thrombophilic coagulation defects. Arterioscler Thromb Vasc Biol 1997;17:2924–2929.

194. Kottke-Marchant K. Genetic polymorphisms associated with venous and arterial thrombosis: an

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196. Schlesselman L. Novel risk factors for atherosclerotic disease. MedScape CME. 2001. Available from:

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197. Mandel H, Brenner B, Berant M, et al. Coexistence of hereditary homocystinuria and factor V

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198. Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of

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199. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996;98:5–7.

200. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by

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201. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired

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202. Upchurch GR, Welch GN, Randev V, et al. The effect of homocysteine on endothelial nitric oxide

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205. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease.

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206. Towne JB, Bandyk DF, Hussey CV, et al. Abnormal plasminogen: a genetically determined cause of

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207. Kwaan HC, Levin M, Sakurai S, et al. Digital ischemia and gangrene due to red blood cell

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210. Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired

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218. Marcucci R, Liotta AA, Cellai AP, et al. Increased plasma levels of lipoprotein(a) and the risk of

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219. Ignatescu M, Kostner K, Zorn G, et al. Plasma Lp(a) levels are increased in patients with chronic

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factor VIII: C levels and associated venous thrombosis. Thromb Haemost 1998;80:561–565.

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236. Larson PJ, High KA. Biology of inherited coagulopathies: factor IX. Hematol Oncol Clin North Am

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Chapter 7

Inflammation

Matthew R. Rosengart and Timothy R. Billiar

Key Points

1 Innate immunity, a system already poised to respond prior to any stimulus, provides the initial

defense against microbes. Subsequent reinforcement is provided by the more specific adaptive

immune system, which possesses exquisite specificity for subsequent exposure to individual microbes

and the capacity to learn and modify subsequent responses to repeated exposures. Both are

composed of cellular and humoral components.

2 Implicit with the capacity for pathogen elimination is the potential for destruction of host tissues.

Numerous regulatory mechanisms provide temporal and spatial control of the inflammatory

processes, including programmed cell death (i.e., apoptosis).

3 Over 30 randomized controlled clinical trials have been conducted to assess the efficacy of

modulating inflammation, in particular systemic cytokine concentrations, in reducing mortality.

4 The TH1 inflammatory response (i.e., cell-mediated immunity or delayed-type hypersensitivity) is

induced by interleukin-12 (IL-12) derived from phagocytes and provides one major arm of the

adaptive immune response; it is mediated by CD4+ and CD8+ lymphocytes and macrophages, which

regulate production of opsonizing and complement fixing antibodies and are effectors of phagocytedependent responses.

5 The principal stimulus for TH2 differentiation is IL-4, which is derived from T cells, mast cells, and

basophils. As the cellular effectors of humoral immunity, they provide the other major arm of the

adaptive immune response, which is mediated by TH2 CD4+ cells, B cells, plasma cells, and

antibodies.

6 The complement system is integral to both innate and adaptive immunity and has the capacity to

independently eliminate organisms and facilitate host defense by marking foreign particles for

phagocytosis through opsonization.

7 Additional systems, including the vascular (i.e., vasodilatation, adhesion receptors, kinin cascade)

and neuroendocrine (i.e., adrenocorticotropic hormone [ACTH], arginine vasopressin [AVP],

corticotropin-releasing hormone [CRH]), integrate with the immune system, sharing similar

mediators and their receptors, to orchestrate an intense, coordinated response to any injurious/septic

insult.

8 Danger-associated molecular patterns (DAMP) are the endogenous equivalent of PAMPS, represent

danger signals or “alarmins,” and share many characteristics similar to cytokines. They may be

released following nonprogrammed cell death, such as necrosis, or secreted as mediators by immune

cells, under which circumstance they may facilitate the inflammatory response.

9 Our immune system differentiates pathogens and damaged cells from self using evolutionarily

ancient sets of recognition molecules called pattern recognition receptors (PRR), which bind

conserved molecular structures found in large groups of pathogens, termed pathogen-associated

molecular patterns (PAMPs), an example being the toll-like receptors (TLR).

