, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), attachment of leukocytes to the immune complexes triggers leukocyte activation, but the fixed immune complexes cannot be phagocytosed, and lysosomal enzymes are released into the medium (frustrated phagocytosis). Cytotoxic release occurs after phagocytosis of potentially membranolytic substances, such as urate crystals, which damage the membrane of the phagolysosome. In addition, there is some evidence that proteins in certain granules, particularly the specific (secondary) granules of neutrophils, may be directly secreted by exocytosis.

After phagocytosis, neutrophils rapidly undergo apoptotic cell death and are ingested by macrophages.

Defects in Leukocyte Function

Clinical Examples of Leukocyte-Induced Injury

Acute

Chronic

Acute respiratory distress syndrome

Arthritis

Acute transplant rejection

Asthma

Asthma

Atherosclerosis

Glomerulonephritis

Chronic lung disease

Reperfusion injury

Chronic rejection

Septic shock

Vasculitis

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From the preceding discussion, it is obvious that leukocytes play a central role in host defense. Not surprisingly, therefore, defects in leukocyte function, both genetic and acquired, lead to increased vulnerability to infection. Impairments of virtually every phase of leukocyte function-from adherence to vascular endothelium to microbicidal activity-have been identified, and the existence of clinical genetic deficiencies in each of the critical steps in the process has been described. These include the following:

• Defects in leukocyte adhesion. We previously mentioned the genetic deficiencies in leukocyte adhesion molecules (LAD types 1 and 2). LAD 1 is characterized by recurrent bacterial infections and impaired wound healing. LAD 2 is clinically milder than LAD 1 but is also characterized by recurrent bacterial infections.

• Defects in phagolysosome function. One such disorder is Chédiak-Higashi syndrome, an autosomal recessive condition characterized by neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing. The neutrophils (and other leukocytes) have giant granules, which can be readily seen in peripheral blood smears and which are thought to result from aberrant organelle fusion. In this syndrome, there is reduced transfer of lysosomal enzymes to phagocytic vacuoles in phagocytes (causing susceptibility to infections) and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (generating bleeding disorders). The gene associated with this disorder encodes a large cytosolic protein that is apparently involved in vesicular traffic but whose precise function is not yet known. The secretion of granule proteins by cytotoxic T cells is also affected, accounting for part of the immunodeficiency seen in the disorder.

• Defects in microbicidal activity. The importance of oxygen-dependent bactericidal mechanisms is shown by the existence of a group of congenital disorders with defects in bacterial killing called chronic granulomatous disease, which render patients susceptible to recurrent bacterial infection. Chronic granulomatous disease results from inherited defects in the genes encoding several components of NADPH oxidase, which generates superoxide. The most common variants are an X-linked defect in one of the plasma membrane-bound components (gp91phox) and autosomal recessive defects in the genes encoding two of the cytoplasmic components (p47phox and p67phox).

• Clinically, the most frequent cause of leukocyte defects is bone marrow suppression, leading to reduced production of leukocytes. This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is compromised by tumor metastases to bone.

 Defects in Leukocyte Functions

Disease

Defect

Genetic

Leukocyte adhesion deficiency 1

β chain of CD11/CD18 integrins

Leukocyte adhesion deficiency 2

Fucosyl transferase required for synthesis of sialylated oligosaccharide (receptor for selectin)

Chronic granulomatous disease

Decreased oxidative burst

X-linked

NADPH oxidase (membrane component)

Autosomal recessive

NADPH oxidase (cytoplasmic components)

Myeloperoxidase deficiency

Absent MPO-H₂O₂ system

Chédiak-Higashi syndrome

Protein involved in organelle membrane docking and fusion

Acquired

Thermal injury, diabetes, malignancy, sepsis, immunodeficiencies

Chemotaxis

Hemodialysis, diabetes mellitus

Adhesion

Leukemia, anemia, sepsis, diabetes, neonates, malnutrition

Phagocytosis and microbicidal activity

Although we have emphasized the role of leukocytes recruited from the circulation in the acute inflammatory response, cells resident in tissues also serve important functions in initiating acute inflammation. The two most important of these cell types are mast cells and tissue macrophages. Mast cells react to physical trauma, breakdown products of complement, microbial products, and neuropeptides. The cells release histamine, leukotrienes, enzymes, and many cytokines (including TNF, IL-1, and chemokines), all of which contribute to inflammation. Macrophages recognize microbial products and secrete most of the cytokines important in acute inflammation. These cells are stationed in tissues to rapidly recognize potentially injurious stimuli and initiate the host defense reaction.

TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE

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It is predictable that such a powerful system of host defense, with its inherent capacity to cause tissue damage, needs tight controls to minimize the damage. In part, inflammation declines simply because the mediators of inflammation have short half-lives, are degraded after their release, and are produced in quick bursts, only as long as the stimulus persists. In addition as inflammation develops, the process also triggers a variety of stop signals that serve to actively terminate the reaction. These active mechanisms include a switch in the production of pro-inflammatory leukotrienes to anti-inflammatory lipoxins from arachidonic acid (described below); the liberation of an anti-inflammatory cytokine, transforming growth factor-β (TGF-β), from macrophages and other cells; and neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages. There are, in addition, many other controls whose existence is suspected from the phenotypes of mice in which genes encoding putative regulatory molecules have been knocked out-these mice develop uncontrolled inflammation, but precisely how the regulation works normally is not yet defined. Not surprisingly, there is great interest in defining the molecular basis of the brakes on inflammation, since this knowledge could be used to design powerful anti-inflammatory drugs.

Chemical Mediators of Inflammation

Having described the events in acute inflammation, we caow turn to a discussion of the chemical mediators that are responsible for the events. Many mediators have been identified, and how they function in a coordinated manner is still not fully understood. Here we review general principles and highlight some of the major mediators.

• Mediators originate either from plasma or from cells. Plasma-derived mediators (e.g., complement proteins, kinins) are present in plasma in precursor forms that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. Cell-derived mediators are normally sequestered in intracellular granules that need to be secreted (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins, cytokines) in response to a stimulus. The major cellular sources are platelets, neutrophils, monocytes/macrophages, and mast cells, but mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can also be induced to elaborate some of the mediators.

• The production of active mediators is triggered by microbial products or by host proteins, such as the proteins of the complement, kinin, and coagulation systems, that are themselves activated by microbes and damaged tissues.

• Most mediators perform their biologic activity by initially binding to specific receptors on target cells. Some, however, have direct enzymatic activity (e.g., lysosomal proteases) or mediate oxidative damage (e.g., reactive oxygen and nitrogen intermediates).

• One mediator can stimulate the release of other mediators by target cells themselves. These secondary mediators may be identical or similar to the initial mediators but may also have opposing activities. They provide mechanisms for amplifying-or in certain instances counteracting-the initial mediator action.

• Mediators can act on one or few target cell types, have diverse targets, or may even have differing effects on different types of cells.

• Once activated and released from the cell, most of these mediators are short-lived. They quickly decay (e.g., arachidonic acid metabolites) or are inactivated by enzymes (e.g., kininase inactivates bradykinin), or they are otherwise scavenged (e.g., antioxidants scavenge toxic oxygen metabolites) or inhibited (e.g., complement regulatory proteins break up and degrade activated complement components). There is thus a system of checks and balances in the regulation of mediator actions.

• Most mediators have the potential to cause harmful effects.

We now discuss some of the more important mediators of acute inflammation.

Extensive acute inflammation may lead to abscess formation, as seen here with rounded abscesses (the purulent material has drained out after sectioning to leave a cavity) in upper lobe and lower lobe.

VASOACTIVE AMINES

The two amines, histamine and serotonin, are especially important because they are present in preformed stores in cells and are therefore among the first mediators to be released during inflammation.

Histamine

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Histamine is widely distributed in tissues, the richest source being the mast cells that are normally present in the connective tissue adjacent to blood vessels It is also found in blood basophils and platelets. Preformed histamine is present in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli: (1) physical injury such as trauma, cold, or heat; (2) immune reactions involving binding of antibodies to mast cells  (3) fragments of complement called anaphylatoxins (C3a and C5a); (4) histamine-releasing proteins derived from leukocytes; (5) neuropeptides (e.g., substance P); and (6) cytokines (IL-1, IL-8).

