MATOLOGY

~d factor-I
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CHAPTER

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SO years that tile modern techniques of biochemistry. tissue culture,

monoclonal 8.lIlibody production, recombinant D A technology, and
the genetic manipulation of isolated cells and whole animal~. have
enabled a more detailed understanding of the cellular and molecular
mechanisms which characterize the inilammatory response. These
studies, in concert with "ex.periments of nature" such as chronic gran
ulomatous disease (sec Chap. 66) and the leukocyte adhesion defi
ciency disorders (see Chap. 66), have provided for the formulation of
complex, yet legant, models of acute and chronic inflammation and
led to the promise of incisive therapeutic approaches, A vaSI anay of
human diseases is marked by either defects in the development of the
inflammatory response or the deleterious effects of the inflammatory
response itself.

HE INFLAMMATORY RESPONSE

JEFFREY 5 WARREN
PETER A. WARD

ood burst
)f erythro-

Villebrand
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:1tiatlon in
transcrip

mllammatory respon e is charact.erized by a rapid but reI

I) short-lived increase in local blood ftow, an increase in
rtll ular permeability, and the sequential recruitment of
not types of leukocytes. Superimposed is a series of reo
JIll' Iii processes (e.g., parenchymal regeneration angioge
. production of extracellular matrix, and scar formation).
early hemodynamic changes at a site of inflammation es
bll h conditions that enable marginated leukocytes to engage
10 nity seleclin-mediated rolling interactions with en
hrlial cells. In response to locally produced oluble and cell
rf t mediator, endotheliaJ cells and rolling leukoc}1es be
a~livated and :equentially expre. sets of complementary
'un molecules that include/32 integrins. selectins, and
btr'l
the immunoglobulin superfamily. Leukocyte and
IlllIolbclial cell adhesion molecutes mediate the bigh-affinity
lie interactions necessary for leukocyte emigration from
\ ular pace and along chemotactic gradients. Analogous,
.lIy regulated, soluble mediators and cellular adhesion
111 s aL~o orchestrate succeeding monocyte and lympbo.
rl b chronic inflammatory responses. This basic paradigm
mudulaled by 11 large number of surface-active and soluble
mmatory mediators. Botb recruited leukocytes and cells
OIlUS to the anatomic site of inflammation play critical
10 host defense and Ii, sue repair.

GENERAL CHARACTERISTICS OF INFLAMMATION

While necessarily contrived, it is useful to consider inflammation as
an acute or chronic process. "Acute" inflamm tion lasts from minutes
to a few days and is characterized by local hemodynamic and micro
vascular changes and leukocyte accumulation 2 The acute inflamma
tory response is consistently marked by microvascular leakage and the
accumulation of neutrophils. The four cardinal signs of inflammation,
alluded to above. can be accounted for within the phy~iologic terms
of acute inflammation.
In contrast, the chronic inflammatory response, which lasts much
longer and is more varied in its effects, is also marked by the prolif
eration of resident fibroblasts and the growth of new capillaries. 2 el
lular infiltrates include primarily lymphocytes and monocytes but ther
are many variations in the cellular composition, anatomic distrihution,
and tempo of development of chronic inflammatory lesions. Chronic
inflammatory processes are classified according to these variation, For
example, granulomatous inflammation is a chronic process marked by
nodular aggregates of mononuclear phagocytes that have become
"transformed" into so-called epithelioid hi~tiocytes because of their
similar appearance to epithelial cells. Granulomas may be distributed
along blood vessels (e.g" angiocentric), along airways (e.g., broncho
centric), or randomly throughout the interstitium or parenchyma of an
organ. Other chronic inflammatory proce~ses are marked by a prepon
derance of plasma cells or eosinophils. In contrast to the more stereo
typed appearance of an acute inflammatory lesion, the particular ap
pearance of a chronic inflammatory lesion can sometimes provide
insight into its cause (e.g., caseating granulomas in tuberculosis, eo
sinophil-rich infiltrates in a parasitic infection, and plasma-cell-rich
infiltrates in viral hepatitis),
Superimposed upon the acute and chronic inflammatory response
is repair 2 Repair may entail the regeneration of parenchymal cells
damaged as the direct result of an insult per se or as "bystanders" to
the inflammatory response. R pair is characterized by the growth of
new capillaries (angiogene~is) and the activation of fibroblasts which
produce extracellular matrix. molecules (e.g.. scar ti sue). In some cir
cumstance an acute inilammatory response is self-limited (e.g., sun
burn), whereas in ther situations the response becomes chronic and
can persist for year (e.g., tuberculous granulomas).
This chapter first addresses acute inflammation, which encom
passes localized changes in blood flow, alterations in microvascular
permeahility, and neutrophil exudation. There has been great progress
in understanding of the processes of endothelial cell activation, leu
kocyte-endothelial cell rolling, and so-called stationary adhesive in
teractions, leukocyte emigration, leukocyte activation, and thl: subse
quent dampening of an inflammatory response. The second section of
this chapter introduces the vast array of soluble and surface-active
med iators that orchestrate both acute and chronic inflammatory re
spons s. These mediators include substance, that range from short
lived reactive oxygen and nitrogen intermediates to entire regulatory

or

liates my
menl pro

: and neu
le colony-

y
nlinel clinical features of acute inflammation, rubor, calor, tu
nd dolor, have been recognizl:d for 5000 years. Dr. John Hunter,
, ntlwned late 18th centur Scottish surgeon, observed that the
I matory response is not a disease per se but rather a nonspecific
IUIHr' response to a variety of insults. Through his microscopic
If ltons ultransparent vital membrane preparations, Julius Cohn
'Included that the inflammatory response is fundamentaUy a
1 r phenomenon. Phagocytosis was discovered late in the 19th
IT' hy Eli Metchnikoff and his colleagues. Morphologic studies,
I Ih live animals and fixed histologic preparations, transformed
III rstanding of inflammation and led to the currentiy held con
,I tntlammation-associated hemodynamic alterations, "acute" in
1m linn. and "chronic" inflammation.' It has been during the past

