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formation by eNOS.292 Hsp70 has been reported to prevent apoptosis, which may promote propagation

rather than resolution of inflammation. In addition, the body’s immune response to bacterial and

parasitic stress proteins likely protects the host from infection. The bacterial homologue of Hsp60,

GroEL, is a major target of the mammalian humoral response to bacterial infections. Many activators of

HSF1 are potent inhibitors of the proinflammatory transcription factor NFκB. Aspirin and other NSAIDs

activate HSF while inhibiting NFκB. Therefore, the anti-inflammatory effects associated with the stress

response might be related more to the inhibition of NFκB activation.287,293

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The Acute-Phase Response

The acute-phase response consequent to trauma or cellular injury is characterized by alterations in

hepatic metabolism; activation of the central nervous system, leading to fever and adaptive behaviors;

altered hematopoiesis; activation of complement and the fibrinolytic and coagulation cascades; and the

release of neuropeptides, kinins, and hormones. It is a rapid, nonspecific response that accompanies

both acute and chronic inflammatory disorders. Many of the processes induced during the acute-phase

response are mediated by cytokines. IL-6, IL-1, and TNFα play particularly central roles.294,295 Though

considered a defense mechanism promoting host survival, aberrant or unregulated production of many

of these inflammatory mediators can be lethal.

Acute-Phase Proteins

An acute-phase protein is defined as a protein whose concentration increases by at least 25% during

inflammation (Table 7-7).295,296 These changes are primarily due to altered hepatic synthesis and

typically occur within approximately 6 hours of the inciting stimulus. The function is to restore

homeostasis: hemostatic functions (fibrinogen), microbicidal and phagocytic functions (complement

components, C-reactive protein [CRP]), antithrombotic properties (plasminogen, protein S), antioxidant

properties (haptoglobin), and antiproteolytic actions (α2 macroglobulin, α1 protease, α1 chymotrypsin).

The negative acute-phase proteins albumin, prealbumin, transferrin, and retinol-binding protein

decrease by at least 25%. Levels of the negative acute-phase proteins, albumin and transferrin, drop

almost immediately after operation and remain depressed for several days. The rapid initial loss of these

proteins is likely due to increased vascular permeability and loss to the extravascular space. The

magnitude of the response is proportional to the severity of the stress. Whereas trauma and burns lead

to significant increases in acute-phase reactants, exercise and psychiatric illness induce more moderate

responses.

The two major acute-phase proteins in humans are CRP and serum amyloid A (SAA). CRP, named

because of its reaction with pneumococcal C-polysaccharide, displays both proinflammatory and antiinflammatory effects. It has been shown to activate complement, recognize foreign pathogens, bind

phagocytic cells, and enhance activation of tissue factor, the main initiator of coagulation. CRP can also

inhibit superoxide production by neutrophils and inhibit neutrophil adhesion by decreasing surface

expression of L-selectin. Changes in plasma or serum CRP, although nonspecific, may reflect the

magnitude of an inflammatory process and may aid the differentiation of inflammatory from

noninflammatory conditions. Measurement of CRP is more precise than the erythrocyte sedimentation

rate; the latter largely depends on plasma fibrinogen levels and is influenced by a variety of other,

unrelated factors in the circulation. SAA may promote chemotaxis and adhesion of phagocytes during

inflammation.39

C1 inhibitor is of special interest as an acute-phase protein because of its effects outside of the

complement cascade. This antiprotease inhibits the activity of HF, limiting kinin production and factor

XI production. Thus, enhanced expression of a complement inhibitor protein during acute inflammation

may also influence coagulation, fibrinolysis, and kinin pathways.

Systemic Manifestations of the Acute-Phase Response

Systemic manifestations include neuroendocrine changes, shifts in the hematologic profile, and

metabolic and chemical alterations. The classic neuroendocrine manifestation is fever. IL-1, IL-6, and

TNFα mediate the fever response by resetting the hypothalamic temperature setpoint through the

synthesis of PGE2

. The secretion of neuropeptides, such as CRH and AVP, and of hormones, such as

glucagon, insulin, thyroxin, and aldosterone, is also characteristic of the acute-phase response. CRH and

AVP are released by the hypothalamus and increase ACTH and cortisol levels. The rise in plasma cortisol

levels occurs rapidly and may function to inhibit the fever response and cytokine gene expression,

thereby serving a potential negative regulatory function in the acute-phase response. Glucocorticoids

also stimulate macrocortin synthesis, which by inhibiting synthesis of PLA2

, limits the availability of

arachidonic acid for prostaglandin synthesis. Glucocorticoids increase the rate of synthesis of certain

acute-phase proteins involved in connective tissue repair and clotting, as well as antioxidants and

antiproteinases. They also may function to counteract the hypoglycemic response to insulin

overproduction during infection or stress.

