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Best Practice & Research Clinical Anaesthesiology

Vol. 18, No. 3, pp. 385–405, 2004

available online at

Mechanisms of the inflammatory response

Edward R. Sherwood* MD, PhD

Associate Professor
Tracy Toliver-Kinsky PhD

Assistant 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 management

challenges for anaesthesiologists. Major surgery, trauma, burns and sepsis all have large
inflammatory components. Acute inflammation is characterized by vasodilatation, fluid exudation
and neutrophil infiltration. These processes are activated and amplified by a series of intracellular
and extracellular factors that tightly co-ordinate the inflammatory process. The innate immune
system responds rapidly to infection or injury. Macrophages, natural killer cells, CD8 þ T-
lymphocytes and neutrophils provide an early response to injurious factors in an effort to contain
and eliminate harmful stimuli. The adaptive immune response requires prior exposure to
microbial antigens, is mediated primarily by CD4 þ T-lymphocytes and serves to further amplify
acute inflammation. Although acute inflammation is fundamentally beneficial, severe inflammation
can precipitate the systemic inflammatory response syndrome. This syndrome is characterized by
hyperinflammation 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 for
patients 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 encountered

by anaesthesiologists and critical care practitioners on a daily basis. Surgery, sepsis,
major trauma, burns, adult respiratory distress syndrome and ischaemia –reperfusion
injuries have major inflammatory components. Our understanding of the basic
immunology of inflammation has progressed significantly during the past 10 years.
However, these advancements in knowledge have not translated into widespread
application in the clinical setting. This review will address the basic mechanisms of

* Corresponding author. Tel.: þ1-409-772-1221; Fax: þ1-409-772-1224.

E-mail address:, (E.R. Sherwood).

1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
386 E. R. Sherwood and T. Toliver-Kinsky

inflammation. In later chapters, authors will discuss how inflammatory processes

present in the operating room and intensive care unit.


Vasodilatation, fluid exudation and leukocyte migration

Inflammation is a response to infection, antigen challenge or tissue injury that is

designed to eradicate microbes or irritants and to potentiate tissue repair. Excessive
inflammation may, however, lead to tissue injury and can, if severe, cause physiological
decompensation, organ dysfunction and death. Inflammation can be divided into two
major categories—acute and chronic—based on timing and pathological features.
Chronic inflammatory diseases include rheumatoid arthritis, systemic lupus erythe-
matosus, silicosis, atherosclerosis and inflammatory bowel disease. These disorders are
characterized by a prolonged duration (weeks to months to years) in which active
inflammation, tissue destruction and attempts at tissue repair are occurring
simultaneously.1 Infiltration of mononuclear cells and fibrosis are typical histological
features of chronic inflammation.2 Chronic inflammatory diseases commonly pose
management challenges to anaesthesiologists. However, disease processes caused by
acute inflammation present some of the most intense management problems for
anaesthesiologists and critical care practitioners. Sepsis, severe trauma and major
surgery all have major acute inflammatory components. Acute inflammation is typically
of relatively short duration (hours to days) and is characterized by vasodilatation, the
exudation 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 characterized
by redness and warmth at the site of injury. The purpose of the vasodilatory response is
to facilitate the local delivery of soluble mediators and inflammatory cells. Inflammation-
induced vasodilatation is mediated primarily by nitric oxide (NO) and vasodilatory
prostaglandins. NO is produced from L -arginine through the action of nitric oxide
synthase (NOS) (Figure 1). Three isoforms of NOS have been identified. Endothelial
NOS (eNOS) and neuronal NOS (nNOS) are constitutively produced, and their
expression is increased by calcium flux. Activated leukocytes produce inducible NOS
(iNOS) after exposure to microbial products or pro-inflammatory cytokines.5 The NO
produced causes subsequent smooth muscle relaxation through cyclic GMP-dependent
mechanisms.6 The primary vasodilatory prostaglandins are prostacyclin (PGI2), PGD2,
PGE2 and PGF2a (Figure 2). These lipid mediators are produced from arachadonic acid
through the action of cyclo-oxygenase.7 Inflammation-induced vasodilatation initially
involves arterioles followed by the opening of new microvascular beds. In cases of severe
systemic inflammation such as sepsis, widespread vasodilatation can cause systemic
hypotension and shock.8 These cardiovascular alterations are potentiated by sepsis-
induced myocardial depression, a condition that is induced by the actions of NO and pro-
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 the
transvascular flux of protein-rich fluid from the intravascular compartment into the
interstitium as a result of the actions of histamine, bradykinin, leukotrienes,
complement components, substance P and platelet-activating factor (PAF).10,11 These
factors markedly alter the barrier functions of small blood vessels and increase the
permeability of capillaries and venules for both water and protein.12,13 At the same
Vascular smooth muscle relaxation and vasodilation

