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2
Mechanisms of the inflammatory response
Edward R. Sherwood* MD, PhDAssociate Professor
Tracy Toliver-Kinsky PhDAssistant Professor
Department of Anesthesiology, University of Texas Medical Branch, The Shriners Hospital for Children,
301 University Boulevard, Galveston, TX 77555-0591, USA
The physiological alterations induced by acute inflammation present significant managementchallenges for anaesthesiologists. Major surgery, trauma, burns and sepsis all have largeinflammatory components. Acute inflammation is characterized by vasodilatation, fluid exudationand neutrophil infiltration. These processes are activated and amplified by a series of intracellularand extracellular factors that tightly co-ordinate the inflammatory process. The innate immunesystem responds rapidly to infection or injury. Macrophages, natural killer cells, CD8 T-lymphocytes and neutrophils provide an early response to injurious factors in an effort to containand eliminate harmful stimuli. The adaptive immune response requires prior exposure tomicrobial antigens, is mediated primarily by CD4 T-lymphocytes and serves to further amplifyacute inflammation. Although acute inflammation is fundamentally beneficial, severe inflammationcan precipitate the systemic inflammatory response syndrome. This syndrome is characterized byhyperinflammation and can cause organ injury, shock and death in its most severe forms. Overall,our understanding of inflammation has increased tremendously during the past 20 years.However, these basic science advances have not yet translated into widespread benefit forpatients suffering from trauma, sepsis and systemic inflammation.
Key words: inflammation; innate immunity; acquired immunity; coagulation; toll-like receptors;cytokines; chemokines; adhesion molecules.
Inflammation plays an important role in the pathophysiology of conditions encounteredby anaesthesiologists and critical care practitioners on a daily basis. Surgery, sepsis,major trauma, burns, adult respiratory distress syndrome and ischaemiareperfusioninjuries have major inflammatory components. Our understanding of the basicimmunology of inflammation has progressed significantly during the past 10 years.However, these advancements in knowledge have not translated into widespreadapplication in the clinical setting. This review will address the basic mechanisms of
1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical AnaesthesiologyVol. 18, No. 3, pp. 385405, 2004
doi:10.1016/j.bpa.2003.12.002
available online at http://www.sciencedirect.com
*Corresponding author. Tel.:
1-409-772-1221; Fax:
1-409-772-1224.E-mail address: [email protected], [email protected] (E.R. Sherwood).
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inflammation. In later chapters, authors will discuss how inflammatory processespresent in the operating room and intensive care unit.
INITIATION OF THE INFLAMMATORY RESPONSE
Vasodilatation, fluid exudation and leukocyte migration
Inflammation is a response to infection, antigen challenge or tissue injury that isdesigned to eradicate microbes or irritants and to potentiate tissue repair. Excessiveinflammation may, however, lead to tissue injury and can, if severe, cause physiologicaldecompensation, organ dysfunction and death. Inflammation can be divided into twomajor categoriesacute and chronicbased on timing and pathological features.Chronic inflammatory diseases include rheumatoid arthritis, systemic lupus erythe-matosus, silicosis, atherosclerosis and inflammatory bowel disease. These disorders arecharacterized by a prolonged duration (weeks to months to years) in which activeinflammation, tissue destruction and attempts at tissue repair are occurringsimultaneously.1 Infiltration of mononuclear cells and fibrosis are typical histologicalfeatures of chronic inflammation.2 Chronic inflammatory diseases commonly posemanagement challenges to anaesthesiologists. However, disease processes caused byacute inflammation present some of the most intense management problems foranaesthesiologists and critical care practitioners. Sepsis, severe trauma and majorsurgery all have major acute inflammatory components. Acute inflammation is typicallyof relatively short duration (hours to days) and is characterized by vasodilatation, theexudation of protein-rich fluid (plasma) and a migration of cells (primarily neutrophils)into the site of injury and, in some cases, activation of the coagulation cascade.3,4
Vasodilatation is a classic feature of acute inflammation and is clinically characterizedby redness and warmth at the site of injury. The purpose of the vasodilatory response isto facilitate the local delivery of soluble mediators and inflammatory cells. Inflammation-induced vasodilatation is mediated primarily by nitric oxide (NO) and vasodilatoryprostaglandins. NO is produced from L-arginine through the action of nitric oxidesynthase (NOS) (Figure 1). Three isoforms of NOS have been identified. EndothelialNOS (eNOS) and neuronal NOS (nNOS) are constitutively produced, and theirexpression is increased by calcium flux. Activated leukocytes produce inducible NOS(iNOS) after exposure to microbial products or pro-inflammatory cytokines.5 The NOproduced causes subsequent smooth muscle relaxation through cyclic GMP-dependentmechanisms.6 The primary vasodilatory prostaglandins are prostacyclin (PGI2), PGD2,PGE2 and PGF2a (Figure 2). These lipid mediators are produced from arachadonic acidthrough the action of cyclo-oxygenase.7 Inflammation-induced vasodilatation initiallyinvolves arterioles followed by theopening of new microvascular beds. In cases of severesystemic inflammation such as sepsis, widespread vasodilatation can cause systemichypotension and shock.8 These cardiovascular alterations are potentiated by sepsis-induced myocardial depression, a condition that is induced by theactions of NO andpro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a) (Figure 2).9
Another early sign of inflammation is oedema formation. Oedema is caused by thetransvascular flux of protein-rich fluid from the intravascular compartment into theinterstitium as a result of the actions of histamine, bradykinin, leukotrienes,complement components, substance P and platelet-activating factor (PAF).10,11 Thesefactors markedly alter the barrier functions of small blood vessels and increase thepermeability of capillaries and venules for both water and protein.12,13 At the same
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Figure 1. Nitric oxide (NO) in the regulation of vasodilation during inflammation. NO production is mediated by several nitric oxide synthase (NOS) isoforms includineNOS, nNOS and iNOS. Expression of eNOS and nNOS are regulated by transcellular calcium flux whereas as iNOS production is induced by inflammatory mediators suas TNF-a and IL-1. NO causes vascular smooth muscle relaxation via cyclic GMP-mediated mechanisms resulting in vasodilation at the site of inflammation. (Adapted froR. Cotran, V. Kumar, T. Collins, Pathologic Basis of Disease, Saunder, 1999, with permission).