111 and abbreviation' Ibat appear in tbi, chapter include: BPI, baclcri
r-mne:lbilit\, increa,ing prolein; CAP37, cationic antimicrobial protein:
[, tel of differentiation; eNOS, endothelial nitric oxide synthase; HPETE,
~)'eico"'tctraenoic acid; rCAM, intercellular adhesion molecule: Ig,
~Jo>h~lin; IL, lllterleuk.in; iNOS, inducible nitric oxide synthase: L T, leu
.: LTB.I C, 1D.I E,. leukolriene B4 1 C4 I D4 1 E4; M SP, mannanIt-c[in~'sociatcd
,erine protease; MElL, mannan-binding lectin;
Ilf J. reduced nicotinamide adenine dmucleOlide phospale; nNOS, neuronal
lidesynthase; I 0, nitric oxide; NOS, nilric oxide synthase; PAF, platl"
ttn~ fa '[or; PSGLI, P-selectin glycoprotein ligand-I; RG ,arginine
panic acid peptide sequence; T F. tumor necrosis factor; VCAM, vas
Il :ldhr~ion molecule; VLA. very late anligen,

221

222

PART III MOLECULAR AND CELLULAR HEMATOLOO

systems (e.g., complement system and coagulation cascade). Finally,

a brief overview of chronic inflammation and tissue repair is provided.
This chapter provides a framework for understanding the basic pro
cesses of inflammation while promoting an appreciation for the highly
complex and integrated nature of the regulated inflammatory response.

ACUTE INFLAMMATION
HEMODYNAMIC CHANGES
The hemodynamic changes that occur early in the acute phase of in
flammation include arteriolar vasodilatation and a localized increase
in microvascular permeability (Fig. 16-1). In many circumstances, ar
teriolar vasodilatation follows a rapid and transient period of vasocon
striction. 3 Arteriolar vasodilatation results in increased blood flow,
thus explaining the familiar redness and warmth which characterize a
site of acute inflammation. The increase in blood flow, coupled with

NORMAL

Arteriole

increases in microvascular permeability, results in hemoconcentratiOll

and a localized increase in blood viscosity. These localized hemody
namic changes are critical to subsequent leukocyte emigration becau,e
selectin-mediated, low-affinity, rolling leukocyte-endothelial adh
sive interactions can efficiently occur only under conditions of reduced
shear force. Experimental studies using in vitro flow chambers and
live animals indicate that selectin-mediated leukocyte-endotheli~
rolling adhesive interactions cannot occur in the face of the shw
forces exerted by normal blood flow. Increased microvascular per
meability leads to protein-rich plasma exudation, which is charaCle!
istic of acute inflammation. Microvascular leakage occurs through a
variety of mechanisms, including venular endothelial cell contraction.
which is accompanied by widening of intercellular junctions; so-calloo
endothelial cell retraction, which is not well understood but involl'el
cytoskeletal changes; leukocyte-mediated endothelial cell injury; di
rect endothelial injury; and leakage via new capillaries that do not yet
possess fully "closed" intercellular junctions. 3 An increase in the mil
of transcytosis in which pi . ma constituenll
cross endothelial cells in vesicles or vacuole,
has a role in neoplastic blood vessels and may
playa role in inflammation.' Alterations in local
blood flow occur at the level of arterioles, whicb
are regulated largely by the autonomic nervo
system, vasoactive peptides, and eicosanoids.A
variety of soluble mediators can induce in
creases in microvascular penneability through
several of the above-mentioned mechanisms.
Venule

] INFLAMED

Edema expands
extracellular malrix

LEUKOCYTE RECRUITMENT
The orchestrated recruitment of leukocytes into
a site of inflammation is a fundamental char$
teristic of the inflammatory response. l The im
portance of white blood cells in host defense II
highlighted in patients with genetic defects iii
white cell function. Leukocytes are critical be
cause of their central role in the phagocytosil
and containment or killing of microbes and in
the digestion of necrotic tissue debris. leuko
cyte-derived products such as proteolytic en
zymes and reactive oxygen intermediates COl!
tribute to tissue injury.

LEUKOCYTE ADHESION AND

TRANSMIGRATION

Expansion of
capillary bed

FIGURE 16-1

Early hemodynamic events in acute inflammation. Vascular dilatation, increased mi

crovascular penneability, fluid transudation, and leukocyte recruitment and emigration occur after a
transient period of arteriolar vasoconstriction. (Modified and redrawn with permission from Robbins
Parh%gie Basis of Disease, 6th ed. WB Saunders, Philadelphia, 1999.)