Calcium influx NO Macrophage NO

and NOS
NO2 + OH2 ¬ O + NO

Microbe Activation
Endothelial iNOS

Mechanisms of the inflammatory response 387

Endothelium Cytotoxicity

Figure 1. Nitric oxide (NO) in the regulation of vasodilation during inflammation. NO production is mediated by several nitric oxide synthase (NOS) isoforms including
eNOS, nNOS and iNOS. Expression of eNOS and nNOS are regulated by transcellular calcium flux whereas as iNOS production is induced by inflammatory mediators such
as 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 from
R. Cotran, V. Kumar, T. Collins, Pathologic Basis of Disease, Saunder, 1999, with permission).
388 E. R. Sherwood and T. Toliver-Kinsky


Membrane Arachidonic PGG2 PGH2

Phospholipids Acid

Cyclooxygenase PGE2

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, PGE2
and PGF2a. COX, cyclo-oxygenase; PG, prostaglandin.

time, capillary hydrostatic pressure is increased at the site of injury early during
inflammation or injury as a result of local vasodilatation. The outpouring of protein-rich
fluid causes a concentration of erythrocytes in small vessels and increased viscosity of
the blood. This transvascular fluid flux eventually returns intravascular pressures at the
site of inflammation to normal. At the same time, the loss of plasma proteins decreases
the intravascular oncotic pressure. Together, the increase in vascular permeability,
transient augmentation of capillary hydrostatic pressure and fall in plasma oncotic
pressure act to induce a transvascular flux of fluid and protein into the inflamed
interstitium. The function of these alterations is to allow the delivery of soluble factors
such as antibodies and acute-phase proteins to the site of injury. Severe systemic
inflammation can, however, cause inappropriate increases in vascular permeability that
can result in oedema formation in the lungs and extremities. The accumulation of fluid
in the lungs causes the acute respiratory distress syndrome, a major source of
morbidity and mortality in critically ill patients.13 Oedema accumulation in the
extremities may lead to compartment syndrome and the loss of vital perfusion in the
distal extremities.14
Vasodilatation and fluid exudation are accompanied by leukocyte margination,
adhesion and migration. Neutrophils are the first and most abundant leukocytes to be
delivered to a site of infection or inflammation. The process of neutrophil migration
from 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 of
neutrophil movement from the central bloodstream to the periphery of the vessel. This
phenomenon is facilitated by stasis following fluid exudation at the site of inflammation
and physical interactions between erythrocytes and neutrophils.16 After margination, a
weak 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, rolling
velocity being proportional to red cell velocity.17
The adhesive interactions that permit leukocyte rolling are facilitated by selectins
and their ligands (Table 1). Selectins are a family of glycoprotein surface molecules that
are expressed on leukocytes (L-selectin), endothelial cells (E-selectin) and platelets (P-
selectin) that bind sialylated carbohydrate determinants on adjacent cells.18,19 The
combined forces of selectin– ligand interaction and vascular shear forces promote
neutrophil rolling. As rolling progresses, a high-affinity adhesive interaction known


L-selectin CD11b


Mechanisms of the inflammatory response 389

Bacteria 5

Figure 3. Mechanisms of neutrophil rolling, adherence, diapedesis and chemotaxis. Inflammation causes neutrophil margination followed by development of loose
interactions between endothelial cells and neutrophils. These interactions are mediated by selectins and their ligands, which facilitates neutrophil rolling. Neutrophil
adherence is then potentiated by interactions between beta-integrins and intercellular adhesion molecules (ICAM). Neutrophils then migrate to the site of inflammation by
interaction with chemoattractant molecules such as chemokines and bacterial products. (Adapted from Seely et al, Critical Care 2003; 7: 291–307 with permission).
390 E. R. Sherwood and T. Toliver-Kinsky