Other alterations include a prominent leukocytosis, thrombocytosis, and the “anemia of chronic

disease.” Metabolic changes include altered lipid metabolism and negative nitrogen balance. Changes in

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the chemical and enzymatic profile include increased hepatic production of metallothionein, iNOS, HO,

manganese superoxide dismutase, and glutathione (GSH). Plasma levels of zinc and iron are noted to

drop, whereas copper levels increase slightly. This persists for the duration of inflammation and is likely

due to sequestration induced by IL-6, glucocorticoids, and catecholamines. Low levels of iron and zinc

may confer protective antimicrobial effects because they are essential micronutrients for microbial

growth.39

Mediators of the Acute-Phase Response

Bacterial products such as LPS are probably the most potent activators of tissue macrophages, the

initiators of the acute-phase response. LPS, through its interactions with LBP, CD14, and TLR, induces

macrophage synthesis of ROS, including NO; lipid derivatives (e.g., PGE2

, thromboxane A2

, and PAF);

and acute-phase cytokines (e.g., TNFα, IL-6). Additional mediators inducing the synthesis of acute-phase

cytokines in the absence of bacterial infection include free radicals, prostaglandins, and the release of

DAMPs from injured tissues.39 Indeed the response to the sterile insult of trauma mirrors much of what

is observed during severe sepsis, a similarity that may be the consequence of substantial overlap in

signaling mechanisms, such as TLR4.

Acute-phase cytokines can be proinflammatory (IL-1, TNFα, IFNγ, IL-8) or anti-inflammatory (IL-10,

IL-4, IL-13, TNFβ). However, it is IL-6 and IL-6-type cytokines that are most critical in the acute-phase

response. IL-6 is the major inducer of acute-phase proteins synthesis and, together with IL-1 and TNFα,

is responsible for the systemic features classically associated with the acute-phase response (fever,

anorexia, leukocytosis, and hormonal changes).39

In addition to the aforementioned cytokines, IFNγ is a potent inducer of complement components.

The anti-inflammatory cytokine TGFβ stimulates synthesis of antiproteases, urokinase, and negative

acute-phase proteins. IL-4 is inhibitory to some acute-phase proteins. Growth factors, including

hepatocyte growth factor and TGFβ are also able to modulate the synthesis of acute-phase proteins.

Glucocorticoids augment the response to cytokines, and insulin attenuates the cytokine-induced rise in

acute-phase proteins.39

Effects of the cytokines are influenced by cytokine receptors, receptor antagonists, and hormones. IL1RA competes with IL-1 and attenuates the acute-phase response in vivo. Soluble receptors for IL-1 and

TNFα act as antagonists. In contrast, soluble receptors for IL-6 act as agonists.

Regulation of Acute-Phase Cytokines and Proteins

Several major families of transcription factors participate in the upregulation of acute-phase cytokines

and proteins, the most important being NF-IL-6, AP-1, and NFκB.297 NF-IL6 participates in the

expression of the cytokines IL-1, TNFα, IL-6, and IL-8. Activation through the NFκB is probably the

predominant pathway. The triggering of IL-6 in monocytes in vitro by IFNγ involves a change in the

amount of the phosphorylated transcription factor Sp1, together with the induction and activation of

IFN-regulatory factor.

All known acute-phase proteins are regulated primarily at the transcriptional level. Activation of

TNFα and IL-1 receptors triggers signaling pathways that activate transcription factors AP-1 and NFκB.

Many type I acute-phase proteins genes contain response elements for NFκB, NF-IL6, and AP-1. Acutephase protein responses to IL-6 are mediated through the JAK-STAT signal transduction pathway. In

addition, both IL-1 and IL-6 signal transduction mechanisms activate the MAPK pathway that activates

transcription factors NF-IL6, linking the IL-1 and IL-6 pathways.

Reperfusion Injury

Prolonged tissue ischemia produces irreversible injury and cell death. Timely restoration of perfusion

may salvage some tissue, though paradoxically can induce injury as well. Reperfusion injury is the

damage caused by the restoration of blood flow in previously ischemic tissue (i.e., myocardial ischemia,

transplantation, vascular surgery). Injury is the direct consequence of activation of the inflammatory

response, especially complement activation and neutrophil recruitment. Components of the complement

cascade promote tissue damage through the generation of anaphylatoxins and by the formation of the

MAC. Invading neutrophils injure tissue through the generation of ROS and the release of proteolytic

enzymes. Recent evidence points to TLR4 as a sensor of tissue stress, the signal of which is probably

through release of DAMPs from ischemic cells.32

Alterations in the microvascular endothelium are central to the pathophysiologic process of

reperfusion injury. Early loss of constitutive NO production facilitates neutrophil adherence, the

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