Vascular smooth muscle relaxation and vasodilation
NO
Endothelialstimulation
Microbe
Macrophage
Activationstimulus
Calcium influxand NOSactivation
Cytotoxicity
NO
OS
eNOSnNOS
Endothelium
NO2
+ OH2 O2- + NO
iNOS
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time, capillary hydrostatic pressure is increased at the site of injury early duringinflammation or injury as a result of local vasodilatation. The outpouring of protein-richfluid causes a concentration of erythrocytes in small vessels and increased viscosity ofthe blood. This transvascular fluid flux eventually returns intravascular pressures at thesite of inflammation to normal. At the same time, the loss of plasma proteins decreasesthe intravascular oncotic pressure. Together, the increase in vascular permeability,transient augmentation of capillary hydrostatic pressure and fall in plasma oncoticpressure act to induce a transvascular flux of fluid and protein into the inflamedinterstitium. The function of these alterations is to allow the delivery of soluble factorssuch as antibodies and acute-phase proteins to the site of injury. Severe systemicinflammation can, however, cause inappropriate increases in vascular permeability thatcan result in oedema formation in the lungs and extremities. The accumulation of fluidin the lungs causes the acute respiratory distress syndrome, a major source ofmorbidity and mortality in critically ill patients.13 Oedema accumulation in theextremities may lead to compartment syndrome and the loss of vital perfusion in thedistal extremities.14
Vasodilatation and fluid exudation are accompanied by leukocyte margination,adhesion and migration. Neutrophils are the first and most abundant leukocytes to bedelivered to a site of infection or inflammation. The process of neutrophil migrationfrom the intravascular space into the inflamed interstitium occurs primarily in post-capillary venules in the systemic circulation and in pulmonary capillaries in the lung.15
The transmigration phenomenon is divided into several distinct steps: margination,rolling, adhesion, diapedesis and chemotaxis (Figure 3). Margination is the process ofneutrophil movement from the central bloodstream to the periphery of the vessel. Thisphenomenon is facilitated by stasis following fluid exudation at the site of inflammationand physical interactions between erythrocytes and neutrophils.16 After margination, aweak adhesive interaction develops between neutrophils and vascular endothelial cells,causing neutrophils to remain in close proximity to the vascular endothelium.Neutrophil rolling is facilitated by the shear stress of passing erythrocytes, rollingvelocity being proportional to red cell velocity.17
The adhesive interactions that permit leukocyte rolling are facilitated by selectinsand their ligands (Table 1). Selectins are a family of glycoprotein surface molecules thatare expressed on leukocytes (L-selectin), endothelial cells (E-selectin) and platelets (P-selectin) that bind sialylated carbohydrate determinants on adjacent cells.18,19 Thecombined forces of selectin ligand interaction and vascular shear forces promoteneutrophil rolling. As rolling progresses, a high-affinity adhesive interaction known
MembranePhospholipids
ArachidonicAcid
PGG2
PGH2
PGD2
PGE2
PGF2
PGI2
Cyclooxygenase
(COX-1,COX-2)
Phospholipases
Figure 2. Vasodilatory prostaglandins are produced through the actions of phospholipase and cyclo-oxygenase. The major vasodilatory prostaglandins are prostacyclin (PGI2) and the prostaglandins PGD2, PGE2and PGF2a. COX, cyclo-oxygenase; PG, prostaglandin.
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Transmigration
Adherence
Rolling
Chemotaxis
Apoptosis
Bacteria
I-CAM 1L-selectin CD11b
Endothelium
Phagocytosis
5
4
3
6
Figure 3. Mechanisms of neutrophil rolling, adherence, diapedesis and chemotaxis. Inflammation causes neutrophil margination followed by development of loointeractions between endothelial cells and neutrophils. These interactions are mediated by selectins and their ligands, which facilitates neutrophil rolling. Neutropadherence is then potentiated by interactions between beta-integrins and intercellular adhesion molecules (ICAM). Neutrophils then migrate to the site of inflammationinteraction with chemoattractant molecules such as chemokines and bacterial products. (Adapted from Seely et al, Critical Care 2003; 7: 291307 with permission).
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as adherence develops. Adherence is necessary for subsequent neutrophil diapedesisand chemotaxis, and is mediated by the action of integrins and their ligands (Table 1).