When vascular stasis occurs as the result of the

hemodynamic changes of early acute inflam
mation, leukocytes are displaced from the cen
tral axial column of blood cells to a position
along the endothelial surface. This process is en
hanced under conditions of slowed blood flow.;
Individual leukocytes adhere transiently and
weakly to the endothelial surface. Studies using
vital membrane preparations and flow chamoo
studies using endothelial cell monolayers and
suspensions of purified leukocytes reveal (hsi
cells roll along the endothelial surface 6 Rolling
neutrophil-endothelial adhesive interactio
occur within minutes of the initiation of an aculf
inflammatory response and can, depending Oil
the time within the evolution of an inftammatof)
response, involve neutrophils, lymphocytes.
monocytes, basophils, or eosinophils. The leu

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6' ADHESION MOLECULES IN INFLAMMATION

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223

R 6 THE INFLAMMATORY RESPONSE

uglobulin
n'amily

({3,; leukocyte)

STRUCTURE

N-terminal lectin domain.

epidermal growth factor
domain, multiple complement
regulatory repeats,
transmembrane, and short
cytoplasmic tail
Multiple immunoglobulin
domains, transmembrane
region and cytoplasmic tail
Heterodimers: distinct Cl subunits
with common f3 subunits

EMBERS

P-selectin

E-selectin

L-selectin

TISSUE OISTRIBUTJO

Endothelium, platelets
Endothelium
Leukocytes

ICAM-!

Endothelium
ICAM-2

ICAM-3

VCAM-l

Endothelium
COl la/C018 (LFA-I)
Neutrophils, monocytes,
macro phages, and
lymphocytes
COllb/COI8 (Mac-I)
Neutrophils, monocytes, and macrophages
VLA-4

Monocytes and lymphocytes

COUNTERRECEPTOR

PSGL- I, Slex glycoprotein

PSGL-l, SLex glycoprotein
PSGL-l

COl la/COl 8
COllb/COI8
VLA-4
1 AM-!
rCAM-2
ICAM-3
ICAi\1-1, iC3b, LPS, and
fibronectin
VCAM-I and fibronectin

hlllt:r of difftrenriarion; ICAM, intercellular adhesion molecule; LPS, lipopolysaccharide; PSGL-l, P-selectin glycoprotein ligand-I; VCAM, vascular cell adhesion molecule:
lule antigen.

\\C-endothelial cell rolling adhesive interaction is a specific and

SLeX-bearing molecules), and is shed when the leukocyte is activated
(Table 16_1)9.10,14 L-selectin shedding facilitates leukocyte emigration
, Step that precedes high-affinity, or so-called stationary, ad
(n and emigration 6 .7 Early rolling adhesive interactions are medi
by allowing the white blood cell to detach from the endothelium. Low
affinity rolling adhesive interactions set the stage for ,I3-integrin and
hugely by selectins and their counterreceptors. 6 In tum, the cell
immunoglobulin superfamily mediated, high-affinity adhesive inter
;l;. txpression of selectins (and other intercellular adhesion mole
actions and leukocyte transmigration. 6,8.9
below) is regulated by a number of locally produced proin
1II1110ry mediators 6 ,7
Relatively weak selectin-mediated and high-affinity stationary ad
hesive interactions are not temporally or mechanistically discrete. For
l~tins contain an extracellular N-terminal carbohydrate-binding
example, TNF-a and !L-,13 induce both E-selectin, which is not ex
00 Ihat is homologous to mammalian lectins, an epidermal growth
pressed by quiescent cells, and increases in endothelial expression of
Inr-hke domain, a series of complement regulatory domains, and a
intercellular adhesion molecule (ICAM)-I and vascular cell adhesion
phluc transmembrane domain (Table 16-1 ).8.9 P-seleetin is expressed
molecule (VCAM)-I, which are constitutively expressed in low con
thelia! cells and platelets, E-selectin by endothelial cells, and L
centrations and, in the case of rCAM-I, are involved in the recruitment
~III by most white blood cells. P-selectin is stored in endothelial
of all types of leukocytes, and in the case of VCAM-l, are involved
:jloplasmic granules called Weibel-Palade bodies. 9-11 When en
in the recruitment of all types of chronic inflammatory leukocytes
Iial cells are exposed to histamine, thrombin, or platelet-activating
(lymphocytes, monocytes, eosinophil. and basophils).5 TCAM-! binds
(PAF), P-selectin is rapidly (within minutes) translocated to the
to ,132 (leukocyte) integrins, which are heterodimeric structures that
I
lial surface where it engages marginated leukocytes via carbo
contain varied alpha chains (CDlla, CDllb, CDIlc, CDlld) and a
\\lr,~ moieties lhal contain sialic acid residues (e.g., P-selectin gly
common beta chain (CD 18).15.16 VCAM-l binds to ,131 integrins (e.g.,
tein ligand-l [PSGL-I))8-11 This transient, low-affinity, binding
VLA-4/Cl4 ,131) (see Table 16-1).5.7 Activated endothelial cells secrete
tion, which can withstand only the low-flow shear force condi
lound in stasis, accounts in part for the early
Illig Interactions (Fig. 16-2). The development
Ingl knockout mice (i.e., lack individual se
[P-{-; E-/-; L-/-)), double knockout
Rolling
Transmigration
(e.g., Etp-/-), and even triple knockout
hal confirmed that rolling can be almost
letely accounted for by selectins. 46 .47 Ex
of endothelial cells to tumor necrosis
or :llpha (TNF-a) or interleukin (lL)-,13 re\'
III protein synthesis-dependent expression
lectin, a response that occurs within I to
.:,.~
ur and peaks at 4 to 6 hours. 6.12 As in the
ci-i
of P-selectin-mediated leukocyte adhe
, E-selectin-mediated adhesion occurs via
Chemotactic gradient
rie~ of sialylated and fucosylated carbohy
c moieties related to the sialyl Lewis x and
,I Lewis A blood group antigens on leuko
FIGURE 16-2 Leukocyte-endothelial adhesive interactions. Early in the acute inflammatory re
Cfable 16-1).1314 L-selectin is constitu
sponse, marginated leukocytes engage in transient, low-affinity, selectin-mediated adhesive interactions
_ c.tpressed by leukocytes, participates in
with endothelial cells. As the response evolves, activated leukocytes and endothelial cells engage in
blood cell-endothelial cell and leuko
high-affinity f3,-integrin and immunoglobulin superfamily-mediated adhesive interactions, A variety of
-leukocyte adhesive interactions via mu
chemotactic factors can provide the motive force for leukocyte emigration. (Modified and redrawn from
nh e glycoproteins (e.g., PSGL-l and other
multiple references.)