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 Adherence
CD11b/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,
platelet –endothelial cell adhesion molecule-1.

as adherence develops. Adherence is necessary for subsequent neutrophil diapedesis

and 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 beta
subunits. The beta-2 integrins are the most widely studied and understood. These
molecules are composed of distinct alpha subunits (CD11a, CD11b, CD11c) that are
bound to a common beta subunit (CD18).20 beta-2 integrins are expressed on the
surface 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 and
facilitate diapedesis and chemotaxis. beta-2 integrins and ICAMs are constitutively
present on the surface of neutrophils and endothelial cells, but their expression is
upregulated during periods of inflammation, which promotes the transition from rolling
to adherence.21
Following adherence, the neutrophil must penetrate the endothelium and basement
membrane to enter the extravascular inflammatory environment. Neutrophils pass
through endothelial cell junctions, a process that is partly facilitated by endothelial
retraction.22 In addition, adhesion molecules such as platelet – endothelial cell adhesion
molecule-1 (PECAM-1) facilitate diapedesis (Table 1). PECAM-1 is present on the
lateral surfaces of endothelial cells as well as on neutrophils. The binding of PECAM-1
decreases neutrophil adhesion to ICAM-1, resulting in the inhibition of adherence and
the promotion of diapedesis.23 The processes of rolling, adherence and diapedesis are
therefore mediated through complex interactions between adhesion molecules on
neutrophils and endothelial cells. The ultimate goal of these interactions is to facilitate
the migration of neutrophils from the intravascular compartment and into the
interstitium at sites of infection or injury.
Neutrophils and other leukocytes also require chemoattractants to facilitate their
migration to sites of injury or infection. Chemoattractants are soluble molecules such
as 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 leukocyte
specificity. Classical chemoattractants include N-formylated peptides produced by
bacteria, complement components and leukotrienes.24 – 26
Chemoattractant cytokines or chemokines are leukocyte products that also serve
to attract leukocytes into tissues (Table 2). They are a group of more than 40 peptides
with 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
Mechanisms of the inflammatory response 391

Table 2. Classification of chemokines.

Chemokine type Target cell

IL-8 Neutrophils
GROa (mouse equivalent is GRO/KC) Neutrophils
GROb (mouse equivalent is GRO/KC) Neutrophils
GROg (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
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-lymphocytes
TECK 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

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 of
the family that are lymphocyte chemoattractants. The beta chemokines are
chemoattractants for a variety of leukocytes including basophils, monocytes,
eosinophils and lymphocytes. The alpha chemokines act in concert with beta
chemokines and cytokines to mediate the pro-inflammatory response to injury and
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
392 E. R. Sherwood and T. Toliver-Kinsky

the inflammatory infiltrate within injured tissue is determined by the profile of

chemokine secretion induced by a particular disease or inflammatory process.27
Leukocyte migration is further regulated by chemokine receptors that exhibit
specificity for both the cell type on which they are expressed and the chemokine
that they bind.28 Chemokine receptors are a family of G-protein-coupled proteins with
seven transmembrane regions. Although these receptors are structurally similar, they
are 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 is