Integrins are a family of heterodimeric proteins that are composed of alpha and betasubunits. The beta-2 integrins are the most widely studied and understood. Thesemolecules are composed of distinct alpha subunits (CD11a, CD11b, CD11c) that arebound to a common beta subunit (CD18).20 beta-2 integrins are expressed on thesurface of neutrophils and interact with ligands, particularly intercellular adhesion
molecule-1 (ICAM-1), that are present on the endothelial cell membrane (Table 1).These interactions cause tight adherence of the neutrophil to the endothelium andfacilitate diapedesis and chemotaxis. beta-2 integrins and ICAMs are constitutivelypresent on the surface of neutrophils and endothelial cells, but their expression isupregulated during periods of inflammation, which promotes the transition from rollingto adherence.21
Following adherence, the neutrophil must penetrate the endothelium and basementmembrane to enter the extravascular inflammatory environment. Neutrophils passthrough endothelial cell junctions, a process that is partly facilitated by endothelialretraction.22 In addition, adhesion molecules such as plateletendothelial cell adhesionmolecule-1 (PECAM-1) facilitate diapedesis (Table 1). PECAM-1 is present on thelateral surfaces of endothelial cells as well as on neutrophils. The binding of PECAM-1decreases neutrophil adhesion to ICAM-1, resulting in the inhibition of adherence andthe promotion of diapedesis.23 The processes of rolling, adherence and diapedesis aretherefore mediated through complex interactions between adhesion molecules onneutrophils and endothelial cells. The ultimate goal of these interactions is to facilitatethe migration of neutrophils from the intravascular compartment and into theinterstitium at sites of infection or injury.
Neutrophils and other leukocytes also require chemoattractants to facilitate theirmigration to sites of injury or infection. Chemoattractants are soluble molecules suchas bacterial byproducts, complement components and chemoattractant cytokines(chemokines) that serve to attract leukocytes to injured tissues. Many chemoattrac-tants are specific for leukocyte subsets and can be classified based on leukocytespecificity. Classical chemoattractants include N-formylated peptides produced bybacteria, complement components and leukotrienes.2426
Chemoattractant cytokines or chemokines are leukocyte products that also serveto attract leukocytes into tissues (Table 2). They are a group of more than 40 peptideswith molecular weights of 8 10 kDa that share considerable sequence homology.There are at least four families of chemokines, two of which (the alpha and beta
Table 1. Neutrophil and endothelial cell adhesion molecules.
Receptor Cell ligand Cell function
L-selectin Neutrophil sLe EC Rolling
E-selectin EC sLe neutrophil Rolling
P-selectin EC, platelet sLe neutrophil Rolling
CD11a/CD18 Neutrophil ICAMs EC AdherenceCD11b/CD18 Neutrophil ICAMs EC Adherence
PECAM-1 EC CD31 Neutrophil Diapedesis
sLe, surface glycoprotein; EC, endothelial cell; ICAM-1, intercellular adhesion molecule-1; PECAM-1,
plateletendothelial cell adhesion molecule-1.
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families), have been extensively described.27 The alpha chemokines include interleukin(IL)-8, which is a potent chemoattractant for neutrophils, as well as other members ofthe family that are lymphocyte chemoattractants. The beta chemokines arechemoattractants for a variety of leukocytes including basophils, monocytes,eosinophils and lymphocytes. The alpha chemokines act in concert with betachemokines and cytokines to mediate the pro-inflammatory response to injury andinfection.
Tissue injury or invasion results in a marked increase in local chemokine production,causing a selective recruitment of leukocytes to the site of injury. The character of
Table 2. Classification of chemokines.
Chemokine type Target cell
a-Chemokines
IL-8 Neutrophils
GROa (mouse equivalent is GRO/KC) Neutrophils
GROb (mouse equivalent is GRO/KC) NeutrophilsGROg (mouse equivalent is GRO/KC) Neutrophils
ENA-78 Neutrophils
LDGF-PBP Neutrophils, fibroblasts
GCP-2 Neutrophils
PF4 Fibroblasts
Mig T-lymphocytes
IP-10 T-lymphocytes
I-TAC T-lymphocytes
SDF-1a/b T-lymphocytes
b-Chemokines
MIP-1a Monocyte/macrophages, T-cells, B-cells,
NK cells, basophils
MIP-1b Monocyte/macrophages, T-cells, B-cells,
NK cells, basophils
MDC Monocytes, T-lymphocytesTECK Macrophages, T-lymphocytes
TARC T-lymphocytes
RANTES Monocytes/macrophages, T-lymphocytes,
NK cells, basophils
HCC-1 Monocytes
HCC-4 Monocytes, lymphocytes
DC-CK-1 T-lymphocytes
MIP-3a T-lymphocytes
MIP-3b T-lymphocytes
MCP-1 T-lymphocytes, monocytes
MCP-2 T-lymphocytes, monocytes
MCP-3 T-lymphocytes, monocytes
MCP-4 T-lymphocytes, monocytes
Eotaxin Eosinophils
Other chemokines
Lymphotactin T-lymphocytes, NK cells
Fractalkine T-lymphocytes, monocytes, neutrophils
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the inflammatory infiltrate within injured tissue is determined by the profile ofchemokine secretion induced by a particular disease or inflammatory process.27
Leukocyte migration is further regulated by chemokine receptors that exhibitspecificity for both the cell type on which they are expressed and the chemokinethat they bind.28 Chemokine receptors are a family of G-protein-coupled proteins withseven transmembrane regions. Although these receptors are structurally similar, theyare functionally diverse. They display both ligand and leukocyte specificity and thus
determine the character of the inflammatory infiltrate.
Activation of the coagulation cascade during inflammation
Inflammation and coagulation are intimately intertwined. The coagulation cascade isactivated during tissue injury and during infection. It is divided into two pathways thatconverge and ultimately cause the activation of thrombin with the subsequent cleavageof fibrinogen into fibrin (Figure 4). The intrinsic pathway is a series of plasma proteinsthat are activated by Hageman factor (factor XII), a protein synthesized in the liver thatis activated by binding to collagen, basement membrane or activated platelets.29
Activated Hageman factor triggers the activation of a cascade of proteins, resulting inthe formation of thrombin. The intrinsic pathway is most commonly activated by directtissue trauma.