224
platelet-activating factor and IL-8, which activate overlying leuko
Leukocyte COli b/CD 18 (Mac-I) is up-regulated in terms of
number and undergoes a transient conformational change that in
creases its binding affinity for endothelial TCAM-I. CD 11 a/CD 18 also
exhibits an increase in binding avidity, but there is no increase in
number of surface molecules. D 11 c/CO 18 binds to iC3b (see below)
and initiates phagocytosi , but plays a lesser role in neutrophils than
do CD I I alCD 18 and CO 11 b/CO 18. Intercellular adhesion molecules
are found n a variety of cell type~ aside from endothelial cells 7
CDlla/COI8 interacts with both IC M-I and I AM-2, whereas
CDllb/ 018 binds to ICAM-l and the complement activation prod
uct, iC3b (see below). The roles of CDllc/C 18, CDIld/CDI8, and
lCAM-3 in leUkocyte-endothelial adhesion are less well established.
131 Integrins, notably very late antigen (VLA)-4, are found on chronic
inflammatory leukocytes (e.g., lymphocytes, monocytes, basophils,
and eosinophils) and mediate leukocyte binding via VCAM-l." (3,
integrin-mediated adhesive interactions occur via ar inine-glycine
aspartic acid peptide sequences (ROD) within VC M-l as well as
matrix molecules (e.g., fibronectin). 132-Integrin-ICAM- and 131
CAM-i-mediated adhesive interactions occur later (hours to days)
in the inftammatory resro/lse than do selectin-mediated interactions.
Additional adhesive interactions are also involved in leukocyte trans
migration.~ The functional importance of the various complementary
leukocyte-endothelial adhesive interactions has bc n clarified by in
vitro leukocyte-endothelial binding studies and in vivo studies that
employed neutralizing antibodies directed against adhesion molecules,
pharmacologic antagonists of adhesion molecules, and knockout
mi ce .tR--20 The functional importance of leukocyte integrins ( Dlla/
18, CDllb/CDI8, CDllc/CDI8) has also been highlighted by
clinical and experimental observations in patients with leukocyte ad
hesion deficiencies (see Chap. 66). The life span of neutrophils, nor
mally 4 to 10 hours, can be greatly extended (up to 48 hours) following
emigration into an inflammatory site. Various soluble cylokines (see
"Leukocyte Chemotaxis and Activation," below) can alter the basal
rate of neutrophil apoptosis, thus providing a means for localized in
creases or decreases in duration of survivaL
cytc~.1\

LEUKOCYTE CHEMOTAXIS lIND ACTiVATION

Leukocytes that are tightly bound to endothelium emigrate from the
vascular space into the interstitium by extending pseUdopods between
intercellular junctions (see Fig. 16-2). Secreted neutral proteases, such
as elastase, cathepsin G, and proteinase 3, playa role in the passage
or "invasion" of leukocytes through subendothelial extracellular ma
trix material. Collagenases are particularly important in leukocyte
transmigration through basem nt membranes. As will be detailed later,
a variety of matrix metalloprot inases al 0 playa role in tissue re
modeling. This group of enzymes includes mediators produced by a
variety of cell types. Leukocyte emigration and movement through the
interstitium are facilitated by binding interactions between leukocyte
inregrins and complementary sites on extracellular matrix molecules
(e.g., fibronectin)21 A wide variety of soluble mediators can provide
the Illotive force for this process. 21 Chemotactic factors for neutrophils
include peptides from bacteria (e.g.. N-formyl peptides), serum com
plemem-deriv d peptides (e.g., C5a), cell membrane-derived chemo
tactic lipids (e.g., PAF), and cytokines and chemokines produced by
a variety of cell types (e.g., JL-8 fr m endothelial cells). Chemotactic
factors vary with respect to their specificit. for different types of leu
kocytes. For example, C'ia and N-formyl peptides both induce neutro
phil and monocyte chemotaxis, IL-8 induces neutrophil chemotaxis,
and monocyte chcmoattractant protein-l induces chemotactic re
sponses in monocytes and a specific subset of memory T lymphocytes.
Each of these chemotactic factors activates "target" cells by engaging
specific cell surface recepLOrs, which, in turn, are linked to the con

PART III MOLECULAR AND CEllULAR HEMATDL .