In humans, histamine causes dilation of the arterioles and increases the permeability of venules (it, however, constricts large arteries). It is considered to be the principal mediator of the immediate transient phase of increased vascular permeability, causing venular gaps, as we have seen. It acts on the microcirculation mainly via binding to H₁ receptors on endothelial cells.

Serotonin

Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator with actions similar to those of histamine. It is present in platelets and enterochromaffin cells, and in mast cells in rodents but not humans.

Release of serotonin (and histamine) from platelets is stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate (ADP), and antigen-antibody complexes. Platelet aggregation and release are also stimulated by platelet activating factors (PAF) derived from mast cells during IgE-mediated reactions. In this way, the platelet release reaction results in increased permeability during immunologic reactions. As discussed later, PAF itself has many inflammatory properties.

PLASMA PROTEINS

A variety of phenomena in the inflammatory response are mediated by plasma proteins that belong to three interrelated systems, the complement, kinin, and clotting systems.

Complement System

The complement system consists of 20 component proteins (and their cleavage products), which are found in greatest concentration in plasma. This system functions in both innate and adaptive immunity for defense against microbial agents. In the process of complement activation, a number of complement components are elaborated that cause increased vascular permeability, chemotaxis, and opsonization.

Complement proteins are present as inactive forms in plasma and are numbered C1 through C9. Many of these proteins are activated to become proteolytic enzymes that degrade other complement proteins, thus forming a cascade capable of tremendous enzymatic amplification. The critical step in the elaboration of the biologic functions of complement is the activation of the third (and most abundant) component, C3. Cleavage of C3 can occur by one of three pathways: the classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) combined with antigen; the alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, cobra venom, and other substances, in the absence of antibody; and the lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1. Whichever pathway is involved in the early steps of complement activation, they all lead to the formation of an active enzyme called the C3 convertase, which splits C3 into two functionally distinct fragments, C3a and C3b. C3a is released and C3b becomes covalently attached to the cell or molecule where complement is being activated. C3b then binds to the previously generated fragments to form C5 convertase, which cleaves C5 to release C5a. The remaining C5b binds the late components (C6-C9), culminating in the formation of the membrane attack complex (MAC, composed of multiple C9 molecules).

The biologic functions of the complement system fall into two general categories: cell lysis by the MAC, and the effects of proteolytic fragments of complement. Complement-derived factors mediate a variety of phenomena in acute inflammation:

• Vascular phenomena. C3a, C5a, and, to a lesser extent, C4a are split products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis C5a also activates the lipoxygenase pathway of arachidonic acid (AA) metabolism ieutrophils and monocytes, causing further release of inflammatory mediators.

• Leukocyte adhesion, chemotaxis, and activation. C5a is a powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils.

• Phagocytosis. C3b and its cleavage product iC3b (inactive C3b), when fixed to the bacterial cell wall, act as opsonins and favor phagocytosis by neutrophils and macrophages, which bear cell surface receptors for these complement fragments.

Among the complement components, C3 and C5 are the most important inflammatory mediators. In addition to the mechanisms already discussed, C3 and C5 can be activated by several proteolytic enzymes present within the inflammatory exudate. These include plasmin and lysosomal enzymes released from neutrophils (discussed later in this chapter). Thus, the chemotactic effect of complement and the complement-activating effects of neutrophils can set up a self-perpetuating cycle of neutrophil emigration.

The activation of complement is tightly controlled by cell-associated and circulating regulatory proteins.The presence of these inhibitors in host cell membranes protects the host from inappropriate damage during protective reactions against microbes.

Kinin System

The kinin system generates vasoactive peptides from plasma proteins, called kininogens, by the action of specific proteases called kallikreins.^47,48 Activation of the kinin system results in the release of the vasoactive nonapeptide bradykinin. Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. It is triggered by activation of Hageman factor (factor XII of the intrinsic clotting pathway; see later) upon contact with negatively charged surfaces, such as collagen and basement membranes. A fragment of factor XII (prekallikrein activator, or factor XIIa) is produced, and this converts plasma prekallikrein into an active proteolytic form, the enzyme kallikrein. The latter cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin. High-molecular-weight kininogen also acts as a cofactor or catalyst in the activation of Hageman factor. The action of bradykinin is short-lived because it is quickly inactivated by an enzyme called kininase. Any remaining kinin is inactivated during passage of plasma through the lung by angiotensin-converting enzyme. Kallikrein itself is a potent activator of Hageman factor, allowing for autocatalytic amplification of the initial stimulus. Kallikrein has chemotactic activity, and it also directly converts C5 to the chemoattractant product C5a.

Clotting System

The clotting system and inflammation are intimately connected processes. The clotting system is divided into two pathways that converge, culminating in the activation of thrombin and the formation of fibrin .The intrinsic clotting pathway is a series of plasma proteins that can be activated by Hageman factor (factor XII), a protein synthesized by the liver that circulates in an inactive form until it encounters collagen or basement membrane or activated platelets (as occurs at the site of endothelial injury). Factor XII then undergoes a conformational change (becoming factor XIIa), exposing an active serine center that can subsequently cleave protein substrates and activate a variety of mediator systems (see later).

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The Complement System in Health and Disease

The activation of the complement cascade may be divided into early and late steps. In the early steps, three different pathways lead to the proteolytic cleavage of C3. In the late steps, all three pathways converge, and the major breakdown product of C3, C3b, activates a series of other complement components.

The Early Steps of Complement Activation

The pathways of early complement activation are the following (see Figure): The classical pathway is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen, and proteolysis of C2 and C4, and subsequent formation of a C4b2b complex that functions as a C3 convertase. The alternative pathway can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, and cobra venom. It involves a distinct set of plasma components (properdin, and factors B and D). In this pathway, the spontaneous cleavage of C3 that occurs normally is enhanced and stabilized by a complex of C3b and a breakdown product of Factor B called Bb; the C3bBb complex is a C3 convertase. In the lectin pathway, mannose-binding lectin, a plasma collectin, binds to carbohydrate-containing proteins on bacteria and viruses and directly activates C1; the remaining steps are as in the classical pathway. The C3 convertases break down C3 into C3b, which remains attached to the surface where complement is activated, and a smaller C3a fragment that diffuses away.

The Late Steps of Complement Activation

The C3b that is generated by any of the pathways binds to the C3 convertase and produces a C5 convertase, which cleaves C5. C5b remains attached to the complex and forms a substrate for the subsequent binding of the C6-C9 components. Polymerized C9 forms a channel in lipid membranes, called the membrane attack complex, which allows fluid and ions to enter and causes cell lysis.

Collection of fluid in a space is a transudate. If this fluid is protein-rich or has many cells then it becomes an exudate. The large amount of fibrin in such fluid can form a fibrinous exudate on body cavity surfaces. Here, the pericardial cavity has been opened to reveal a fibrinous pericarditis with strands of stringy pale fibrin between visceral and parietal pericardium.

Regulation of Complement Activation

To prevent inappropriate activation of complement and to limit its activation even when appropriate, mammals express many regulatory proteins. (These proteins are generally absent from microbes, which explains why complement is activated by and functions against microbes.) Complement activation can be controlled at several steps:

• Regulation of C3 and C5 convertases. Since the formation of C3 convertase and the generation of C3b are the central features of all complement pathways, it is not surprising that many of the regulatory proteins are directed at controlling these activities. These regulators function by enhancing the dissociation (decay acceleration) of the convertase complex (e.g., decay-accelerating factor [DAF]) or by proteolytically cleaving C3b (e.g., factor I).

• Binding of active complement components by specific proteins in the plasma. The first step in the classical pathway, which is triggered by C1 binding to an immune complex, is blocked by a plasma protein called C1 inhibitor (C1INH). C1INH interferes with the enzymatic activity of two of the proteins in the C1 complex. Excessive complement activation is also prevented by a number of proteins that act to inhibit MAC formation (e.g., CD59, also called membrane inhibitor of reactive lysis).