In contrast, the extrinsic pathway is initiated by the production of tissue factor.Recent studies indicate that the extrinsic pathway is the primary coagulation pathwayactivated during infection and systemic inflammation, particularly during sepsis and thesystemic inflammatory response syndrome (SIRS).30 Tissue factor is expressed ontissue surfaces that are not normally exposed to the vascular compartment, such assubcutaneous tissues and the adventitial layer of blood vessels. In addition, endothelialcells and activated monocytes produce tissue factor during periods of inflammation inresponse to TNF-a, IL-1, IL-6 and C-reactive protein.4 The presence of tissue factorcauses the activation of factor VII, which then forms a complex with tissue factor andultimately causes the formation of thrombin by the activation of a series of coagulationfactors (Figure 4).
Activation of the coagulation cascade is not only important in the formation of fibrinclots, but also has important effects on the pro-inflammatory response. Factor Xa,thrombin and the tissue factorVIIa complex have been shown to elicit pro-inflammatory activity. Specifically, thrombin and the tissue factorVIIa complex caninduce the production of pro-inflammatory cytokines such as TNF-a by mononuclearand endothelial cells.31 This effect appears to be mediated by the binding of thesefactors to protease-activated receptors on the surface of target cells. Therefore, acuteinflammation causes activation of the coagulation cascade, which can then furtherpotentiate the inflammatory response.
Activation of the clotting cascade during inflammation is limited by several factors.This is important because it prevents the uncontrolled induction of pro-coagulantmechanisms. The most well-defined factors are anti-thrombin, the protein C systemand tissue factor pathway inhibitor (TFPI) (Figure 5). Anti-thrombin is produced in theliver and directly binds to and inactivates thrombin.32 The binding of anti-thrombin tothrombin is greatly potentiated by heparin and by glycosaminoglycans present on theendothelial cell surface. In rodents, the interaction of anti-thrombin with theendothelial cell surface promotes the release of PGI2, which inhibits TNF-a productionby monocytes through the inhibition of transcription factor nuclear factor-kB (NF-kB)
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activation.33 Thus, anti-thrombin may have anti-inflammatory properties in addition toits function in regulating coagulation.
Protein C is a circulating protein that is activated by the thrombinthrombomodulincomplex on the surface of endothelial cells. Activation of protein C decelerates theclotting cascade by inactivating factors Va and VIIIa.34 Activated protein C also inhibitsthe thrombin-induced production of TNF-a by monocytes by inhibiting the activationof transcription factors NF-kB and AP-1 (see below).35 Therefore, activated protein Chas both anti-coagulant and anti-inflammatory properties. During sepsis, activatedprotein C can become depleted owing to consumption and the inflammation-induceddown-regulation of thrombomodulin. This results in the unchecked formation of
Prekallikrein
Kallikrein
Extrinsic pathwayTissue injury
Intrinsic pathwaycontact activation
Fibrinogen Solublefibrin
XIIIa
XIIIIIaII
Va + Xa
Xa
TF + VIIaIXa + VIIIa
IX IXa
VIIa VIIXI XIa
XII XIIa XIIf
X
ThrombinProthrombin
I Isol
Istable
Stablefibrin
Tissue factor
Exposure ofconnective tissue or
negatively charged surface
Vessel damage
Subendothelial tissueexposed to blood
Figure 4. The coagulation cascade. The extrinsic and intrinsic pathways of coagulation converge upon thefinal common pathway. The extrinsic pathway is activated by tissue factor, which is exposed upon tissue injuryas well as macrophage activation. The intrinsic pathways is induced by exposure of subendothelial collagen andactivated platelets. The final result is the formation of fibrin clot. (Adapted from Dellinger EP, ClinicalInfectious Diseases 2003; 36: 12591265, with permission).
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thrombin, causing accelerated coagulation and increased pro-inflammatory activity. Theimportance of protein C in regulating thrombin formation during sepsis isdemonstrated by increased mortality in septic patients who have low activated proteinC levels.36
A third important factor in the regulation of thrombin formation is TFPI. TFPI ispresent on the surface of endothelial cells and bound to lipoproteins in the plasma. TFPIinactivates tissue factor by forming a quarternary complex with tissue factor and factorVIIa. Factor Xa comprises the fourth component of the complex.37 The inhibition oftissue factor function inhibits activation of the extrinsic clotting pathway duringinflammation. The infusion of TFPI has also been shown to decrease pro-inflammatorycytokine production during endotoxin infusion in baboons but not humans.4
Complement system
The complement system is a series of proteins that are activated by microbes and serveto promote inflammation and microbial destruction. It is likely that the complementcascade is also activated during tissue injury and plays a role in cellular injury associatedwith major trauma and burns.38 The complement cascade is activated in three ways(Figure 6). IgM or IgG antibodies that are bound to the surface of microbes or otherstructures activate the classical pathway, so called because it was the first pathway to bedefined. The alternative pathway was discovered after the classical pathway but isphylogenetically older. It is triggered directly by microbial surface molecules that bindthe complement component C3 and serve as a platform for the activation ofcomplement proteins. The lectin pathway is activated by mannose-binding lectin, whichinteracts with microbial glycoproteins and glycolipids.