Our appreciation for the complexity and our understanding of the integrated mechanisms collectively

called “inflammation” has undergone considerable revision since the initial description of the four

cardinal signs and symptoms by Celsus in first century AD: “rubor et tumor cum calore et dolore,”

redness and swelling with heat and pain.1 Centuries lapsed before John Hunter postulated that

inflammation provides a survival mechanism to preserve the host. Ironically, he commented that an

exuberant inflammatory response could be deleterious. These are all too true, as the pathologic sequelae

of excessive inflammation (i.e., acute respiratory distress syndrome [ARDS], multiple organ dysfunction

syndrome [MODS]) are encountered ever more frequently as technology affords survival of the initial

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insult.1 The 19th century witnessed milestone contributions to our understanding of this process as

Rudolph Virchow detailed the cellular pathology of inflammation, Julius Cohnheim provided

microscopic details of the acute phases of inflammation (vasodilatation, edema formation, and

leukocyte emigration), and Elie Metchnikoff described the events of phagocytosis.1–3 The integration of

these new data created a novel new paradigm of cellular and humoral concepts of inflammation, both of

which were deemed critical in host defense against foreign pathogens.

In the 20th century, technological advancements in molecular biology and biochemistry facilitated

more detailed investigation and enabled the rapid expansion of knowledge of the many interwoven

facets of the inflammation process. Evidence began to accumulate that the ramifications of these

processes extended beyond the confines of the insult. Many humoral mediators, in addition to local

effects, influenced distant targets as well, such as the liver and neurohormonal centers. Recently it has

become clear that the immune system, endocrine system, and nervous system comprise an integrated

network sharing similar mediators and their receptors. Such an integrative view, introduced by J. Edwin

Blalock, when combined with Hans Selye’s concept of stress, led to the contemporary understanding of

sickness behavior, defined by Robert Dantzer as a highly organized strategy of the organism to fight

infections and to respond to other environmental stressors. Hence, what originated nearly two millennia

ago as a simple concept founded upon a constellation of signs and symptoms is now considered an

intense, coordinated interplay of the nervous, vascular, endocrine, and immune systems to any injurious

insult. It is the culmination of millions of years of evolution. Without it, life would be an arduous,

painful, and brief existence, at best.

This chapter attempts to summarize this enormous quantity of information. An initial description of

the elements involved in inflammation will provide the foundation upon which to discuss the sequence

of events and interactions that comprise the inflammatory cascade.

INNATE VERSUS ADAPTIVE IMMUNITY

1 Innate immunity, a system composed of both cellular and humoral components, already poised to

respond prior to any stimulus, provides our initial security against invading microbes.4 Phylogenetically

it is ancient and conserved, notably providing the primary mechanism of invertebrate host defense. The

response it provides is uniform and consistent with each successive infection. Subsequent reinforcement

is provided by the more specific and targeted efforts of the adaptive immune system. In contrast to

innate immunity, and as the name would suggest, it “adapts” and subsequent exposure to the inciting

elicits responses of increased magnitude and defensive capabilities during.4 This exquisite specificity for

individual microbes, the capacity to “learn,” “remember,” and modify subsequent responses to repeated

exposures, has provided the impetus for the name.

Both arms of immunity are composed of cellular and serum components. In the adaptive immune

response this has been divided into humoral immunity, which is mediated primarily by antibodies, and

cell-mediated immunity. These are not distinct systems and form an integrated system of host defense.

CELLULAR COMPONENTS

Neutrophils

Neutrophils are integral to both innate and humoral immunity, providing the initial defense against

invading viral, bacterial, and parasitic pathogens. This importance is underscored by the fact that 55%

to 60% of the hematopoietic output of bone marrow is dedicated to the production of neutrophils.5 On

exiting the marrow they circulate for 7 to 10 hours before taking up residence in the tissues for 1 to 2

days (Table 7-1).6,7 They are uniquely sensitive to minute concentration gradients of microbial products

and inflammatory mediators and rapidly accumulate at sites of infection, where they ingest and dispose

of a wide array of pathogens with their vast microbicidal armamentarium. This pathogenicity, however,

carries with it an implicit capacity for host injury and accordingly, neutrophil function must be tightly

regulated.