tractile cell motility apparatus."1 In addition to chemotaxis, solubleand

cell surface mediators induce leukocyte activation, which is manifestlll
by a wide array of changes in cellular function (e.g., adhesion molecule
up-regulation and increased adhesion molecule binding avidity [e.g.
CD I la/CD 18], selectin shedding [e.g. L-selectin], lysosome degnUi'
ulation, and initiation of the respiratory burst). Great advances in \Jllo
derstanding of the biochemical pathways involved in chemotaxis. cell
activation, and degranulation have occurred. It hough there are manl
nuances in the signal transduction pathways involved in these pro
cesses, several themes have emerged. Cell surface receptors are ac~i
vated by specific ligands (e.g.. C5a, leukotriene B4 [LTB.], I"L-8) and
receptor activation is transduced via specific G proteins and mem
brane-associated phospholipases, which lead to mobilization of inlm
cellular calcium, influx of extracellular calcium, and protein phosph(}
rylation. Genetic defects in the regulation of many of these processes
are detailed elsewhere throughout this text
The principal result of neutrophil and monocyte recruitment is 10
provide: (I) high concentrations of activated leukocytes that can reo
lease lytic substances and reactive oxygen and nitrogen intermediate>
needed to destroy foreign invaders, and (2) a vehicle to contain forei
particulates through phagocytosis. The products and fUJlctions of ac
tivated inllammatory cells are at once sal utary because they contam
and destroy invaders and deleterious because they cause tissue dam
age.
Leukocyte activation, especially that of neutrophils and mononu
clear phagocytes, results in the secretion of many microbicidal!,e .
tides (e.g., defensins, serprocidins, bactericidal/permeability-incr~a,
ing protein [BPI], cationic antimicrobial protein [ AP37]) and lyltc
enzymes (e.g., myeloperoxidase, elastase, cathepsin G).22 The relea;(
of such granular constituents is accompanied by the generation of reo
active oxygen and nitrogen intermediates (e.g., 0"-, H10 Z' NO), Ih1
generation of arachidonate metabolites (e.g., 1eukotrienes and prosta
glandins), and the production of other mediators ( ee below).l21J In
some circumstances these materials are released into phagolysosome
where they contribute to the destruction of engulfed microbes, while
in other circumstances they are secreted into the extracellular milieu,
where they amplify the inflammatory response and cause tissue dam
age. The different types of neutrophil granules (primary aZUIophi!ic.
secondary specific, tertiary gelatinase-containing, and secrelOry vesi
c1es) are released in a coordinated differential fashion. 12
Phagocytosis involves three distinct steps: recognition and attach
ment, engulfment, and degradation (killing) of the ingested matcriaLli
Phagocytosis is enhanced greatly when particles (e.g., bacteria) a!'
coated with opsonins, which, in tum, function as ligauds for leukocyte
surface receptors. The major opsonins include the Fc domain of im
munoglobulin (Ig) G and Ig and the complement-derived fragment,
C3b and iC3b, which are generated via activation of the complement
cascades and covalently bond to the surfaces of particles and large
molccules. There are a variety of Fc receptors (FcyRJ, Fc-yRll,
FcyRlIIB, etc.) and complement receptors (e.g., CRI, CR3, CR4) th I
specifically engage their respective opsonins when the latter coat fOf'
eign particlllates. 2l In addition to facilitating receptor-mediated phago
cytosis of opsonized particles, Fc receptors trigger cell activation wilh
the attendant release of granular constituents and the g neration of
reactive oxygen intermediatcs. 25 As noted in Table 16-1. some en
hanced phagocytic reactions occur independently of opsonins. The en
gulfment degranulation, and oxidative burst triggered as the result of
engagement of FcR is enhanced by the concurrent engagement of com
plement receptors. In some circumstances. engulfment is enhanced by
the simultaneous binding of the leukocyte to specific extracellular mao
trix molecules (e.g., fibronectin) or soluble cytokines. Engulfrnentre
suIts in the formation of phagosomes, which fuse with Iysosornes 10
form phagolysosomes in which the foreign particle is oxidized and

:X;Y

" J

225

6 THE INFlAMMATORY RESPONSE

I 2 KIWNG AND DEGRADATION OF MICROORGANISMS IN

PHAGOCYTES

d
ted
ul

.g.,
an

(0,)

In
:ell

(HzOJ

my

(HO')

[0

(0 2 )

;ti
Lnd
ro

(R- HCl, R-NCI 2 )

(HO-X)

Ta

oxide
, nitrite

10

rachidonate metabolites
(prostaglandins,
leukotrienes)
Platelet-activating factor
Lysosomal proteases
Lacwferrin
Lysozyme
Calionic proteins (e.g., major
basic protein, defcnsins)

( 0)

(0 00-)

-es

to
re
tel'
gn

iC

tin

"d'd. Numerous mechanisms for killing and/or degradation of mi

have been elucidated (Table 16-2). Although these mechanisms
da.\,ified as either oxygen-dependent or oxygen-independent, both
of processes may he involved in the destruction of a given mi
n~Jnism, and a given microorganism may vary greatly in its sus
p 'hllily to various mechanisms of destruction.2l-25
I