Disorders of the Complement System

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Defects in complement proteins may result in increased susceptibility to infections, or to pathologic activation if the deficiencies affect regulatory proteins. Inherited deficiencies of many complement proteins have been described in humans. Deficiency of C3 results in increased susceptibility to infections that is fatal unless treated. Deficiencies of the alternative pathway proteins are also associated with defective resistance to infections. Paradoxically, deficiencies of C2 and C4 are associated with autoimmune diseases, notably systemic lupus erythematosus, probably because of a failure to clear immune complexes that are formed. Deficiencies of the late components of complement result in defective formation of the MAC. For unknown reasons, the only infections these patients appear to suffer from are by Neisseria organisms.

Genetic deficiencies of complement regulatory proteins are also the cause of significant diseases. For example, paroxysmal nocturnal hemoglobinuria is a disease caused by mutations in the gene encoding the enzyme required to synthesize phosphatidylinositol linkages for membrane proteins. As a result, cells show defective expression of phosphatidylinositol-linked membrane proteins, including DAF and CD59, and the result is uncontrolled complement activation on these cells. Paroxysmal nocturnal hemoglobinuria is characterized by recurrent bouts of intravascular hemolysis resulting from complement-mediated lysis of red blood cells, leading to chronic hemolytic anemia. Deficiency of C1 inhibitor (C1INH) is associated with the syndrome of hereditary angioneurotic edema, characterized by episodic edema accumulation in the skin and extremities as well as in the laryngeal and intestinal mucosa, provoked by emotional stress or trauma. In patients with this disorder, activation of C1 by immune complexes is not properly controlled, and increased breakdown of C4 and C2 occurs. The mediators of edema formation in patients with the disease include a proteolytic fragment of C2, called C2 kinin, and bradykinin. C1INH is an inhibitor of other plasma serine proteases besides C1, including kallikrein and coagulation factor XII, and both activated kallikrein and factor XII can promote increased formation of bradykinin.

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The protease thrombin provides the main link between the coagulation system and inflammation. Activation of the clotting system results in the activation of thrombin (factor IIa) from precursor prothrombin (factor II),. Thrombin is the enzyme that cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot and is the major coagulation protease. It binds to receptors that are called protease-activated receptors (PARs) because they bind multiple trypsin-like serine proteases in addition to thrombin. These receptors are seven-transmembrane G protein-coupled receptors that are expressed on platelets, endothelial and smooth muscle cells, and many other cell types. Engagement of the so-called type 1 receptor (PAR-1) by proteases, particularly thrombin, triggers several responses that induce inflammation. They include mobilization of P-selectin, production of chemokines, and expression of endothelial adhesion molecules for leukocyte integrins; induction of cyclooxygenase-2 and production of prostaglandins; production of PAF and nitric oxide; and changes in endothelial shape. As we have seen, these responses promote the recruitment of leukocytes and many other reactions of inflammation.

At the same time that factor XIIa is inducing clotting, it can also activate the fibrinolytic system. This cascade counterbalances clotting by cleaving fibrin, thereby solubilizing the fibrin clot. The fibrinolytic system contributes to the vascular phenomena of inflammation in several ways. Plasminogen activator (released from endothelium, leukocytes, and other tissues) cleaves plasminogen, a plasma protein that binds to the evolving fibrin clot to generate plasmin, a multifunctional protease. Plasmin is important in lysing fibrin clots, but in the context of inflammation it also cleaves C3 to produce C3 fragments, and it degrades fibrin to form fibrin split products, which may have permeability-inducing properties. Plasmin can also activate Hageman factor, which can trigger multiple cascades, amplifying the response.

From this discussion of the plasma proteases activated by the kinin, complement, and clotting systems, a few general conclusions can be drawn:

• Bradykinin, C3a, and C5a (as mediators of increased vascular permeability); C5a (as the mediator of chemotaxis); and thrombin (which has effects on endothelial and many other cell types) are likely to be the most important in vivo.

• C3a and C5a can be generated by several types of reactions: (1) immunologic reactions, involving antibodies and complement (the classical pathway); (2) activation of the alternative or lectin complement pathways by microbes, in the absence of antibodies; and (3) agents not directly related to immune responses, such as plasmin, kallikrein, and some serine proteases found iormal tissue.

• Activated Hageman factor (factor XIIa) initiates four systems involved in the inflammatory response: (1) the kinin system, which produces vasoactive kinins; (2) the clotting system, which induces formation of thrombin, fibrinopeptides, and factor X, which have inflammatory properties; (3) the fibrinolytic system, which produces plasmin and degrades the fibrin; and (4) the complement system, which produces anaphylatoxins. Some of the products of this initiation-particularly kallikrein-can, by feedback, activate Hageman factor, resulting in profound amplification of the effects of the initial contact.

It should be evident from the preceding that coagulation and inflammation are tightly linked. Acute inflammation, by activating or damaging the endothelium, can trigger coagulation and induce thrombus formation . Conversely, the coagulation cascade induces inflammation, primarily via the actions of thrombin.

ARACHIDONIC ACID METABOLITES: PROSTAGLANDINS, LEUKOTRIENES, AND LIPOXINS

When cells are activated by diverse stimuli, their membrane lipids are rapidly remodeled to generate biologically active lipid mediators that serve as intracellular or extracellular signals to affect a variety of biologic processes, including inflammation and hemostasis. These lipid mediators are thought of as autocoids, or short-range hormones that are formed rapidly, exert their effects locally, and then either decay spontaneously or are destroyed enzymatically.

Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. It does not occur free in the cell but is normally esterified in membrane phospholipids. It is released from membrane phospholipids through the action of cellular phospholipases (e.g., phospholipase A₂), which may be activated by mechanical, chemical, and physical stimuli or by other mediators (e.g., C5a). The biochemical signals involved in the activation of phospholipase A₂ include an increase in cytoplasmic Ca²⁺ and activation of various kinases in response to external stimuli. AA metabolites, also called eicosanoids, are synthesized by two major classes of enzymes: cyclooxygenases (prostaglandins and thromboxanes) and lipoxygenases (leukotrienes and lipoxins) . Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation. They can be found in inflammatory exudates, and their synthesis is increased at sites of inflammation. Structurally distinct agents that suppress cyclooxygenase activity (aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], and COX-2 inhibitors) reduce inflammation in vivo.

 Inflammatory Actions of Eicosanoids

Action

Metabolite

Vasoconstriction

Thromboxane A₂, leukotrienes C₄, D₄, E₄

Vasodilation

PGI₂, PGE₁, PGE₂, PGD₂

Increased vascular permeability

Leukotrienes C₄, D₄, E₄

Chemotaxis, leukocyte adhesion

Leukotriene B₄, HETE, lipoxins

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The cyclooxygenases and lipoxygenase produce different mediators from the AA precursor.

• The cyclooxgenase pathway, initiated by two different enzymes (the constitutively expressed COX-1 and the inducible enzyme COX-2), leads to the generation of prostaglandins. Prostaglandins are divided into series based on structural features as coded by a letter (PGD, PGE, PGF, PGG, and PGH) and a subscript numeral (e.g., 1, 2), which indicates the number of double bonds in the compound. The most important ones in inflammation are PGE₂, PGD₂, PGF_2α, PGI₂ (prostacyclin), and TxA₂ (thromboxane), each of which is derived by the action of a specific enzyme on an intermediate in the pathway. Some of these enzymes have restricted tissue distribution. For example, platelets contain the enzyme thromboxane synthetase, and hence TxA₂ is the major product in these cells. TxA₂, a potent platelet-aggregating agent and vasoconstrictor, is itself unstable and rapidly converted to its inactive form TxB₂. Vascular endothelium lacks thromboxane synthetase but possesses prostacyclin synthetase, which leads to the formation of prostacyclin (PGI₂) and its stable end product PGF_1α. Prostacyclin is a vasodilator, a potent inhibitor of platelet aggregation, and also markedly potentiates the permeability-increasing and chemotactic effects of other mediators. A thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels. The prostaglandins are also involved in the pathogenesis of pain and fever in inflammation. PGE₂ is hyperalgesic in that it makes the skin hypersensitive to painful stimuli. It causes a marked increase in pain produced by intradermal injection of suboptimal concentrations of histamine and bradykinin and is involved in cytokine-induced fever during infections (described later). PGD₂ is the major metabolite of the cyclooxygenase pathway in mast cells; along with PGE₂ and PGF_2α (which are more widely distributed), it causes vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation.
  There has been great interest in the COX-2 enzyme because it is induced by a variety of inflammatory stimuli and is absent in most tissues under normal “resting” conditions. COX-1, by contrast, is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues. This difference has led to the notion that COX-1 is responsible for the production of prostaglandins that are involved in inflammation but also serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX-2 stimulates the production of the prostaglandins that are involved in inflammatory reactions.