activated during tissue injury and during infection. It is divided into two pathways that
converge and ultimately cause the activation of thrombin with the subsequent cleavage
of fibrinogen into fibrin (Figure 4). The intrinsic pathway is a series of plasma proteins
that are activated by Hageman factor (factor XII), a protein synthesized in the liver that
is activated by binding to collagen, basement membrane or activated platelets.29
Activated Hageman factor triggers the activation of a cascade of proteins, resulting in
the formation of thrombin. The intrinsic pathway is most commonly activated by direct
tissue 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 pathway
activated during infection and systemic inflammation, particularly during sepsis and the
systemic inflammatory response syndrome (SIRS).30 Tissue factor is expressed on
tissue surfaces that are not normally exposed to the vascular compartment, such as
subcutaneous tissues and the adventitial layer of blood vessels. In addition, endothelial
cells and activated monocytes produce tissue factor during periods of inflammation in
response to TNF-a, IL-1, IL-6 and C-reactive protein.4 The presence of tissue factor
causes the activation of factor VII, which then forms a complex with tissue factor and
ultimately causes the formation of thrombin by the activation of a series of coagulation
factors (Figure 4).
Activation of the coagulation cascade is not only important in the formation of fibrin
clots, but also has important effects on the pro-inflammatory response. Factor Xa,
thrombin and the tissue factor–VIIa complex have been shown to elicit pro-
inflammatory activity. Specifically, thrombin and the tissue factor– VIIa complex can
induce the production of pro-inflammatory cytokines such as TNF-a by mononuclear
and endothelial cells.31 This effect appears to be mediated by the binding of these
factors to protease-activated receptors on the surface of target cells. Therefore, acute
inflammation causes activation of the coagulation cascade, which can then further
potentiate 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-coagulant
mechanisms. The most well-defined factors are anti-thrombin, the protein C system
and tissue factor pathway inhibitor (TFPI) (Figure 5). Anti-thrombin is produced in the
liver and directly binds to and inactivates thrombin.32 The binding of anti-thrombin to
thrombin is greatly potentiated by heparin and by glycosaminoglycans present on the
endothelial cell surface. In rodents, the interaction of anti-thrombin with the
endothelial cell surface promotes the release of PGI2, which inhibits TNF-a production
by monocytes through the inhibition of transcription factor nuclear factor-kB (NF-kB)
Mechanisms of the inflammatory response 393

Intrinsic pathway Extrinsic pathway

contact activation Tissue injury

Exposure of Vessel damage

connective tissue or Subendothelial tissue
negatively charged surface exposed to blood


Tissue factor



X Xa

Va + Xa

Prothrombin Thrombin


I Isol Istable
Fibrinogen Soluble Stable
fibrin fibrin

Figure 4. The coagulation cascade. The extrinsic and intrinsic pathways of coagulation converge upon the
final common pathway. The extrinsic pathway is activated by tissue factor, which is exposed upon tissue injury
as well as macrophage activation. The intrinsic pathways is induced by exposure of subendothelial collagen and
activated platelets. The final result is the formation of fibrin clot. (Adapted from Dellinger EP, Clinical
Infectious Diseases 2003; 36: 1259–1265, with permission).

activation.33 Thus, anti-thrombin may have anti-inflammatory properties in addition to

its function in regulating coagulation.
Protein C is a circulating protein that is activated by the thrombin – thrombomodulin
complex on the surface of endothelial cells. Activation of protein C decelerates the
clotting cascade by inactivating factors Va and VIIIa.34 Activated protein C also inhibits
the thrombin-induced production of TNF-a by monocytes by inhibiting the activation
of transcription factors NF-kB and AP-1 (see below).35 Therefore, activated protein C
has both anti-coagulant and anti-inflammatory properties. During sepsis, activated
protein C can become depleted owing to consumption and the inflammation-induced
down-regulation of thrombomodulin. This results in the unchecked formation of
394 E. R. Sherwood and T. Toliver-Kinsky

Macrophage/ TNF Endothelial

Monocyte Cell
Protein C
Tissue Factor Pathway
1. Degradation of
VIIa Va and VIIIa
Tissue Factor 2. Inhibition of
Pathway Inhibitor VIIIa IXa inflammation
Binds tissue
Factor–VII a
complex Va
Fibrin clot

Anti-Thrombin Macrophage/
III Thrombin
Binds thrombin Activation

Figure 5. Regulation of the coagulation cascade during inflammation. Several endogenous pathways regulate
the coagulation cascade. These include activated protein C, tissue factor pathway inhibitor and anti-thrombin III.

thrombin, causing accelerated coagulation and increased pro-inflammatory activity. The

importance of protein C in regulating thrombin formation during sepsis is
demonstrated by increased mortality in septic patients who have low activated protein
C levels.36
A third important factor in the regulation of thrombin formation is TFPI. TFPI is
present on the surface of endothelial cells and bound to lipoproteins in the plasma. TFPI
inactivates tissue factor by forming a quarternary complex with tissue factor and factor
VIIa. Factor Xa comprises the fourth component of the complex.37 The inhibition of
tissue factor function inhibits activation of the extrinsic clotting pathway during
inflammation. The infusion of TFPI has also been shown to decrease pro-inflammatory
cytokine 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 serve
to promote inflammation and microbial destruction. It is likely that the complement
cascade is also activated during tissue injury and plays a role in cellular injury associated
with 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 other
structures activate the classical pathway, so called because it was the first pathway to be
defined. The alternative pathway was discovered after the classical pathway but is
phylogenetically older. It is triggered directly by microbial surface molecules that bind
the complement component C3 and serve as a platform for the activation of
complement proteins. The lectin pathway is activated by mannose-binding lectin, which
interacts with microbial glycoproteins and glycolipids.
Any of these pathways will activate the cleavage of complement component C3 into
C3a and C3b. C3a serves as a neutrophil chemoattractant. C3b binds to the surface of
Mechanisms of the inflammatory response 395