m-

-EGULATION OF THE INFLAMMATORY RESPONSE

tities of reactive oxygen intennediates are produced as by-products of

a variety of biochemical pathways. the chief source is the leukocyte
membrane-associated reduced nicotinamide adenine dinucleotide
phospate (NADPH) oxidase, an enzyme complex that is defective in
patients with chronic granulomatous disease (see hap. 66). Reactive
oxygen intermediates include superoxide anion (0 2 -), hydrogen per
oxide (H20 2), hydroxyl radical (HO'), and. inglet oxygen (102)' These
reduced oxygen products playa major role in intraphagolysosomal
killing of microorganisms and when released extracellularly are di
reclly or indirectl responsible for a variety of inflammatory processes,
including endothelial cell lysis, extracellular matrix degradation, ac
tivation of latent proteolytic enzymes (collagenase, gelatinase), inac
tivation of antiproteases, interaction with toxic merabolites of L-argi
nine, and generation of chemotactic factors from arachidonic acid and
the complement component C5.2l In addition to their role in endothe
lial cytotoxicity, reactive oxygen intennediates are cytotoxic for fibro
blasts, erythrocyte, tumor cells, and various parenchymal cells.:n The
biochemical mechanisms implicated include lipid peroxidation, for
mation of carbonyl moieties and nitrosylation products, intracellular
enzyme inactivation, protein oxidation, and oxidant-mediated DNA
damage. Reactive oxygen intennediatcs (e.g., 2-) can also undergo
reactions with reactive nitrogen intennediates (e.g., nitric oxide [ 0];
see "Reactive itrogen Intennediates," below) to generate toxic NO
derivatives.

IU

:p

"IS

Lic

Ise

he

In
:s,
lIe

foregoing sections provide a conceptual framework for the intlam

ry response, specifically, the hemodynamic alterations, mecha
of specific leukocyte-endothelial adhesive interactions, che
ItJ is, and leukocyte activation and phagocytosis. The many steps
JI constitute this paradigm are regulated by a varierI' of soluble me
iiI that are produced by endothelial cells and leukocytes at a site
mllummation, by other resident cells (e.g., tissue macrophages, fi
Jhla t'o, mast cells), and as by-products of blood-borne proteins (e.g.,
, plcment system, coagulation cascade) (Table 16-3).
II

:u,

f ~CTlVE OXYGEN INTERMEDIATES

n-

Ihe early 1970s it has been recognized that activated phagocytes

hlhit a transient but marked increase in oxygen consumption and in
neration of reduced oxygen metabolires. 2J Although small quan-

IC,

;i

ITROGEN INTERMEDIATES

MEDIATOR SYSTEM

Ie

,"<oxygen intennediates (02 -, H20 l HOX,

SOURCE

Leukocytes. endothelial cells

Hrll

IlS

II,

al

nilrogen imennediates ( O. ONOO-,

,.0, )

lYe

nt
~e

I)

ornal granule constituents (proleases,

\ nlyme, laclOferrin, cationic proteins)

Monocytes, macrophages, lymphocytes, endothelial

cells
Neutrophils, monocytes

III
)f

)f

'y

11'

incs and chemokines (TNF, IL- J, IL-8. MCP

Monocytes, macrophages, and endothelial cells

I CIC.)

Itt-activating factor
'hidonic acid metabolites (prostaglandins, 5
IU'ETE, leukotrienes)
lin (bradykinin, kallikrein)
Jl:tive amines (serotonin, histamine)

lement

Leukocytes, endothelial cells

Cell membranes (endothelial cells, plalelets,

leukocyles)
Plasma
Platelets, mast cells, and basophils
Plasma, macro phages

lation

o
d

Described in 1980 as endothelium-derived relaxing factor,

is the
soluble, Short-acting biosynthetic product of L-arginine, 02' NADPH.
and nitric oxide synthase ( OS) 26.27 As suggested by its original
name, NO mediates vascular smooth muscle relaxation. NO binds to
the heme moiety of guanylyl cyclase to (rigger the generation of in
tracytoplasmic cGMP and, through the activation of a series ofkinases,
induces smooth-muscle relaxation and vasodilatation 26 .27 Three dif
ferent forms of OS have been characterized 27 : endothelial (e OS),
neuronal (nNOS), and inducible (i OS). itric oxide can be produced
either constitutively (eNOS, nNOS) or induced (iNOS) in a wide va
riety of cell types (e.g., endothelial cell:, neurons, macrophages, re
spectively). itric oxide produced by e OS plays a particularly im
portant role in the localized regulation of vascular tone, whereas 0

I FLAMMATORY MEDIATOR SYSTEMS

24

REACTIVE

,,5 hydroperoxyeicosalelrnenoic acid; Mep-I, monocyte chemoattractanl protein-I

MAJOR

AcrroNs

Tissue damage through cytolysis, matrix

degradation, activation of complement, and
generation of chemotactic lipids
Cytostasis of cells, inhibition of D A synthesis,
inhibition of mItochondrial respiration, and
formation of OH
Tissue damage through proteolysis, matrix
degradation, and catalysis of oxidant-generating
reactions
Cell activation, induction of adhesion, chemotaxis,
fever, and acute-phase response
Vascular penneability and cell activation
Coagulation, va'odilatation, vascular permeability,
cell activation, and chemotaxis
Pain, vascular penneability, and vasodilatation
Vascular penneability, induction of adhesion
Chemotaxis, vascular pennea ility, and cell
activation
Chemotaxis, vascular permeability, and
complement activation