• In the lipoxygenase pathway, the initial products are generated by three different lipoxygenases, which are present in only a few types of cells. 5-lipoxygenase (5-LO) is the predominant enzyme ieutrophils. The main product, 5-HETE, which is chemotactic for neutrophils, is converted into a family of compounds collectively called leukotrienes. LTB₄ is a potent chemotactic agent and activator of neutrophil functional responses, such as aggregation and adhesion of leukocytes to venular endothelium, generation of oxygen free radicals, and release of lysosomal enzymes. The cysteinyl-containing leukotrienes C₄, D₄, and E₄ (LTC₄, LTD₄, and LTE₄) cause intense vasoconstriction, bronchospasm, and increased vascular permeability. The vascular leakage, as with histamine, is restricted to venules. Leukotrienes are several orders of magnitude more potent than histamine in increasing vascular permeability and causing bronchospasm. Leukotrienes mediate their actions by binding to cysteiny leukotreine 1 (CysLT1) and CysLT2 receptors. They are important in the pathogenesis of bronchial asthma.

• Lipoxins are a recent addition to the family of bioactive products generated from AA, and transcellular biosynthetic mechanisms (involving two cell populations) are key to their production. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes. Lipoxins A₄ and B₄ (LXA₄, LXB₄) are generated by the action of platelet 12-lipoxygenase on neutrophil-derived LTA₄. Cell-cell contact enhances transcellular metabolism, and blocking adhesion inhibits lipoxin production. The principal actions of lipoxins are to inhibit leukocyte recruitment and the cellular components of inflammation. They inhibit neutrophil chemotaxis and adhesion to endothelium. There is an inverse relationship between the amount of lipoxin and leukotrienes formed, suggesting that the lipoxins may be endogenous negative regulators of leukotriene action and may thus play a role in the resolution of inflammation.

• A new class of arachidonic acid-derived mediators, called resolvins, have been identified in experimental animals treated with aspirin. These mediators inhibit leukocyte recruitment and activation, in part by inhibiting the production of cytokines. Thus, the anti-inflammatory activity of aspirin is likely attributable to its ability to inhibit cyclooxygenases (see below) and, perhaps, to stimulate the production of resolvins.

• 

Microscopically, the fibrinous exudate is seen to consist of pink strands of fibrin jutting from the pericardial surface at the upper left. Below this, there are a few scattered inflammatory cells.

Anti-inflammatory therapy can be directed at many targets along the eicosanoid biosynthetic pathways:

• Cyclooxygenase inhibitors include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin. They function by inhibiting prostaglandin synthesis; aspirin does this by irreversibly acetylating and inhibiting cyclooxygenase. COX-2 inhibitors are a newer class of these drugs. The finding that COX-2 is inducibly expressed only in response to inflammatory stimuli was the impetus for developing antagonists against this enzyme to reduce inflammation without interfering with the physiologic functions of AA metabolites. COX-2 inhibitors are now widely used as anti-inflammatory drugs and generally produce less toxicity than the older COX-1 inhibitors.

• Lipoxygenase inhibitors. 5-lipoxygenase is not affected by NSAIDs, and many new inhibitors of this enzyme pathway have been developed. Pharmacologic agents that inhibit leukotriene production or block leukotriene receptors (CysLT1 and CysLT2) have been found useful in the treatment of asthma.

• Broad-spectrum inhibitors include glucocorticoids. These powerful anti-inflammatory agents may act by down-regulating the expression of specific target genes, including the genes encoding COX-2, phospholipase A₂, proinflammatory cytokines (such as IL-1 and TNF), and nitric oxide synthase (iNOS) (see later). Glucocorticoids also up-regulate genes that encode potent anti-inflammatory proteins, such as lipocortin 1. Lipocortin 1 inhibits release of AA from membrane phospholipids.

• Another approach to manipulating inflammatory responses has been to modify the intake and content of dietary lipids by increasing the consumption of fish oil. The basis for this approach is that fish oil fatty acids serve as poor substrates for conversion to active metabolites by both the cyclooxygenase and the lipoxygenase pathways.

PLATELET-ACTIVATING FACTOR (PAF)

PAF is another bioactive phospholipid-derived mediator.  Its name comes from its initial discovery as a factor derived from antigen-stimulated, IgE-sensitized basophils that causes platelet aggregation, but it is now known to have multiple inflammatory effects. Chemically, PAF is acetyl-glyceryl-ether-phosphorylcholine (AGEPC), a phospholipid with a typical glycerol backbone, a long-chain fatty acid in the A position, an unusually short chain substituent in the B location, and a phosphatidylcholine moiety.

PAF mediates its effects via a single G-protein-coupled receptor, and its effects are regulated by a family of inactivating PAF acetylhydrolases. A variety of cell types, including platelets, basophils (and mast cells), neutrophils, monocytes/macrophages, and endothelial cells, can elaborate PAF, in both secreted and cell-bound forms. In addition to platelet stimulation, PAF causes vasoconstriction and bronchoconstriction, and at extremely low concentrations it induces vasodilation and increased venular permeability with a potency 100 to 10,000 times greater than that of histamine. PAF also causes increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding), chemotaxis, degranulation, and the oxidative burst. Thus, PAF can elicit most of the cardinal features of inflammation. PAF also boosts the synthesis of other mediators, particularly eicosanoids, by leukocytes and other cells. A role for PAF in vivo is supported by the ability of synthetic PAF receptor antagonists to inhibit inflammation in some experimental models. There are as yet no drugs approved for clinical use that function as specific PAF antagonists.

CYTOKINES AND CHEMOKINES

Cytokines are proteins produced by many cell types (principally activated lymphocytes and macrophages, but also endothelium, epithelium, and connective tissue cells) that modulate the functions of other cell types. Long known to be involved in cellular immune responses, these products have additional effects that play important roles in both acute and chronic inflammation. Here we review the properties of cytokines that are involved in acute inflammation.

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Tumor Necrosis Factor and Interleukin-1

TNF and IL-1 are two of the major cytokines that mediate inflammation. They are produced mainly by activated macrophages. A cytokine resembling TNF, called lymphotoxin (previously called TNF-β, to distinguish it from TNF, which was called TNF-α), is produced by activated T lymphocytes, and IL-1 may be produced by many other cell types as well. The secretion of TNF and IL-1 can be stimulated by endotoxin and other microbial products, immune complexes, physical injury, and a variety of inflammatory stimuli. Their most important actions in inflammation are their effects on endothelium, leukocytes, and fibroblasts, and induction of systemic acute-phase reactions. In endothelium, they induce a spectrum of changes-mostly regulated at the level of gene transcription-referred to as endothelial activation. In particular, they induce the synthesis of endothelial adhesion molecules and chemical mediators, including other cytokines, chemokines, growth factors, eicosanoids, and nitric oxide (NO); production of enzymes associated with matrix remodeling; and increases in the surface thrombogenicity of the endothelium TNF also induces priming of neutrophils, leading to augmented responses of these cells to other mediators.

IL-1 and TNF (as well as IL-6) induce the systemic acute-phase responses associated with infection or injury. Features of these systemic responses include fever, loss of appetite, slow-wave sleep, the release of neutrophils into the circulation, the release of corticotropin and corticosteroids and, particularly with regard to TNF, the hemodynamic effects of septic shock-hypotension, decreased vascular resistance, increased heart rate, and decreased blood pH . TNF also regulates body mass by promoting lipid and protein mobilization and by suppressing appetite. Sustained production of TNF contributes to cachexia, a pathologic state characterized by weight loss and anorexia that accompanies some infections and neoplastic diseases.

Chemokines

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Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. About 40 different chemokines and 20 different receptors for chemokines have been identified. They are classified into four major groups, according to the arrangement of the conserved cysteine (C) residues in the mature proteins:

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

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

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

• CX₃C chemokines contain three amino acids between the two cysteines. The only known member of this class is called fractalkine. This chemokine exists in two forms: the cell surface-bound protein can be induced on endothelial cells by inflammatory cytokines and promotes strong adhesion of monocytes and T cells, and a soluble form, derived by proteolysis of the membrane-bound protein, has potent chemoattractant activity for the same cells.