antigen/antibody C3 microorganisms

Classic Pathway Alternative Pathway


Lectin Pathway
C3a C3b


C5-C9 Membrane attack

terminal sequences complex(MAC)

Figure 6. The complement system. The complement cascade is activated by several mechanisms including
the classic, alternative and lectin pathways. The major mediators of the complement pathway are C3a and C3b
that act as pro-inflammatory factors. In addition, formation of the membrane attack complex (C5-C9) causes
disruption of cellular membranes.

microbes to facilitate recognition by phagocytes and promote phagocytosis.39 In

addition, C3b forms a proteolytic complex with other complement components to
cause the cleavage of C5 into C5a and C5b.40 C5a is a chemotactic factor for
neutrophils and also alters vascular permeability at the site of inflammation. C5b binds
to the microbial surface and facilitates the formation of the membrane attack complex
composed of C6, C7, C8 and C9.41 The membrane attack complex causes disruption of
the microbial cell membrane and subsequent death.


Innate immune system

The immune response to tissue injury or infection can be divided into innate and
adaptive responses. The innate immune system mounts the initial response to tissue
invasion. The previously discussed phases of vasodilatation, increased vascular
permeability and cellular infiltration are part of the innate immune response. The
primary cellular components of the innate immune system are macrophages, dendritic
cells, natural killer (NK) cells and neutrophils (Figure 7). In addition to these cellular
components, circulating effector proteins such as complement, acute-phase reactants
and the coagulation cascade play important roles in innate immunity.
The activity of cytokines and non-cytokine mediators of inflammation largely
determines the magnitude of the innate response. Cytokines are polypeptides that are
produced by cells of the immune system in response to infection or tissue injury.1 They
serve to regulate immune and inflammatory reactions. The production of cytokines is
generally self-limited, although some cytokines can persist in the circulation for long
periods 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
396 E. R. Sherwood and T. Toliver-Kinsky
Infection, Tissue Injury, Antigen exposure

Innate Response Acquired Response

NK cells
T Lymphocytes
Endothelial cells B Lymphocytes

Phagocytosis Production Th1

of CD8+ CD4+
Production Complement Cytokines, Th2
of ROS Activation Eicosanoids,
Chemokines, IgE
Antigen Tissue factor Cytokine IgG1
Presentation secretion IgG2

Cell lysis
Opsonization Parasite killing
Complement Allergy

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, natural
killer; ROS, reactive oxygen species; CD, cluster of differentiation; Ig, immunoglobulin; Th, T helper.
Mechanisms of the inflammatory response 397

isotype-switching in B-cells to cause the production of opsonizing IgG subclasses of

antibodies, and stimulates T-helper-1 (Th1) cell differentiation in T-cells.42 Redundancy
among cytokines also exists. The classic examples are TNF-a and IL-1. Both of these
cytokines have the capacity to induce fever, stimulate the production of acute-phase
proteins by the liver and cause endothelial cell activation. Cytokines are therefore
multifunctional groups of proteins that frequently have overlapping functions. For this
reason, the blockade of a single cytokine will often have limited effects on the overall
inflammatory response.43
The classical cytokine-secreting cells of the innate immune system are macrophages.
Dendritic cells were also recently recognized as important effector cells for microbial
recognition and cytokine production during innate immunity.44,45 Macrophages and
dendritic cells have the ability to respond to a variety of microbial products through
pattern-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-associated
molecular patterns and subsequent intracellular signalling.46 TLRs form associations
with other molecules to form cell surface receptor complexes that are relatively
specific for certain ligands such as lipopolysaccharide from Gram-negative bacteria,
lipoproteins from Gram-positive organisms and bacterial DNA (Table 3). However, all
of 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 are
the best understood.47 Binding of ligand to the TLR complex causes the recruitment of
several cytoplasmic signalling proteins, including the adapter protein MyD88 and the IL-
1 receptor-associated kinase (IRAK). IRAK recruitment causes autophosphorylation
and the dissociation of IRAK from MyD88. Phosphorylated IRAK induces the activation
of 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 the
subsequent release of cytoplasmic NF-kB. Transcription factor NF-kB then
translocates into the nucleus to bind gene promoter regions and regulate the
transcription of genes encoding pro-inflammatory mediators such as TNF-a, IL-1b, IL-6
and iNOS.48 The activation of TRAF-6 also causes the induction of mitogen-activated
protein (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
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
398 E. R. Sherwood and T. Toliver-Kinsky

