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280 Part IV: Molecular and Cellular Hematology Chapter 19: The Inflammatory Response 281

caseating granulomas in tuberculosis, eosinophil-rich infiltrates in a vasodilation follows a rapid and transient period of vasoconstriction.
2,3
parasitic infection and plasma cell-rich infiltrates in viral hepatitis). Arteriolar vasodilation results in increased blood flow, thus explaining
Superimposed upon acute and chronic inflammatory responses the familiar redness and warmth that characterize a site of acute inflam-
2,5
is repair. Resolution or termination of the inflammatory response is mation. The increase in blood flow, coupled with increases in microvas-
an important step in the pathway to repair; it occurs through a com- cular permeability, results in hemoconcentration and increased local
5
plex set of regulated processes. Repair, which may entail the regener- viscosity. These hemodynamic changes are critical to subsequent
ation of parenchymal cells damaged as the result of an insult per se or leukocyte emigration because selectin-mediated low-affinity rolling
as “bystanders” to the inflammatory response, is characterized by the leukocyte–endothelial adhesive interactions occur only under such
growth of new capillaries (angiogenesis) and the activation of fibrob- conditions of low shear force. Experimental studies using in vitro flow
lasts which produce extracellular matrix molecules (e.g., scar tissue). chambers and transparent vital membrane preparations in live animals
In some circumstances an inflammatory response is self-limited (e.g., indicate that selectin-mediated leukocyte–endothelial rolling adhesive
sunburn), whereas in other situations the response may persist for many interactions cannot occur in the face of the shear forces that exist under
years (e.g., tuberculous granulomas). The elimination or persistence of conditions of normal blood flow velocity. Increased microvascular
an insult has a major influence on outcome–whether ongoing chronic permeability leads initially to protein-poor transudation followed by
inflammation, complete regeneration or scar formation. There is great protein-rich plasma exudation, another characteristic of acute inflam-
complexity in terms of the networks of proinflammatory and antiin- mation. Microvascular leakage occurs through a variety of temporally
2
flammatory soluble mediators (e.g., cytokines) and the phenotypes, as regulated mechanisms, including rapid, reversible, and short-lived ven-
well as the functional and regulatory roles of both indigenous cells and ular endothelial cell contraction attended by widening of intercellular
recruited inflammatory cells in inflammation, resolution and repair. 2,3,5–7 junctions; so-called endothelial cell retraction, which is less-well under-
This chapter first addresses acute inflammation, which encom- stood but involves long-lived cytokine-mediated cytoskeletal changes;
passes localized changes in blood flow, alterations in microvascular direct endothelial injury and disruption by physical trauma; leukocyte-
permeability and neutrophil exudation. In addition to hemodynamic mediated endothelial cell injury; and leakage via new capillaries that do
2,3
2
changes, inflammation encompasses endothelial cell activation, low- not yet possess completely “closed” intercellular junctions. Increases in
affinity leukocyte–endothelial adhesion, high-affinity or stationary rate of transcytosis by which plasma constituents cross endothelial cells
leukocyte–endothelial adhesive interactions, leukocyte emigration, leu- in vesicles or vacuoles (vesiculovacuolar organelles) occur in neoplastic
2,8
kocyte activation, and the subsequent dampening and resolution of the blood vessels and may play a role in inflammation. Alterations in local
inflammatory response. The highly regulated migration of leukocytes from blood flow occur at the level of arterioles, the key to vascular resistance
the vasculature into sites of inflammation and of lymphocytes through sec- and regulated largely by the autonomic nervous system, nitric oxide
ondary lymphoid tissues and, in turn, into sites of microbial invasion, are (NO) (formerly called endothelium-derived relaxing factor), vasoactive
pivotal to host defense in the contexts of inflammation and immunity. 2,3,6 peptides, and eicosanoids. A variety of soluble mediators can induce
This extraordinary complexity of regulatory processes that control inflam- increases in microvascular permeability through several of the above-
mation is exemplified by, but not limited to, proinflammatory cytokines (e.g., mentioned mechanisms.
tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6) that drive inflam-
mation, countered by rises in antiinflammatory cytokines (e.g., IL-4, IL-10, LEUKOCYTES
IL-11, IL-13, transforming growth factor [TGF]-β, IL-1ra and soluble cytok- The recruitment of leukocytes into a site of inflammation is a funda-
ine receptors) that dampen inflammatory responses (see “Cytokines and mental characteristic of the inflammatory response. 2,3,9 The orches-
Chemolines”). Both the termination of an inflammatory process and the trated recruitment of particular types of leukocytes into specific tissues,
2,7
transition from an active inflammatory milieu to a wound-healing, tissue- whether sites of acute inflammation, in the course of physiologic lym-
remodeling environment are actively regulated processes. The concept of phocyte recirculation through lymph nodes or in the cellular immune
“active” termination of the inflammatory response, including the roles of response to microbial invasion, is referred to as homing. The general
3
chemokine depletion, neutrophil apoptosis, resolvins and protectins, and mechanisms of leukocyte homing are similar, but the leukocytes and
the shift from interferon (IFN)-γ–driven “classical M1” macrophages to particular mediator molecules vary. For example, neutrophils bind and
IL-4/IL-13–driven “alternative M2” macrophages, is introduced at the end traverse postcapillary venules in acute inflammation, naïve T lympho-
of the first section of this chapter (M1 and M2 Macrophages). The section cytes bind and traverse lymph node high-endothelial venules (HEVs)
“Regulators of the Inflammatory Response” of this chapter introduces (and in lymphocyte recirculation, and effector and memory T lymphocytes
where appropriate, reiterates) the vast array of soluble and surface-active bind and traverse postcapillary endothelial cells in sites of chronic infec-
mediators that regulate both acute and chronic inflammatory responses, as tion. The importance of white blood cells in host defense is highlighted
3
well as some aspects of resolution. These mediators include substances that in patients with either numerical leukocyte deficiencies or functional
range from short-lived reactive oxygen and nitrogen intermediates to entire defects. Leukocytes are critical because of their central role in the phago-
regulatory systems (e.g., complement and coagulation). Many mediators of cytosis and killing or containment of microbes and in the digestion of
inflammation have become targets for therapeutic interruption strategies. necrotic tissue debris. Leukocyte-derived products, such as proteolytic
See section “Chronic Inflammation and Repair.” This chapter provides a enzymes and reactive oxygen intermediates, contribute to tissue injury.
framework for understanding the basic processes of inflammation while
promoting an appreciation for the highly complex and integrated nature of Leukocyte Adhesion and Transmigration
the regulated inflammatory response. Vascular stasis that results from the hemodynamic changes of early
acute inflammation leads to displacement of leukocytes from the central
ACUTE INFLAMMATION axial column of circulating blood cells to positions along the endothe-
lial surface. This process, margination, is enhanced under conditions
HEMODYNAMIC CHANGES of slow blood flow. Leukocytes adhere transiently and weakly to the
2,3
The hemodynamic changes that occur early in acute inflammation endothelial surface. Vital membrane preparations and flow chamber
include arteriolar vasodilatation and localized increases in microvas- studies using endothelial cell monolayers and suspensions of puri-
cular permeability (Fig. 19–1). In many circumstances, arteriolar fied leukocytes have revealed that cells “tumble and roll” along the

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