Chemokines mediate their activities by binding to seven transmembrane G-protein-coupled receptors. These receptors (called CXCR or CCR, for C-X-C or C-C chemokine receptors) usually exhibit overlapping ligand specificities, and leukocytes generally express more than one receptor type. certain chemokine receptors (CXCR-4, CCR-5) act as coreceptors for a viral envelope glycoprotein of human immunodeficiency virus (HIV-1) and are thus involved in binding and entry of the virus into cells.

Chemokines stimulate leukocyte recruitment in inflammation and control the normal migration of cells through various tissues. Some chemokines are produced transiently in response to inflammatory stimuli and promote the recruitment of leukocytes to the sites of inflammation. Other chemokines are produced constitutively in tissues and function in organogenesis to organize different cell types in different anatomic regions of the tissues. In both situations, chemokines may be displayed at high concentrations attached to proteoglycans on the surface of endothelial cells and in the extracellular matrix.

NITRIC OXIDE (NO)

NO, a pleiotropic mediator of inflammation, was discovered as a factor released from endothelial cells that caused vasodilation by relaxing vascular smooth muscle and was therefore called endothelium-derived relaxing factor. NO is a soluble gas that is produced not only by endothelial cells, but also by macrophages and some neurons in the brain. NO acts in a paracrine manner on target cells through induction of cyclic guanosine monophosphate (GMP), which, in turn, initiates a series of intracellular events leading to a response, such as the relaxation of vascular smooth muscle cells. Since the in vivo half-life of NO is only seconds, the gas acts only on cells in close proximity to where it is produced.

NO is synthesized from l-arginine by the enzyme nitric oxide synthase (NOS). There are three different types of NOS-endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) (-which exhibit two patterns of expression. eNOS and nNOS are constitutively expressed at low levels and can be activated rapidly by an increase in cytoplasmic calcium ions. Influx of calcium into cells leads to a rapid production of NO. iNOS, in contrast, is induced when macrophages and other cells are activated by cytokines (e.g., TNF, IFN-γ) or other agents.

NO plays an important role in the vascular and cellular components of inflammatory responses. NO is a potent vasodilator by virtue of its actions on vascular smooth muscle. In addition, NO reduces platelet aggregation and adhesion inhibits several features of mast cell-induced inflammation, and serves as an endogenous regulator of leukocyte recruitment. Blocking NO production under normal conditions promotes leukocyte rolling and adhesion in postcapillary venules, and delivery of exogenous NO reduces leukocyte recruitment. Thus, production of NO is an endogenous compensatory mechanism that reduces inflammatory responses Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes, and hypertension .

NO and its derivatives are microbicidal, and thus NO is also a mediator of host defense against infection. Evidence supporting the importance of this antimicrobial activity of NO includes the following: (1) reactive nitrogen intermediates derived from NO possess antimicrobial activity; (2) interactions occur between NO and reactive oxygen intermediates, leading to the formation of multiple antimicrobial metabolites; (3) production of NO is increased during host responses to infection; and (4) genetic inactivation of iNOS enhances microbial replication in experimental animal models. High levels of NO production by a variety of cells appear to limit the replication of bacteria, helminths, protozoa, and viruses (as well as tumor cells).

LYSOSOMAL CONSTITUENTS OF LEUKOCYTES

Neutrophils and monocytes contain lysosomal granules, which, when released, may contribute to the inflammatory response. Neutrophils have two main types of granules). The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. The large azurophil (or primary) granules contain myeloperoxidase, bactericidal factors (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Both types of granules can empty into phagocytic vacuoles that form around engulfed material, or the granule contents can be released into the extracellular space. The specific granules are secreted extracellularly more readily and by lower concentrations of agonists, whereas the potentially more destructive azurophil granules release their contents primarily within the phagosome and require high levels of agonists to be released extracellularly.

Different granule enzymes serve different functions. Acid proteases degrade bacteria and debris within the phagolysosomes, in which an acid pH is readily reached. Neutral proteases are capable of degrading various extracellular components. These enzymes can attack collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes. Neutral proteases can also cleave C3 and C5 directly, releasing anaphylatoxins, and release a kinin-like peptide from kininogen. Neutrophil elastase has been shown to degrade virulence factors of bacteria and thus combat bacterial infections.⁶⁹ Monocytes and macrophages also contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator. These may be particularly active in chronic inflammatory reactions.

Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further increases in vascular permeability and tissue damage. These harmful proteases, however, are held in check by a system of antiproteases in the serum and tissue fluids. Foremost among these is α₁-antitrypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α₁-antitrypsin deficiency . Macroglobulin is another antiprotease found in serum and various secretions.

OXYGEN-DERIVED FREE RADICALS

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Oxygen-derived free radicals may be released extracellularly from leukocytes after exposure to microbes, chemokines, and immune complexes, or following a phagocytic challenge. Their production is dependent, as we have seen, on the activation of the NADPH oxidative system. Superoxide anion , hydrogen peroxide (H₂O₂), and hydroxyl radical (OH) are the major species produced within the cell, and these metabolites can combine with NO to form other reactive nitrogen intermediates. Extracellular release of low levels of these potent mediators can increase the expression of chemokines (e.g., IL-8), cytokines, and endothelial leukocyte adhesion molecules, amplifying the cascade that elicits the inflammatory response. As mentioned earlier, the physiologic function of these reactive oxygen intermediates is to destroy phagocytosed microbes. At higher levels, release of these potent mediators can be damaging to the host. They are implicated in the following responses:

• Endothelial cell damage, with resultant increased vascular permeability. Adherent neutrophils, when activated, not only produce their own toxic species, but also stimulate xanthine oxidation in endothelial cells themselves, thus elaborating more superoxide.

• Inactivation of antiproteases, such as α₁-antitrypsin. This leads to unopposed protease activity, with increased destruction of extracellular matrix.

• Injury to other cell types (parenchymal cells, red blood cells).

NEUROPEPTIDES

Neuropeptides, similar to the vasoactive amines and the eicosanoids previously discussed, play a role in the initiation and propagation of an inflammatory response. The small peptides, such as substance P and neurokinin A, belong to a family of tachykinin neuropeptides produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of secretion by endocrine cells, and increasing vascular permeability. Sensory neurons appear to produce other pro-inflammatory molecules, which are thought to link the sensing of dangerous stimuli to the development of protective host responses.

OTHER MEDIATORS

The mediators described above account for inflammatory reactions to microbes, toxins, and many types of injury, but may not explain why inflammation develops in some specific situations. Recent studies are providing clues about the mechanisms of inflammation in two frequently encountered pathologic conditions.

• Response to hypoxia Hypoxia by itself is also an inducer of the inflammatory response. This response is mediated largely by a protein called hypoxia-induced factor 1α, which is produced by cells deprived of oxygen and activates many genes involved in inflammation, including VEGF, which increases vascular permeability.

• Response to necrotic cells. Although it has been known for many years that necrotic cells elicit inflammatory reactions that serve to eliminate these cells, the molecular basis of this reaction has been largely unknown. One participant may be uric acid, which is a product of DNA breakdown, and crystallizes when present at sufficiently high concentrations in extracellular tissues. Uric acid crystals stimulate inflammation and subsequent immune response. This pro-inflammatory action of uric acid is the basis of the disease gout, in which excessive amounts of uric acid are produced and crystals deposit in joints and other tissues.