Any of these pathways will activate the cleavage of complement component C3 intoC3a and C3b. C3a serves as a neutrophil chemoattractant. C3b binds to the surface of
Tissue Factor
TNF
IL-1
VIIIa IXa
Va
Xa
Thrombin
ActivatedProtein C
1. Degradation of
Va and VIIIa2. Inhibition of
inflammation
Anti-ThrombinIII
IntrinsicPathway
+
VIIaTissue Factor
Pathway Inhibitor
Binds tissueFactorVII a
complex
Binds thrombin
Macrophage/Monocyte
EndothelialCell
Fibrin clot
Macrophage/MonocyteActivation
Figure 5. Regulation of the coagulation cascade during inflammation. Several endogenous pathways regulatethecoagulationcascade.Theseincludeactivated proteinC, tissue factor pathwayinhibitor andanti-thrombin III.
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microbes to facilitate recognition by phagocytes and promote phagocytosis.39 Inaddition, C3b forms a proteolytic complex with other complement components tocause the cleavage of C5 into C5a and C5b.40 C5a is a chemotactic factor forneutrophils and also alters vascular permeability at the site of inflammation. C5b bindsto the microbial surface and facilitates the formation of the membrane attack complexcomposed of C6, C7, C8 and C9.41 The membrane attack complex causes disruption ofthe microbial cell membrane and subsequent death.
AMPLIFICATION OF THE INFLAMMATORY RESPONSE
Innate immune system
The immune response to tissue injury or infection can be divided into innate andadaptive responses. The innate immune system mounts the initial response to tissueinvasion. The previously discussed phases of vasodilatation, increased vascularpermeability and cellular infiltration are part of the innate immune response. Theprimary cellular components of the innate immune system are macrophages, dendriticcells, natural killer (NK) cells and neutrophils (Figure 7). In addition to these cellularcomponents, circulating effector proteins such as complement, acute-phase reactantsand the coagulation cascade play important roles in innate immunity.
The activity of cytokines and non-cytokine mediators of inflammation largelydetermines the magnitude of the innate response. Cytokines are polypeptides that areproduced by cells of the immune system in response to infection or tissue injury.1 Theyserve to regulate immune and inflammatory reactions. The production of cytokines isgenerally self-limited, although some cytokines can persist in the circulation for longperiods of time. In addition, the effects of cytokines are pleiotropic and redundant.Pleiotropism means that one cytokine has numerous functions. For example,interferon-g (IFN-g) causes macrophage activation and the induction of
C5a
Membrane attackcomplex(MAC)
C5-C9terminal sequences
Alternative Pathway(innate)
antigen/antibodycomplexes(adaptive)
microorganisms
Classic Pathway
C3a C3b
C3
Lectin Pathway
Figure 6. The complement system. The complement cascade is activated by several mechanisms includingthe classic, alternative and lectin pathways. The major mediatorsof the complement pathwayare C3a and C3bthat act as pro-inflammatory factors. In addition, formation of the membrane attack complex (C5-C9) causesdisruption of cellular membranes.
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Figure 7. Overview of the immune response to injury and infection. These responses are divided into innate and acquired immunity as described in the text. NK, naturkiller; ROS, reactive oxygen species; CD, cluster of differentiation; Ig, immunoglobulin; Th, T helper.
Innate Response
MacrophagesNK cells
NeutrophilsEndothelial cells
Phagocytosis
Productionof ROS
AntigenPresentation
Leukocyte
Recruitment
Cytolysis
ComplementActivation
Productionof
Cytokines,Eicosanoids,Chemokines,Tissue factor
T Lymphocytes
Infection, Tissue Injury, Antigen exposure
Acquired Response
B Lymphocytes
Cytokinesecretion
Cell lysis
Th1
Th2
Opsonization
ComplementActivation
Parasite killingAsthmaAllergy
IgEIgG
1IgG
2
CD4+CD8+
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isotype-switching in B-cells to cause the production of opsonizing IgG subclasses ofantibodies, and stimulates T-helper-1 (Th1) cell differentiation in T-cells.42 Redundancyamong cytokines also exists. The classic examples are TNF-a and IL-1. Both of thesecytokines have the capacity to induce fever, stimulate the production of acute-phaseproteins by the liver and cause endothelial cell activation. Cytokines are thereforemultifunctional groups of proteins that frequently have overlapping functions. For thisreason, the blockade of a single cytokine will often have limited effects on the overall
inflammatory response.43The classical cytokine-secreting cells of the innate immune system are macrophages.
Dendritic cells were also recently recognized as important effector cells for microbialrecognition and cytokine production during innate immunity.44,45 Macrophages anddendritic cells have the ability to respond to a variety of microbial products throughpattern-recognition receptors present on their surfaces.
A family of recently identified cell surface proteins known as toll-like receptors(TLRs) have been shown to be critical for the recognition of pathogen-associatedmolecular patterns and subsequent intracellular signalling.46 TLRs form associationswith other molecules to form cell surface receptor complexes that are relativelyspecific for certain ligands such as lipopolysaccharide from Gram-negative bacteria,lipoproteins from Gram-positive organisms and bacterial DNA (Table 3). However, allof these receptor complexes share common signalling pathways, although some
signalling mechanisms are likely to be unique for specific TLR complexes.Pathways leading to the activation of the transcription factors NF-kB and AP-1 arethe best understood.47 Binding of ligand to the TLR complex causes the recruitment ofseveral cytoplasmic signalling proteins, including the adapter protein MyD88 and the IL-1 receptor-associated kinase (IRAK). IRAK recruitment causes autophosphorylationand the dissociation of IRAK from MyD88. Phosphorylated IRAK induces the activationof TNF-R-associated factor 6 (TRAF-6), which then activates the inhibitor of NF-kB(IkB) cascade, resulting in the degradation of the inhibitory protein IkB and thesubsequent release of cytoplasmic NF-kB. Transcription factor NF-kB thentranslocates into the nucleus to bind gene promoter regions and regulate thetranscription of genes encoding pro-inflammatory mediators such as TNF-a, IL-1b, IL-6and iNOS.48 The activation of TRAF-6 also causes the induction of mitogen-activatedprotein (MAP) kinase pathways, with the ultimate activation of the transcription factor
Table 3. Known toll-like receptors (TLRs) and their ligands.