Recruitment

Neutrophil recruitment, conceptually, is a sequence of events progressing from (1) initial adhesion to

activated endothelium, to (2) subsequent extravasation and emigration toward inflammatory foci, to (3)

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the ultimate elimination of foreign microorganisms through phagocytosis, the generation of reactive

oxygen species (ROS), and the release of microbial substances.4

After injury, local and regional vasodilation induces hyperemia which facilitates the leukocyte

delivery to the focus of injury. Extravasation of plasma creates edema, and in combination with the

release of vasoactive substances leads to hemoconcentration, which promotes the peripheral

margination of leukocytes.8,9 Circulating neutrophils transiently interact with the endothelial cell

surface molecules during “rolling,” a process that involves a series of loose and reversible attachments

between the neutrophil and endothelium. (Fig. 7-1). These interactions, prerequisite for subsequent

tighter cell–cell interactions, are mediated by the family of selectin receptors which bind with their

counterligands, the sialyl Lewis family and other fucosylated and sulfated structures. E-selectin and Pselectin are present on endothelium and L-selectin is found on leukocytes.4

After stimulation by inflammatory mediators (thrombin, histamine, complement fragments, oxygen

species, lipopolysaccharide [LPS], and cytokines such as IL-1, TNFα, and IFNγ), the vascular

endothelium expresses P- and E-selectin, which engage neutrophil surface glycoprotein P-selectin

glycoprotein ligand 1 (PSGL-1) or sialyl Lewis. P-selectin is stored intracellularly and can be rapidly

mobilized for expression within minutes of cellular activation. Endothelial cells also translocate ligands

for neutrophil L-selectin and release mediators like platelet-activating factor (PAF) and IL-8. Cytokines

such as TNFα, granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony

stimulating factor (G-CSF) increase the affinity of leukocyte L-selectin for its counterreceptor. In

addition to mechanical anchorage, these selectins induce signal transduction pathways that influence

cellular function. P-selectin facilitates neutrophil degranulation and superoxide production, and crosslinking L-selectin primes the neutrophil for increased superoxide production.10–12

After rolling, L-selectin is rapidly shed in preparation for leukocyte diapedesis and emigration into the

interstitium. Subsequent exposure to chemoattractant gradients results in conversion of the neutrophil

to a state of tight stationary adhesion (Fig. 7-1). The receptors mediating this interaction are members

of the β2

integrin family, most importantly leukocyte function antigen-1 (LFA-1, CD11a/CD18) and

Mac-1 (CD11b/CD18). Their expression is enhanced in response to selectin binding, and thus explains

the prerequisite nature of the early cell–cell interactions to neutrophil recruitment. Both integrin

receptors engage the intercellular adhesion molecules ICAM-1 and ICAM-2 in mediating adhesion; yet,

each provides additional important functions. Leukocyte emigration is primarily an LFA-1–dependent

process, as mice deficient in this receptor exhibit reduced neutrophil attachment to ICAM-1 and

endothelial cells. By contrast, mice lacking Mac-1 demonstrate impaired degranulation, superoxide

production, and phagocytosis. Mac-1 also binds fibrinogen, heparin, and factor X and is implicated in

neutrophil phagocytosis-induced apoptosis, a process essential for resolution of the inflammatory

process (see below). The very late antigen 4 (VLA-4) binds vascular cellular adhesion molecule 1

(VCAM-1) and may provide an additional mechanism for tight adhesion. In addition to providing

mechanical anchorage, these receptors interact with the cytoskeleton and other structural proteins and

signaling cascades and are thought to represent a biochemical link between the external environment and

intracellular signal transduction cascades that induce a cellular phenotype more appropriate for the

inflammatory environment (Fig. 7-2).13–15

Table 7-1 Leukocyte Subsets

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