SUMMARY OF CHEMICAL MEDIATORS OF ACUTE INFLAMMATION

Summary of Mediators of Acute Inflammation

Action

Mediator

Source

Vascular Leakage

Chemotaxis Other

Histamine and serotonin

Mast cells, platelets

+

–

Bradykinin

Plasma substrate

+

–

Pain

C3a

Plasma protein via liver

+

–

Opsonic fragment (C3b)

C5a

Macrophages

+

+

Leukocyte adhesion, activation

Prostaglandins

Mast cells, from membrane phospholipids

Potentiate other mediators

–

Vasodilation, pain, fever

Leukotriene B₄

Leukocytes

–

+

Leukocyte adhesion, activation

Leukotriene C₄, D₄, E₄

Leukocytes, mast cells

+

–

Bronchoconstriction, vasoconstriction

Oxygen metabolites

Leukocytes

+

–

Endothelial damage, tissue damage

PAF

Leukocytes, mast cells

+

+

Bronchoconstriction, leukocyte priming

IL-1 and TNF

Macrophages, other

–

+

Acute-phase reactions, endothelial activation

Chemokines

Leukocytes, others

–

+

Leukocyte activation

Nitric oxide

Macrophages, endothelium

+

+

Vasodilation, cytotoxicity

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Outcomes of Acute Inflammation

 Role of Mediators in Different Reactions of Inflammation

Vasodilation

Prostaglandins

Nitric oxide

Histamine

Increased vascular permeability

Vasoactive amines

C3a and C5a (through liberating amines)

Bradykinin

Leukotrienes C₄, D₄, E₄

PAF

Substance P

Chemotaxis, leukocyte recruitment and activation

C5a

Leukotriene B₄

Chemokines

IL-1, TNF

Bacterial products

Fever

IL-1, TNF

Prostaglandins

Pain

Prostaglandins

Bradykinin

Tissue damage

Neutrophil and macrophage lysosomal enzymes

Oxygen metabolites

Nitric oxide

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The discussion of mediators completes the description of the basic, relatively uniform pattern of the inflammatory reaction encountered in most injuries. Although hemodynamic, permeability, and leukocyte changes have been described sequentially and may be initiated in this order, all these phenomena may be concurrent in the fully evolved reaction to injury. As might be expected, many variables may modify this basic process, including the nature and intensity of the injury, the site and tissue affected, and the responsiveness of the host. In general, however, acute inflammation may have one of three outcomes:

1.     Complete resolution. In a perfect world, all inflammatory reactions, once they have succeeded ieutralizing and eliminating the injurious stimulus, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves neutralization or spontaneous decay of the chemical mediators, with subsequent return of normal vascular permeability, cessation of leukocytic infiltration, death (largely by apoptosis) of neutrophils, and finally removal of edema fluid and protein, leukocytes, foreign agents, and necrotic debris from the site Healing by connective tissue replacement (fibrosis). This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation. When the fibrinous exudate in tissue or serous cavities (pleura, peritoneum) cannot be adequately cleared, connective tissue grows into the area of exudate, converting it into a mass of fibrous tissue-a process also called organization. In many pyogenic infections there may be intense neutrophil infiltration and liquefaction of tissues, leading to pus formation. The destroyed tissue is resorbed and eventually replaced by fibrosis.

2.     Progression of the tissue response to chronic inflammation (discussed below). This may follow acute inflammation, or the response may be chronic almost from the onset. Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, owing either to the persistence of the injurious agent or to some interference with the normal process of healing. For example, bacterial infection of the lung may begin as a focus of acute inflammation (pneumonia), but its failure to resolve may lead to extensive tissue destruction and formation of a cavity in which the inflammation continues to smolder, leading eventually to a chronic lung abscess. Another example of chronic inflammation with a persisting stimulus is peptic ulcer of the duodenum or stomach. Peptic ulcers may persist for months or years and, as discussed below, are manifested by both acute and chronic inflammatory reactions.

Morphologic Patterns of Acute Inflammation

Although all acute inflammatory reactions are characterized by vascular changes and leukocyte infiltration, the severity of the reaction, its specific cause, and the particular tissue and site involved introduce morphologic variations in the basic patterns. Several types of inflammation are recognized, which vary in their morphology and clinical correlates.

SEROUS INFLAMMATION

Serous inflammation is marked by the outpouring of a thin fluid that, depending on the size of injury, is derived from either the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities (called effusion). The skin blister resulting from a burn or viral infection represents a large accumulation of serous fluid, either within or immediately beneath the epidermis of the skin.

FIBRINOUS INFLAMMATION

With more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate develops when the vascular leaks are large enough or there is a procoagulant stimulus in the interstitium (e.g., cancer cells). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium and pleura. Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Fibrinous exudates may be removed by fibrinolysis and clearing of other debris by macrophages. As mentioned above, the process of resolution may restore normal tissue structure, but when the fibrin is not removed, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac leads either to opaque fibrous thickening of the pericardium and epicardium in the area of exudation or, more often, to the development of fibrous strands that reduce and may even obliterate the pericardial space.

Here is a purulent exudate in which the exuded fluid also contains a large number of acute inflammatory cells. Thus, the yellowish fluid in this opened pericardial cavity is a purulent exudate.

SUPPURATIVE OR PURULENT INFLAMMATION

Suppurative or purulent inflammation is characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid. Certain bacteria (e.g., staphylococci) produce this localized suppuration and are therefore referred to as pyogenic (pus-producing) bacteria. A common example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by deep seeding of pyogenic bacteria into a tissue . Abscesses have a central region that appears as a mass of necrotic leukocytes and tissue cells. There is usually a zone of preserved neutrophils around this necrotic focus, and outside this region vascular dilation and parenchymal and fibroblastic proliferation occur, indicating the beginning of repair. In time, the abscess may become walled off and ultimately replaced by connective tissue.

A purulent exudate is seen beneath the meninges in the brain of this patient with acute meningitis from Streptococcus pneumoniae infection. The exudate obscures the sulci.

The abdominal cavity is opened at autopsy here to reveal an extensive purulent peritonitis that resulted from rupture of the colon. A thick yellow exudate coats the peritoneal surfaces. A paracentesis yielded fluid with the properties of an exudate: high protein content with many cells (mostly PMN’s).

ULCERS

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in: (1) inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract; and (2) subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances that predispose to extensive necrosis.

Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist. During the acute stage, there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. With chronicity, the margins and base of the ulcer develop fibroblastic proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells.

Summary of Acute Inflammation

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Now that we have described the components, mediators, and pathologic manifestations of acute inflammatory responses, it is useful to summarize the sequence of events in a typical response of this type. When a host encounters an injurious agent, such as an infectious microbe or dead cells, phagocytes that reside in all tissues try to get rid of these agents. At the same time, phagocytes and other host cells react to the presence of the foreign or abnormal substance by liberating cytokines, lipid messengers, and the various other mediators of inflammation. Some of these mediators act on endothelial cells in the vicinity and promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. The recruited leukocytes are activated by the injurious agent and by locally produced mediators, and the activated leukocytes try to remove the offending agent by phagocytosis. As the injurious agent is eliminated and anti-inflammatory mechanisms become active, the process subsides and the host returns to a normal state of health. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation.

The different components of the inflammatory response are mediated by different signals and serve distinct (and overlapping) functions. The vascular phenomena of acute inflammation are characterized by increased blood flow to the injured area, resulting mainly from arteriolar dilation and opening of capillary beds induced by mediators such as histamine. Increased vascular permeability results in the accumulation of protein-rich extravascular fluid, which forms the exudate. Plasma proteins leave the vessels, most commonly through widened interendothelial cell junctions of the venules. The redness (rubor), warmth (calor), and swelling (tumor) of acute inflammation are caused by the increased blood flow and edema. Circulating leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules, transmigrate across the endothelium, and migrate to the site of injury under the influence of chemotactic agents. Leukocytes that are activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage. During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor).

Chronic Inflammation

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Although difficult to define precisely, chronic inflammation is considered to be inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously. Although it may follow acute inflammation, as described earlier, chronic inflammation frequently begins insidiously, as a low-grade, smoldering, often asymptomatic response. This latter type of chronic inflammation is the cause of tissue damage in some of the most common and disabling human diseases, such as rheumatoid arthritis, atherosclerosis, tuberculosis, and chronic lung diseases.

The neutrophils are seen infiltrating the mucosa and submucosa of the gallbladder in this patient with acute cholecystitis and right upper quadrant abdominal pain with tenderness on palpation.

CAUSES OF CHRONIC INFLAMMATION

• At medium power magnification, numerous neutrophils fill the alveoli in this case of acute bronchopneumonia in a patient with a high fever. Pseudomonas aeruginosa was cultured from sputum. Note the dilated capillaries in the alveolar walls from vasodilation with the acute inflammatory process.