TLR Associated proteins Ligands
TLR1 Dimer with TLR2 tri-acetylated lipopeptides, phenol-soluble
modulin lipopeptides from Myobacterium tuberculosis and Borrelia burgdorferi
TLR2 CD18/CD11a, CD18/CD11b, CD14, TLR1, TLR6, dectin-1 lipoproteins,
peptidoglycans, lipoteichoic acis, mannuronic acid, rare lipopolysaccharaide (Porphyromonas
gingivalis)
TLR3 Double-stranded RNA
TLR4 Lipopolysaccharide-binding protein, CD14, MD-2, CD18/CD11b
bacterial lipopolysaccharide HSP60
TLR5 Flagellin
TLR6 As dimer with TLR2 di-acylated lipoproteins
TLR9 Bacterial DNA
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AP-1. Like NF-kB, AP-1 binds the promoter region of genes encoding pro-inflammatorymediators and promotes the production of pro-inflammatory cytokines.49
The prototypical pro-inflammatory cytokine is TNF-a. TNF-a is released primarilyby macrophages within minutes of local or systemic injury and modulates a variety ofimmunological and metabolic events. At sites of local infection or inflammation, TNF-ainitiates an immune response that activates anti-microbial defence mechanisms and,once the infection has been eradicated, tissue repair. It is a potent activator of
neutrophils and mononuclear phagocytes, also serving as a growth factor for fibroblastsand an angiogenesis factor (Table 4).50
The systemic release of TNF-a can, however, precipitate a destructive cascadeof events that can result in tissue injury, organ dysfunction and potentially death.
Table 4. Cytokine mediators of inflammation.
Cytokine Polypeptide
size
Cell
source
Cell
target
Primary
effects
Tumor necrosis
factor-a (TNF-a)
17 kDa Monocytes,
macrophages,
T-lymphocytes
Neutrophil Activation
(inflammation)
Endothelial cell Activation
(inflammation/coagulation),
release of vasodilators
nitric oxide (NO)
Hypothalamus Fever
Liver Acute-phase response
Muscle, fat Catabolism
Heart Myocardial suppression
Macrophages Release of cytokines,
inflammation
T-lymphocytes Inflammation
Various tissues Apoptosis?
Interleukin-1 (IL-1) 17 kDa Monocytes,
macrophages
T-cells Activation (inflammation)
Endothelial cell Activation
(inflammation/coagulation),release of vasodilators (NO)
Liver Acute-phase response
Hypothalamus Fever
Muscle, fat Catabolism
Interleukin-6 (IL-6) 26 kDa Monocytes,
macrophages,
T-cells,
endothelial cells
Liver Acute-phase response
B-cells Activation
Interferon-g (IFN-g) 21 s 24 kDa T-cells, NK cells Macrophages Activation (inflammation)
Interleukin-12 (IL-12) 70 kDa Macrophages T-cells, B-cells,
NK cells
Activation, differentiation
Interleukin-18 Macrophages T-cel ls , NK cel ls Activat ion, differentiation
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Among the systemic effects of TNF-a are induction of fever, stimulation of acute-phaseprotein secretion by the liver, activation of the coagulation cascade, myocardialsuppression, induction of systemic vasodilators with resultant hypotension, catabolismand hypoglycaemia. Numerous studies have shown that the administration of TNF-a toexperimental animals will induce physiological responses that mimic the systemicinflammatory response observed in sepsis and after severe injury.51
Most of the pro-inflammatory and metabolic effects are mediated through the
activation of TNFreceptor II (TNF-RII) complex. This receptor signals through thegroup of linking proteins known as TRAFs, of which six (TRAF-1 through TRAF-6) arecurrently defined.52 These factors induce the expression of pro-inflammatory genesthrough the transduction of signals that activate the NF-kB and AP-1 transcriptionfactors. Another important effect of TNF-a is its ability to induce apoptosis afterbinding to the TNF-RI complex. Activation of TNF-RI causes recruitment of the TNFreceptor death domain (TRADD) to the plasma membrane. TRADD recruits otherproteins such as FAS-associated death domain protein (FADD), which recruits andactivates caspase-8, leading to downstream activation of an apoptosis-inducing caspasecascade.52 Apoptosis is an important process in resolution of the inflammatoryresponse.
The physiological effects of IL-1 are essentially identical to those of TNF-a. IL-1 doesnot, however, induce tissue injury or apoptotic cell death by itself, although it canpotentiate the injurious effects of TNF-a. The IL-1 family of proteins, including IL-18,
are the only group of cytokines for which known natural antagonists have beenidentified.53 The IL-1 receptor antagonists (IL-1ra) bind to the IL-1 receptor but do notinduce receptor activation. These proteins appear to function as competitive inhibitorsof IL-1 action. IL-18-binding protein functions in a similar fashion and inhibits thefunction of IL-18.54 Interestingly, although IL-1 and IL-18 signal through similarmechanisms, their functions are quite different. As mentioned above, IL-1 serves toactivate a variety of pro-inflammatory mechanisms, whereas IL-18 acts in conjunctionwith IL-12 to stimulate IFN-g production by NK and Th1 cells.