AP-1. Like NF-kB, AP-1 binds the promoter region of genes encoding pro-inflammatory
mediators and promotes the production of pro-inflammatory cytokines.49
The prototypical pro-inflammatory cytokine is TNF-a. TNF-a is released primarily
by macrophages within minutes of local or systemic injury and modulates a variety of
immunological and metabolic events. At sites of local infection or inflammation, TNF-a
initiates 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 fibroblasts
and an angiogenesis factor (Table 4).50
The systemic release of TNF-a can, however, precipitate a destructive cascade
of events that can result in tissue injury, organ dysfunction and potentially death.

Table 4. Cytokine mediators of inflammation.

Cytokine Polypeptide Cell Cell Primary

size source target effects

Tumor necrosis 17 kDa Monocytes, Neutrophil Activation

factor-a (TNF-a) macrophages, (inflammation)
Endothelial cell Activation
release of vasodilators
nitric oxide (NO)
Hypothalamus Fever
Liver Acute-phase response
Muscle, fat Catabolism
Heart Myocardial suppression
Macrophages Release of cytokines,
T-lymphocytes Inflammation
Various tissues Apoptosis?
Interleukin-1 (IL-1) 17 kDa Monocytes, T-cells Activation (inflammation)
Endothelial cell Activation
release of vasodilators (NO)
Liver Acute-phase response
Hypothalamus Fever
Muscle, fat Catabolism
Interleukin-6 (IL-6) 26 kDa Monocytes, Liver Acute-phase response
endothelial cells
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, Activation, differentiation
NK cells
Interleukin-18 Macrophages T-cells, NK cells Activation, differentiation
Mechanisms of the inflammatory response 399

Among the systemic effects of TNF-a are induction of fever, stimulation of acute-phase
protein secretion by the liver, activation of the coagulation cascade, myocardial
suppression, induction of systemic vasodilators with resultant hypotension, catabolism
and hypoglycaemia. Numerous studies have shown that the administration of TNF-a to
experimental animals will induce physiological responses that mimic the systemic
inflammatory response observed in sepsis and after severe injury.51
Most of the pro-inflammatory and metabolic effects are mediated through the
activation of TNF – receptor II (TNF-RII) complex. This receptor signals through the
group of linking proteins known as TRAFs, of which six (TRAF-1 through TRAF-6) are
currently defined.52 These factors induce the expression of pro-inflammatory genes
through the transduction of signals that activate the NF-kB and AP-1 transcription
factors. Another important effect of TNF-a is its ability to induce apoptosis after
binding to the TNF-RI complex. Activation of TNF-RI causes recruitment of the TNF
receptor death domain (TRADD) to the plasma membrane. TRADD recruits other
proteins such as FAS-associated death domain protein (FADD), which recruits and
activates caspase-8, leading to downstream activation of an apoptosis-inducing caspase
cascade.52 Apoptosis is an important process in resolution of the inflammatory
The physiological effects of IL-1 are essentially identical to those of TNF-a. IL-1 does
not, however, induce tissue injury or apoptotic cell death by itself, although it can
potentiate 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 been
identified.53 The IL-1 receptor antagonists (IL-1ra) bind to the IL-1 receptor but do not
induce receptor activation. These proteins appear to function as competitive inhibitors
of IL-1 action. IL-18-binding protein functions in a similar fashion and inhibits the
function of IL-18.54 Interestingly, although IL-1 and IL-18 signal through similar
mechanisms, their functions are quite different. As mentioned above, IL-1 serves to
activate a variety of pro-inflammatory mechanisms, whereas IL-18 acts in conjunction
with IL-12 to stimulate IFN-g production by NK and Th1 cells.
IL-6 is another cytokine that is released during inflammation and has several
important effects. Macrophages, endothelial cells and fibroblasts secrete this
polypeptide. The primary effect of IL-6 is to induce the secretion of acute-phase
proteins 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, the
persistent 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 useful
marker of ongoing inflammation.
As described earlier in this chapter, chemokines are a family of proteins that function
primarily as chemotactic factors for leukocytes. IL-8 is produced by macrophages and is
one of the most widely studied chemokines in the setting of inflammation. IL-8 is a
potent chemoattractant for recruiting neutrophils to inflammatory foci. Several studies
have shown that IL-8 plays a role, particularly in the lung, in mediating tissue injury in the
setting of trauma and burn injury.27 It is likely that that other chemokines are also
important mediators of inflammatory injury.
IL-12 is a cytokine produced by activated macrophages and dendritic cells. Its most
important function is to stimulate the production of IFN-g by T-cells and NK cells. In
addition, IL-12 is an important mediator of the early immune response to intracellular
micro-organisms and in the facilitation of adaptive immunity. Many different types of
microbe induce the production of IL-12, which acts in conjunction with IL-15 and IL-18
to induce IFN-g production by NK cells.56 IFN-g is a cytokine involved in
400 E. R. Sherwood and T. Toliver-Kinsky