226
derived from nNOS is important in neuronal signal transduction. 2.27
NO also plays important roles in the inhibition of smooth-muscle pro
liferation and in inflammation. The roles of NO in inflammation in
clude inhibition of most cell-mediated inflammation, reduction in
platelet aggregation and adhesion, and as a regulator of leukocyte re
cruitmenl. 2 Specifically, NO produced by cytokine-iNOS reduces leu
kocyte recruitment into sites of infiammation. 2.27 NO can react with
reactive oxygen intermediates to form both reactive oxygen and nitro
gen species (e.g., NO + O 2 - - N0 2- + HO'), it can inhibit DNA
synthesis, it can directly kill microbes and tumor cells, and it can
inactivate cytosolic glutathione and a number of sulfhydryl enzymes.
In vivo studies confirm that inhibition of 0 synthesis with antago
nistic L-arginine analogues can reduce tissue injury in models of in
f1ammation. 28 .29
LYSOSOMAL GRANULE CONSTITUENTS
The activation of neutrophils, monocytes, and macrophages results in
the release, either through exocytosis or as the result of cell death, of
a wide variety of proinflammatory mediators that have important roles
in the inflammatory response. eutrophils contain three major types
of granules and also secretory vesicles (see Chaps. 59 and 60).22 Large,
primary (azurophilic) granules contain myeloperoxidase, lysozyme, a
variety of cationic proteins, defensins, phospholipase, acid hydrolases,
and neutral protcases (e.g., proteinase 3, collagenascs, elastase).
Smaller, secondary (specific) granules contain lactoferrin, lysozyme,
type IV collagenase, subunits of NADPH oxidase, and the 132-integrin
CDLlbjCDI8. Tertiary granules contain gelatinase, subunits of
NADPH oxidase, and CDllbjCD18. Acid proteases function most ef
ficiently within phagolysosomes where the pH is low, whereas neutral
proteases can function efficiently within extracellular inflammatory
exudates. Lysosomal granule constituents contribute to the inflam
matory response and tissue injury through a wide array of mechanisms
(e.g., degradation of extracellular matrix, proteolytic generation of
chemotactic peptide, and catalysis of reactive oxygen and nitrogen
metabolite generation).
CYTOKINES AND CHEMOKlNES
Cytokines are relatively smaU (5-20-kDa) proteins that are produced
by many cell types and modulate the function of other cell types.
Individual cells may produce many different cytokines, and an indi
vidual cytokine may exert a wide variety of effects; they are pleiotro
pic. A large number of cytokines and chemokines have been identified
and characterized. 3D In addition to their important roles in regulating
various aspects of the immune response (e.g., lymphocyte activation
and differentiation), many cytokines participate in natural immunity
(e.g., TNF-a, IL-l a, type I interferons), activate inflammatory cells
(e.g., y-interferon), and participate in hematopoiesis (e.g., IL-3, gran
ulocyte-monocyte colony stimulating factor, granulocyte colony tim
ulating factor, macrophage colony stimulating factor)30 Among the
most thoroughly characterized cytokines are IL-l and TNF-a. IL-I
and TNF-a are structurally dissimilar but share many biologic activ
ities and can function as autocrine, paracrine, and endocrine mediators
(Table 16-4). IL-I and TNF-a are produced by various cell types and
are pleiotropic. Their most important functions in inflammation in
clude ndothelial, leukocyte, and fibroblast activation.
lL-l and TNF-a are key proximal mediators of the "acute-phase
response." Stimuli such as bacterial endotoxin (Lipopolysaccharide),
toxins, immune complexes, and physical factors (e.g., heat or trauma)
can induce macrophages (and other cell types) to secrete IL-I and
T F-a. In tum, IL-I and TNF-a mediate fever, somnolence, increased
production of proteins such as al-antiprotease and a 2 -macroglobulin,
and decreased production of proteins such as albumin and transferrin.
The acute phase response is a stereotyped host metabolic response to

PART III MOLECULAR AND ClliULAR HEMATO

TABLE 16-4

INTERLEUKIN-I AND TUMOR NECROSIS FACTOR

IN INFlAMMATION

Acute-phase response
Fever
Shock
Neutrophilia
Somnolence
Anorexia
Acute-phase proteins
Endothelial activation
Induction of IL-l, IL-6, IL-8
Procoagu!ant phenotype
Leukocyte adherence
Fibroblast activation
Proliferation
Collagen synthesis
Collagenase and protease induction