IL-6 is another cytokine that is released during inflammation and has severalimportant effects. Macrophages, endothelial cells and fibroblasts secrete thispolypeptide. The primary effect of IL-6 is to induce the secretion of acute-phaseproteins from the liver as well as serve as a growth and differentiation factor for B-lymphocytes.55 Although IL-6 does not appear to mediate tissue injury directly, thepersistent elevation of plasma IL-6 level has been reported to correlate with poor
outcome in trauma patients and during sepsis. In this regard, IL-6 may serve as a usefulmarker of ongoing inflammation.
As described earlier in this chapter, chemokines are a family of proteins that functionprimarily as chemotactic factors for leukocytes. IL-8 is produced by macrophages and isone of the most widely studied chemokines in the setting of inflammation. IL-8 is apotent chemoattractant for recruiting neutrophils to inflammatory foci. Several studieshave shown that IL-8 plays a role, particularly in the lung, in mediating tissue injury in thesetting of trauma and burn injury.27 It is likely that that other chemokines are alsoimportant mediators of inflammatory injury.
IL-12 is a cytokine produced by activated macrophages and dendritic cells. Its mostimportant function is to stimulate the production of IFN-g by T-cells and NK cells. Inaddition, IL-12 is an important mediator of the early immune response to intracellularmicro-organisms and in the facilitation of adaptive immunity. Many different types ofmicrobe induce the production of IL-12, which acts in conjunction with IL-15 and IL-18to induce IFN-g production by NK cells.56 IFN-g is a cytokine involved in
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the amplification of inflammatory responses, particularly the stimulation of cytokinesecretion, phagocytosis and respiratory burst activity by macrophages. IL-12 and IFN-gfunction together to amplify both innate and adaptive immune responses. Specifically,IL-12 produced by macrophages and dendritic cells induces IFN-g production by NKcells. In turn, NK cell-derived IFN-g potentiates macrophage inflammatory functions,including the production of more IL-12. Therefore, the early production of IL-12 andIFN-g during immune responses establishes a positive feedback loop that potentiates
the inflammatory response.42
A blockade of IL-12 or IFN-g production or function hasbeen shown to markedly decrease the deleterious inflammatory effects during septicshock.57 Therefore, IL-12 and IFN-g may be important in the amplification of sepsis andin SIRS.
Several non-cytokine inflammatory mediators have been implicated in thepathogenesis of SIRS. PAF is a phospholipid autocoid released by endothelial cellsthat regulates the release of cytokines and amplifies the pro-inflammatory response.58
It appears to be an important factor in the adhesion of neutrophils to endothelial cells.The prolonged presence of PAF in the serum of patients with SIRS has correlated withpoor outcome. Eicosanoids are arachadonic acid metabolites that regulate manyaspects of the immune response. Leukotrienes (LTC4LTE4) induce contraction of theendothelial cells and encourage capillary leakage. Thromboxane A2, a macrophage andplatelet-derived factor, promotes platelet aggregation, vasoconstriction and, potentially,tissue thrombosis.
The immune response is tightly controlled and usually functions effectively to limitinfection and promote tissue repair. A balance normally exists between pro-inflammatory (TNF-a, IL-1, IL-12 and IFN-g) and anti-inflammatory mediators (IL-10,transforming growth factor-b and certain prostaglandins). IL-10 is an inhibitor ofactivated macrophages and dendritic cells, and serves as an important regulator of theinflammatory response.59 Mice that are depleted of IL-10 exhibit hyperinflammationfollowing challenge with bacterial endotoxin or intact bacteria. The addition ofexogenous IL-10 causes significant suppression of the pro-inflammatory response. Theprimary effect of IL-10 is the suppression of IL-12 production by activated macrophagesand dendritic cells. This results in the subsequent suppression of IFN-g production byNK cells and activated T-cells, causing the disruption of IL-12/IFN-g-mediatedamplification of the pro-inflammatory response.
Another cytokine with anti-inflammatory properties is granulocyte colony-stimulating factor (G-CSF). G-CSF stimulates neutrophil production from bone
marrow and primes neutrophils for enhanced killing activities. Concomitantly, G-CSFdecreases TNF-a, IL-1, and IL-12 production by interacting with G-CSF receptors onmonocytes and macrophages. In addition, G-CSF treatments increase levels of IL-1raand soluble TNF receptors, naturally occurring pro-inflammatory cytokine antagon-ists.60,61 Therefore, G-CSF promotes local anti-microbial defence through theenhancement of neutrophil functions while exerting anti-inflammatory effectssystemically.6264
In cases in which the pro-inflammatory response predominates, severe systemicinflammation may ensue, as typified by sepsis and SIRS.65 Conversely, predominance ofthe anti-inflammatory response may cause a state of relative immunosuppression todevelop. This phenomenon often results after major trauma or thermal injury, or in thepost-septic state, and has been termed the counter-anti-inflammatory responsesyndrome (CARS).66 Several studies have shown that IL-10 predominance is a factor inthe development of post-inflammatory immunosuppression. Patients exhibiting CARSmay be more susceptible to infectious complications. In either case, multisystem organ
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dysfunction (MODS), organ failure and death can occur as a result of severeinflammation (SIRS), overwhelming infection (CARS) or both if pro- and anti-inflammatory mechanisms are not in balance.