MORPHOLOGIC FEATURES

In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly neutrophilic infiltration, chronic inflammation is characterized by:

• Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells.

• Tissue destruction, induced by the persistent offending agent or by the inflammatory cells.

• Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis.

MONONUCLEAR CELL INFILTRATION

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The macrophage is the dominant cellular player in chronic inflammation, and we begin our discussion with a brief review of its biology. Macrophages are one component of the mononuclear phagocyte system). The mononuclear phagocyte system (sometimes called reticuloendothelial system) consists of closely related cells of bone marrow origin, including blood monocytes and tissue macrophages. The latter are diffusely scattered in the connective tissue or located in organs such as the liver (Kupffer cells), spleen and lymph nodes (sinus histiocytes), and lungs (alveolar macrophages). Mononuclear phagocytes arise from a common precursor in the bone marrow, which gives rise to blood monocytes. From the blood, monocytes migrate into various tissues and differentiate into macrophages. The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. The journey from bone marrow stem cell to tissue macrophage is regulated by a variety of growth and differentiation factors, cytokines, adhesion molecules, and cellular interactions.

As discussed previously, monocytes begin to emigrate into extravascular tissues quite early in acute inflammation, and within 48 hours they may constitute the predominant cell type. Extravasation of monocytes is governed by the same factors that are involved ieutrophil emigration, that is, adhesion molecules and chemical mediators with chemotactic and activating properties. When the monocyte reaches the extravascular tissue, it undergoes transformation into a larger phagocytic cell, the macrophage. Macrophages may be activated by a variety of stimuli, including cytokines (e.g., IFN-γ) secreted by sensitized T lymphocytes and by NK cells, bacterial endotoxins, and other chemical mediators (Activation results in increased cell size, increased levels of lysosomal enzymes, more active metabolism, and greater ability to phagocytose and kill ingested microbes. Activated macrophages secrete a wide variety of biologically active products that, if unchecked, result in the tissue injury and fibrosis characteristic of chronic inflammation (

In short-lived inflammation, if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way into the lymphatics and lymph nodes). In chronic inflammation, macrophage accumulation persists, and is mediated by different mechanisms 

1.     Recruitment of monocytes from the circulation, which results from the expression of adhesion molecules and chemotactic factors. Most of the macrophages present in a focus of chronic inflammation are recruited from circulating monocytes. The process of monocyte recruitment is fundamentally similar to the recruitment of neutrophils, described earlier Chemotactic stimuli for monocytes include chemokines produced by activated macrophages, lymphocytes, and other cell types (e.g., MCP-1); C5a; growth factors such as platelet-derived growth factor and transforming growth factor-α (TGF-α); fragments from the breakdown of collagen and fibronectin; and fibrinopeptides. Each of these may play a role under given circumstances; for example, chemokines are major stimuli for macrophage accumulation in delayed-hypersensitivity immune reactions.

2.     Local proliferation of macrophages after their emigration from the bloodstream. Once thought to be an unusual event, macrophage proliferation is now known to occur prominently in some chronic inflammatory lesions, such as atheromatous plaques

3.     Immobilization of macrophages within the site of inflammation. Certain cytokines and oxidized lipids  can cause such immobilization.

The products of activated macrophages serve to eliminate injurious agents such as microbes and to initiate the process of repair, and are responsible for much of the tissue injury in chronic inflammation. Some of these products are toxic to microbes and host cells (e.g., reactive oxygen and nitrogen intermediates) or extracellular matrix (proteases); some cause influx of other cell types (e.g., cytokines, chemotactic factors); and still others cause fibroblast proliferation, collagen deposition, and angiogenesis (e.g., growth factors). This impressive arsenal of mediators makes macrophages powerful allies in the body’s defense against unwanted invaders, but the same weaponry can also induce considerable tissue destruction when macrophages are inappropriately activated. Thus, tissue destruction is one of the hallmarks of chronic inflammation.

A variety of substances in addition to the products of macrophages may contribute to tissue damage in chronic inflammation. Necrotic tissue itself can perpetuate the inflammatory cascade through the activation of kinin, coagulation, complement and fibrinolytic systems, the release of mediators from leukocytes responding to the necrotic tissue, and liberation of substances like uric acid from dying cells. In cellular immune reactions, T lymphocytes may directly kill cells (see Chapter 6). Thus, ongoing tissue destruction can activate the inflammatory cascade by diverse mechanisms, so that features of both acute and chronic inflammation may coexist in certain circumstances.

OTHER CELLS IN CHRONIC INFLAMMATION

Other cell types present in chronic inflammation include lymphocytes, plasma cells, eosinophils, and mast cells:

• Lymphocytes are mobilized in both antibody-mediated and cell-mediated immune reactions and even ionimmune inflammation. Antigen-stimulated (effector and memory) lymphocytes of different types (T, B) use various adhesion molecule pairs (predominantly the integrins and their ligands) and chemokines to migrate into inflammatory sites. Cytokines from activated macrophages, mainly TNF, IL-1, and chemokines, promote leukocyte recruitment, setting the stage for persistence of the inflammatory response.

• Lymphocytes and macrophages interact in a bidirectional way, and these reactions play an important role in chronic inflammation . Macrophages display antigens to T cells, and produce membrane molecules (costimulators) and cytokines (notably IL-12) that stimulate T-cell responses. Activated T lymphocytes produce cytokines, and one of these, IFN-γ, is a major activator of macrophages. Plasma cells develop from activated B lymphocytes and produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components. In some strong chronic inflammatory reactions, the accumulation of lymphocytes, antigen-presenting cells, and plasma cells may assume the morphologic features of lymphoid organs, particularly lymph nodes, even containing well-formed germinal centers. This pattern of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis.

• Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections . The recruitment of eosinophils involves extravasation from the blood and their migration into tissue by processes similar to those for other leukocytes. One of the chemokines that is especially important for eosinophil recruitment is eotaxin. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells. They may thus be of benefit in controlling parasitic infections but they contribute to tissue damage in immune reactions 

• Mast cells are widely distributed in connective tissues and participate in both acute and persistent inflammatory reactions. Mast cells express on their surface the receptor that binds the Fc portion of IgE antibody (FcεRI). In acute reactions, IgE antibodies bound to the cells’ Fc receptors specifically recognize antigen, and the cells degranulate and release mediators, such as histamine and products of AA oxidation . This type of response occurs during anaphylactic reactions to foods, insect venom, or drugs, frequently with catastrophic results. When properly regulated, this response can benefit the host. Mast cells are also present in chronic inflammatory reactions, and may produce cytokines that contribute to fibrosis.

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

Much smaller abscesses are seen here. These could be termed “microabscesses” due to their small size. Abscesses can come in a variety of sizes. Perhaps the most common abscess is the pimple on the face of a teenager.

An abscess is a localized collection of PMN’s. Here is a microabscess in the myocardium. The irregular dark purple center is a collection of bacteria that are the cause for this abscess.

One consequence of acute inflammation is ulceration. This occurs on epithelial surfaces. Here the gastric mucosa has been lost, or ulcerated. A larger ulcer and several adjacent smaller ones with surrounding erythema appear at the left of center.

GRANULOMATOUS INFLAMMATION

Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelial-like (epithelioid) appearance. It is encountered in a limited number of immunologically mediated, infectious and some noninfectious conditions. Its genesis is firmly linked to immune reactions.. Tuberculosis is the prototype of the granulomatous diseases, but sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, leprosy, brucellosis, syphilis, some mycotic infections, berylliosis, and reactions of irritant lipids are also included . Recognition of the granulomatous pattern in a biopsy specimen is important because of the limited number of possible conditions that cause it and the significance of the diagnoses associated with the lesions.

Cellular interactions with chronic inflammation are diagrammed.

Chronic inflammation is more difficult to understand, because it is so variable. Seen here is chronic endometritis with lymphocytes as well as plasma cells in the endometrial stroma. In general, the inflammatory infiltrate of chronic inflammation consists mainly of mononuclear cells (“round cells”): lymphocytes, plasma cells, and macrophages.

Here is chronic cervicitis. Prolonged acute inflammation or repeated bouts of acute inflammation may lead to the appearance of more mononuclear cells, and chronic inflammation. In this case the inflammation is severe enough to produce mucosal damage with hemorrhage.