the amplification of inflammatory responses, particularly the stimulation of cytokine

secretion, phagocytosis and respiratory burst activity by macrophages. IL-12 and IFN-g
function together to amplify both innate and adaptive immune responses. Specifically,
IL-12 produced by macrophages and dendritic cells induces IFN-g production by NK
cells. 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 and
IFN-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 has
been shown to markedly decrease the deleterious inflammatory effects during septic
shock.57 Therefore, IL-12 and IFN-g may be important in the amplification of sepsis and
in SIRS.
Several non-cytokine inflammatory mediators have been implicated in the
pathogenesis of SIRS. PAF is a phospholipid autocoid released by endothelial cells
that 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 with
poor outcome. Eicosanoids are arachadonic acid metabolites that regulate many
aspects of the immune response. Leukotrienes (LTC4 – LTE4) induce contraction of the
endothelial cells and encourage capillary leakage. Thromboxane A2, a macrophage and
platelet-derived factor, promotes platelet aggregation, vasoconstriction and, potentially,
tissue thrombosis.
The immune response is tightly controlled and usually functions effectively to limit
infection 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 of
activated macrophages and dendritic cells, and serves as an important regulator of the
inflammatory response.59 Mice that are depleted of IL-10 exhibit hyperinflammation
following challenge with bacterial endotoxin or intact bacteria. The addition of
exogenous IL-10 causes significant suppression of the pro-inflammatory response. The
primary effect of IL-10 is the suppression of IL-12 production by activated macrophages
and dendritic cells. This results in the subsequent suppression of IFN-g production by
NK cells and activated T-cells, causing the disruption of IL-12/IFN-g-mediated
amplification 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-CSF
decreases TNF-a, IL-1, and IL-12 production by interacting with G-CSF receptors on
monocytes and macrophages. In addition, G-CSF treatments increase levels of IL-1ra
and soluble TNF receptors, naturally occurring pro-inflammatory cytokine antagon-
ists.60,61 Therefore, G-CSF promotes local anti-microbial defence through the
enhancement of neutrophil functions while exerting anti-inflammatory effects
systemically.62 – 64
In cases in which the pro-inflammatory response predominates, severe systemic
inflammation may ensue, as typified by sepsis and SIRS.65 Conversely, predominance of
the anti-inflammatory response may cause a state of relative immunosuppression to
develop. This phenomenon often results after major trauma or thermal injury, or in the
post-septic state, and has been termed the counter-anti-inflammatory response
syndrome (CARS).66 Several studies have shown that IL-10 predominance is a factor in
the development of post-inflammatory immunosuppression. Patients exhibiting CARS
may be more susceptible to infectious complications. In either case, multisystem organ
Mechanisms of the inflammatory response 401

dysfunction (MODS), organ failure and death can occur as a result of severe
inflammation (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 and
promotes the differentiation of naı̈ve T-cells into the Th1 phenotype.67 The adaptive
immune response is, however, induced primarily by the presentation of foreign antigens
to CD4 þ and CD8 þ T-cells. CD4 þ T-cell activation causes further cytokine
production and amplifies the innate and acquired immune systems. The specific
cytokines produced by CD4 þ cells are dependent on the immunological
microenvironment at the time of antigen presentation.
The best-defined subsets of CD4 þ T-cells are the Th1 and Th2 cells (Figure 8).
These subsets are primarily defined by the cytokines that they produce. The primary