Acquired immune response
The innate immune response also serves to activate and amplify acquired immunity.This effect is primarily mediated by IL-12, which causes the activation of T-cells andpromotes the differentiation of nave T-cells into the Th1 phenotype.67 The adaptiveimmune response is, however, induced primarily by the presentation of foreign antigensto CD4 and CD8 T-cells. CD4 T-cell activation causes further cytokineproduction and amplifies the innate and acquired immune systems. The specificcytokines produced by CD4 cells are dependent on the immunologicalmicroenvironment at the time of antigen presentation.
The best-defined subsets of CD4 T-cells are the Th1 and Th2 cells (Figure 8).These subsets are primarily defined by the cytokines that they produce. The primary
APCnaveT cell
IL-2
IL-12IL-18
Macrophagesuppression
ActivatedT cells
Activationof CTL
IL-4IL-4/IL-10
IFN C /IL-2
Type 1 Tcell Type IITcell
IFNC
IFN C
LT
IL-4 IL-5Neutrophilactivation
Eosinophilactivation
Macrophageactivation
B cell productionof complement
binding and opsonizingantibodies(IgG
2a)
B cell productionof neutralizing IgG(IgG
1,IgG
4)and IgE
Figure 8. The acquired immune system. Acquired immunity is divided into Th1 and Th2 responses. Th1
responses are facilitated by macrophage activation and IL-12 production. Helminths and allergens induce Th2responses. CTL, cytotoxic T lymphocyte; LT, lymphotoxin.
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cytokine produced by Th1 cells is IFN-g.68 IFN-g further amplifies the pro-inflammatory response by causing macrophage activation and stimulating the cytolyticfunctions of CD8 T-cells. IFN-g also stimulates B-cells to produce opsonizing andcomplement-binding IgG2a antibodies. The induction of the Th1 response is promotedby macrophage and dendritic cell-produced IL-12. Intracellular bacteria, bacterialproducts and some parasites, particularly Leishmania, stimulate IL-12 production. IL-12activates the transcription factor STAT4 in activated T-cells and promotes Th1
differentiation.69
Another transcription factor that is important in Th1 differentiation ist-bet. T-bet activation is induced by IFN-g, thus providing an amplification mechanismfor Th1 development.70 The primary function of Th1 cells is to promote phagocyte-mediated anti-microbial immunity.
Helminths and allergen exposure cause Th2 differentiation. These stimuli causeprolonged T-cell stimulation without a significant innate immune response ormacrophage activation. Th2 differentiation is induced by IL-4.71 Prolonged T-cellstimulation by helminths and allergens promotes IL-4 production yet causes little IL-12to be produced because of the minimum amount of macrophage activation. IL-4 causesactivation of the transcription factor STAT6, which promotes Th2 differentiation.72
Differentiated Th2 cells preferentially produce IL-4, IL-5, IL-10 and IL-13 (Figure 8). IL-4,along with IL-10 and IL-13, causes macrophage suppression as well as the production ofIgG1 and IgE antibodies that mediate allergic reactions, asthma and anti-parasiticimmune responses.71 Eosinophil activation is induced by IL-5. Therefore, the primary
function of Th2 cells is host defence against helminthic infections, although these cellsalso play a pathological role in the facilitation of asthma and allergic reactions.
Two additional subsets of T-cells are Th3 and T-regulatory 1 (Tr1) cells. Th3 cellsproduce TGF-b and play an important role in the development of immune tolerance,particularly after exposure to antigens delivered via the gastrointestinal tract.73 Tr1cells produce TGF-b and IL-10. These cells can be distinguished by the surfaceexpression of CD25.74 TGF-b suppresses the functions of Th1 and Th2 cells,macrophages, NK cells and B-cells. The importance of TGF-b in regulating the immuneresponse is demonstrated by the hyperinflammatory state that develops in mice thatare devoid of TGF-b owing to genetic manipulation. These mice exhibit markedsystemic inflammation and death within weeks of birth. Some recent studies alsoindicate that the overproduction of TGF-b, and IL-10, causes immunosuppression inpatients exposed to prior trauma, burns or sepsis.
SUMMARY
The hallmarks of acute inflammation are vasodilatation, oedema and leukocyteinfiltration. A tightly orchestrated process involving numerous soluble and cell-associated factors mediates these alterations. The innate immune system plays a criticalrole in the activation of inflammation. Macrophages produce pro-inflammatorycytokines, chemokines, tissue factor and NO that serve to amplify the pro-inflammatory response and activate the coagulation cascade. Non-cytokine factorssuch as the complement system, eicosanoids and PAF are also important. Thecoagulation cascade is a well-recognized component of the pro-inflammatory response.Recent studies have shown that thrombin is not only important in the induction offibrinclot formation, but also has direct pro-inflammatory functions. Endogenous anti-coagulant factors such as activated protein C, TFPI and anti-thrombin III serve tocontrol pro-coagulant mechanisms.
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Anaesthesiologists care for a variety of patients in whom inflammatory processesplay an important role in disease pathogenesis. Our understanding of the cellular andmolecular mechanisms causing inflammatory injury has advanced markedly during thepast decade. However, this knowledge has not yet translated into major advances in thetreatment of SIRS. Currently, meticulous attention to details such as adequate volumeresuscitation, optimizing tissue perfusion and oxygen delivery, aggressive treatment ofinfection, removal of necrotic tissue and enteral feeding provides mechanisms for
improving recovery in patients suffering critical injury and sepsis.
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