You can find both acute and chronic inflammation here. This type of mixed inflammation is typical of repeated or recurrent inflammation. Examples of this process include diagnoses such as “acute and chronic cholecystitis” or “acute and chronic cervicitis”.

Microscopically, this abscess has a mixture of inflammatory cells, but the wall of the abscess is “organizing” with ingrowth of capillaries (filled with red blood cells) and fibroblasts. As organization continues there is resolution with decreasing size of the abscess, until only a scar remains. If the body’s defensive systems cannot contain the agent causing the abscess, then the process may continue and even spread.

Examples of Diseases with Granulomatous Inflammations

Disease

Cause

Tissue Reaction

Tuberculosis

Mycobacterium tuberculosis

Noncaseating tubercle (granuloma prototype): a focus of epithelioid cells, rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cell; caseating tubercle: central amorphous granular debris, loss of all cellular detail; acid-fast bacilli

Leprosy

Mycobacterium leprae

Acid-fast bacilli in macrophages; non-caseating granulomas

Syphilis

Treponema pallidum

Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic without loss of cellular outline

Cat-scratch disease

Gram-negative bacillus

Rounded or stellate granuloma containing central granular debris and recognizable neutrophils; giant cells uncommon

A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. In the usual hematoxylin and eosin stained tissue sections, the epithelioid cells have a pale pink granular cytoplasm with indistinct cell boundaries, often appearing to merge into one another. The nucleus is less dense than that of a lymphocyte, is oval or elongate, and may show folding of the nuclear membrane. Older granulomas develop an enclosing rim of fibroblasts and connective tissue. Frequently, epithelioid cells fuse to form giant cells in the periphery or sometimes in the center of granulomas. These giant cells may attain diameters of 40 to 50 μm. They have a large mass of cytoplasm containing 20 or more small nuclei arranged either peripherally (Langhans-type giant cell) or haphazardly (foreign body-type giant cell) . There is no known functional difference between these two types of giant cells, a fact that does not deter students from remembering the morphologic differences!

There are two types of granulomas, which differ in their pathogenesis. Foreign body granulomas are incited by relatively inert foreign bodies. Typically, foreign body granulomas form when material such as talc (associated with intravenous drug abuse) sutures, or other fibers are large enough to preclude phagocytosis by a single macrophage and do not incite any specific inflammatory or immune response. Epithelioid cells and giant cells form and are apposed to the surface and encompass the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it appears refractile.

Immune granulomas are caused by insoluble particles, typically microbes, that are capable of inducing a cell-mediated immune response. This type of immune response does not necessarily produce granulomas but it does so when the inciting agent is poorly degradable or particulate. In these responses, macrophages engulf the foreign material and process and present some of it to appropriate T lymphocytes, causing them to become activated. The responding T cells produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which is important in activating macrophages and transforming them into epithelioid cells and multinucleate giant cells.

The prototype of the immune granuloma is that caused by the bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis . In contrast, caseous necrosis is rare in other granulomatous diseases. The morphologic patterns in the various granulomatous diseases may be sufficiently different to allow reasonably accurate diagnosis by an experienced pathologist; however, there are so many atypical presentations that it is always necessary to identify the specific etiologic agent by special stains for organisms (e.g., acid-fast stains for tubercle bacilli), by culture methods (e.g., in tuberculosis and fungal diseases), by molecular techniques (e.g., the polymerase chain reaction in tuberculosis), and by serologic studies (e.g., in syphilis). In sarcoidosis, the etiologic agent is unknown .

Resolution of inflammatory processes in body cavities may result in the formation of adhesions, which are thin bands of collagenous connective tissue, as seen here between the right lung and the chest wall at autopsy. Adhesions, if extensive can restrict motion or cause retraction to an abnormal position of internal organs.

Grossly, a granuloma tends to be a focal lesion. Seen here in a hilar lymph node is a granuloma. Granulomas due to infectious agents such as mycobacteria are often described as “caseating” when they have prominent caseous necrosis.

The focal nature of granulomatous inflammation is demonstrated in this microscopic section of lung in which there are scattered granulomas in the parenchyma. This is why the chest radiograph with tuberculosis or other granulomatous diseases is often described as “reticulonodular”. A biopsy could miss such lesions from sampling error, too.

Here are two pulmonary granulomas. Granulomatous inflammation typically consists of mixtures of cells including epithelioid macrophages, giant cells, lymphocytes, plasma cells, and fibroblasts. There may even be some neutrophils.

Giant cells are a “committee” of epithelioid macrophages. Seen here are two Langhans type giant cells in which the nuclei are lined up around the periphery of the cell. Additional pink epithelioid macrophages compose most of the rest of the granuloma.

This is a caseating granuloma. Epithelioid cells surround a central area of necrosis that appears irregular, amorphous, and pink. Grossly, areas of caseation appear cheese-like.

LYMPHATICS IN INFLAMMATION

The system of lymphatics and lymph nodes filters and polices the extravascular fluids. Together with the mononuclear phagocyte system, it represents a secondary line of defense that is called into play whenever a local inflammatory reaction fails to contain and neutralize an external agent, such as a microbe.

Lymphatics are delicate channels that are difficult to visualize in ordinary tissue sections because they readily collapse. They are lined by continuous, thin endothelium with loose, overlapping cell junctions; scant basement membrane; and no muscular support except in the larger ducts. In inflammation lymph flow is increased and helps drain the edema fluid from the extravascular space. Because the junctions of lymphatics are loose, lymphatic fluid eventually equilibrates with extravascular fluid. Not only fluid, but also leukocytes and cell debris may find their way into lymph. Valves are present in collecting lymphatics, allowing lymph content to flow only proximally. Delicate fibrils, attached at right angles to the walls of the lymphatic vessel, extend into the adjacent tissues and serve to maintain patency of the lymphatic channels.

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In severe injuries, the drainage may transport the offending agent, be it chemical or microbial. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis). Therefore, it is not uncommon in infections of the hand, for example, to observe red streaks along the entire arm up to the axilla following the course of the lymphatic channels, accompanied by painful enlargement of the axillary lymph nodes. The nodal enlargement is usually caused by hyperplasia of the lymphoid follicles as well as by hyperplasia of the phagocytic cells lining the sinuses of the lymph nodes. This constellation of nodal histologic changes is termed reactive, or inflammatory, lymphadenitis 

The system of lymph nodes sometimes contains the spread of the infection, but in severe infections the organisms gain access to the vascular circulation, thus inducing a bacteremia. The phagocytic cells of the liver, spleen, and bone marrow constitute the next line of defense, but in massive infections, bacteria seed distant tissues of the body. The heart valves, meninges, kidneys, and joints are favored sites of implantation for blood-borne organisms, and when this happens endocarditis, meningitis, renal abscesses, and septic arthritis may develop.

Consequences of Defective or Excessive Inflammation

Now that we have described the process of inflammation and its outcomes, it is helpful to summarize the clinical and pathological consequences of too much or too little inflammation.

• Defective inflammation typically results in increased susceptibility to infections and delayed healing of wounds and tissue damage. The susceptibility to infections reflects the fundamental role of the inflammatory response in host defense, and is the reason why this response is a central component of the defense mechanisms that immunologists call innate immunity . Delayed repair is because the inflammatory response is essential for clearing damaged tissues and debris, and provides the necessary stimulus to get the repair process started.

• Excessive inflammation is the basis of many categories of human disease. It is well established that allergies, in which individuals mount unregulated immune responses against commonly encountered environmental antigens, and autoimmune diseases, in which immune responses develop against normally tolerated self-antigens, are disorders in which the fundamental cause of tissue injury is inflammation. But recent studies are pointing to an important role of inflammation in a wide variety of human diseases that are not primarily disorders of the immune system. These include cancer, atherosclerosis and ischemic heart disease, and some neurodegenerative diseases such as Alzheimer disease. In addition, prolonged inflammation and the fibrosis that accompanies it are responsible for much of the pathology in many chronic infectious, metabolic and other diseases. The specific diseases are discussed in relevant chapters later in the book. Since these disorders are some of the major scourges of mankind, it is not surprising that the normally protective inflammatory response is being called the “silent killer”.