APC T cell


IL-12 suppression
IL-18 Activated
T cells

of CTL
Type 1 Tcell Type II
IL-4 IL-5
B cell production
Macrophage of complement
activation B cell production
binding and opsonizing of neutralizing IgG
antibodies(IgG2a) (IgG1,IgG4)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 Th2
responses. CTL, cytotoxic T lymphocyte; LT, lymphotoxin.
402 E. R. Sherwood and T. Toliver-Kinsky

cytokine produced by Th1 cells is IFN-g.68 IFN-g further amplifies the pro-
inflammatory response by causing macrophage activation and stimulating the cytolytic
functions of CD8 þ T-cells. IFN-g also stimulates B-cells to produce opsonizing and
complement-binding IgG2a antibodies. The induction of the Th1 response is promoted
by macrophage and dendritic cell-produced IL-12. Intracellular bacteria, bacterial
products and some parasites, particularly Leishmania, stimulate IL-12 production. IL-12
activates the transcription factor STAT4 in activated T-cells and promotes Th1
differentiation.69 Another transcription factor that is important in Th1 differentiation is
t-bet. T-bet activation is induced by IFN-g, thus providing an amplification mechanism
for 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 cause
prolonged T-cell stimulation without a significant innate immune response or
macrophage activation. Th2 differentiation is induced by IL-4.71 Prolonged T-cell
stimulation by helminths and allergens promotes IL-4 production yet causes little IL-12
to be produced because of the minimum amount of macrophage activation. IL-4 causes
activation 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 of
IgG1 and IgE antibodies that mediate allergic reactions, asthma and anti-parasitic
immune responses.71 Eosinophil activation is induced by IL-5. Therefore, the primary
function of Th2 cells is host defence against helminthic infections, although these cells
also 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 cells
produce TGF-b and play an important role in the development of immune tolerance,
particularly after exposure to antigens delivered via the gastrointestinal tract.73 Tr1
cells produce TGF-b and IL-10. These cells can be distinguished by the surface
expression 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 immune
response is demonstrated by the hyperinflammatory state that develops in mice that
are devoid of TGF-b owing to genetic manipulation. These mice exhibit marked
systemic inflammation and death within weeks of birth. Some recent studies also
indicate that the overproduction of TGF-b, and IL-10, causes immunosuppression in
patients exposed to prior trauma, burns or sepsis.


The hallmarks of acute inflammation are vasodilatation, oedema and leukocyte

infiltration. A tightly orchestrated process involving numerous soluble and cell-
associated factors mediates these alterations. The innate immune system plays a critical
role in the activation of inflammation. Macrophages produce pro-inflammatory
cytokines, chemokines, tissue factor and NO that serve to amplify the pro-
inflammatory response and activate the coagulation cascade. Non-cytokine factors
such as the complement system, eicosanoids and PAF are also important. The
coagulation cascade is a well-recognized component of the pro-inflammatory response.
Recent studies have shown that thrombin is not only important in the induction of fibrin
clot formation, but also has direct pro-inflammatory functions. Endogenous anti-
coagulant factors such as activated protein C, TFPI and anti-thrombin III serve to
control pro-coagulant mechanisms.
Mechanisms of the inflammatory response 403

Anaesthesiologists care for a variety of patients in whom inflammatory processes

play an important role in disease pathogenesis. Our understanding of the cellular and
molecular mechanisms causing inflammatory injury has advanced markedly during the
past decade. However, this knowledge has not yet translated into major advances in the
treatment of SIRS. Currently, meticulous attention to details such as adequate volume
resuscitation, optimizing tissue perfusion and oxygen delivery, aggressive treatment of
infection, removal of necrotic tissue and enteral feeding provides mechanisms for
improving recovery in patients suffering critical injury and sepsis.


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