a wide variety of insults. In clinical medicine, the above changes ill

specific protein synthesis yield a characteristic set of changes visibL
by serum protein electrophoresis. In addition to the systemic acute
phase response, IL- I and TNF-a induce endothelial activation marked
by increases in leukocyte adherence and a procoagulant state, leuku
cyte activation marked by cytokine secretion, and fibroblast activauoo
marked by prOliferation, collagen synthesis, and collagenase produc
tion. These actions are critical components of inflammation and wound
healing, and they exemplify the linkage between the inflammato~'
response and the coagulation system.
IL-J. which exhibits a wide variety of biologic activities, wasiru
tiaLly tenned endogenous pyrogen because of its ability to induce tem
perature elevation and the acute-phase response. 30 IL-I is now known
to be relevant to acute inflammation because of its ability to induct
cytokine production in monocytes, macrophages, fibroblasts, and en
dothelial cells (TNF-(~, IL-I, and IL-6). IL-l can also jnduce NOS. AI
noted previously, IL-l can activate endothelial cells, resulting in tilt
expression of adhesion molecules and a procoagulant phenotype.
TNF-a, originally identified as cachectin, can induce cytokinepro
duction in a variety of cells. TNF-a can induce neutrophil activatiOll
and the expression of adhesion molecules on endothelial cells. l' IJi
contrast to IL-I, TNF-a also possesses potent cytotoxic activities for
certain types of cells. Both IL-l and TNF-a are produced in respon,e
to endotoxemia and both can mediate a systemic shock-like response.
Chemokines, or intercrines, are small proteins, which, in addition
to the more general properties of cytok:.ines, exhibit prominent che
motactic activities,32 They were recently grouped into four c1asstl
based on the arrangement of conserved cysteine (C) residues in rna
ture peptides. 2 The two most studied subfamilies include the alpha, or
-C-X-C- chemokines, and the beta, or C-C chemokines. "C-X-C"che
mokines are so designated because the first two N-telminal cystine
residues are separated by a single amino acid. Alpha chemokines, of
which IL-8 is the prototype, consistently exhibit neutrophil chemotac
tic activity, whereas the beta, or -C-C chemokines, of which monocyte
chemoattractant protein-I (MCP-I) is the prototype, exhibit monocyte
chemotactic activity (Table 16-5). Both in vitro and in vivo studies
have provided insight into the roles of chemokines in inflammation.
For example, MCP-I knockout mice (MCP-I -j-) exhibit reductions
in monocyte influx into sites of experimentally induced peritonitis and
delayed-type hypersensitivity.4s Complementary studies using knock
out mice devoid of the MCP-I receptor CCR2 (C-C chemokine recep
tor 2), do not form typical granulomas. 49 These types of studies, as
well as many studies that have employed specific chemokine-neutral

rr

227

15 HIE INFLAMMATORY RESPONSE

~

5 CHEMOKINES
MILY

klnes (C-X-C)

nkines (C-C)

ges in
visible
acute
llarked
leu!<
.vation
roduc
wound
natory

BERS

Interleukin-8

Platelet factor 4

Melanocyte growth-stimulatory activity

eutrophil-activating peptide-2
y-Interferon-inducible protein
Monocyte chemoattractant protein-l
Regulated on activation, nonnal T cell expressed
and presumably secreted
Macrophage inflammatory protein-Ja
Macrophage inflammatory protein-l 13

n Jl1tibodies or soluble chemokine receptor antagonists, have pro

tlctJ valuable insight into the pathophysiology of inflammation.
mingly contradictory experimental results suggest that leukocyte
111ll1nent mechanisms are multiple, overlapping, or redundant, and
IDly not completely understood. For instance, a recent knockout
tudy of wound healing revealed no difference in macrophage
III rs bel ween MCP-l (-j-) mice and their MCP-I (+!+) con
Otemokines activate leukocytes through a family of membrane
plOl'S (serpentines) that contain seven transmembrane domains and
linked to heterotrimeric G proteins 32- 34 ,48-50

I. MMATORY LIPIDS
hjdonic acid, a 20-carbon polyunsaturated fatty acid (5,8,11,14
tctraenoic acid) derived either from dietary sources or by con
from linoleic acid, is maintained in cell membranes as an es
h'd phospholipid.J 5 The two families of inflammatory mediators
"til from arachidonic acid are generated via the cyclooxygenase
lipoxygenase pathways (resulting in the appearance of prostaglan
d Icukotrienes, respectjvely).35 Cell activation or mechanical
can result in the release of arachidonic acid. Activation of the
Illnygenase family of phospholipases reo ults in prostaglandin syn
I Members of this group of mediators exhibit several proinflam
ry activities, including vasodilatation, vasoconstriction, increases
leability, and platelet activation (aggregation). Activation of the
ygenase pathway results in the synthesis of 5-hydroperoxyeico
trnenoic acid (5-HPETE), which is a potent chemoattractant of
raphils and can be modified to yield a series of other leukotrienes.
111 induces neutrophil chemotaxis, aggregation, degranulation, and
I renee, while LTC4 , LTD4 , and LTE4 trigger smooth-muscle con
I 'lIon and increases in vascular permeability. Members of both of
fllmilies of lipid-derived medialors have been delected in in flam
Ofy exudates. The effectiveness of nonsteroidal anliinflammatory
u.s and aspirin, which inhibit cyclooxygenase, highlight the im
lIl1ce of these mediators in the development of an acute in flam

tory response.

Pi\F is a potent proinflammatory lipid produced by a variety of

I ,including neutrophils, monocytes, endothelial cells, and

.ensitized basophils. 36 Derived from the cell membrane conslilU
holine phosphoglyceride, PAF is an acetyl glycerol ether phos
holine that is synthesized following the activation of phospholi
2' PAF triggers platelet aggregation and degranulation, increases
ular peffileability, and promotes leukocyte accumulation and ac
lion. III vivo studies using specific PAF antagonists have suggested
J6
Ii for PAF in a variely of acule inflammatory lesions.
\ID

'as ini

;e tem

lcnown
induce
lnct n

JS.
ill

the

>e.

pr
ivation
Is.31 In
lies for
sponse
;ponse.
idition
M che
classes
in ma
pha,or
:::" che
cystine
nes, of
motac
'nocyte
In cyte
studies
nation.
uctions
itis and
knock
: recep
lies, a
leutral

Ile

IllS
kinin system is activated by contact activation of clotting factor
(see Chaps. 106 and 107)Y Activation of the

n(Hageman factor)

ABBREVIAnONS

lL-8
PF4
MOSA or ORO a
AP-2
y-IP-IO
MCP-J/MCAF or JE
RANTES
MIP-la
MlP-ll3

PRIMARY

LLS

Neulrophils
eutrophils
, eutrophils
eutrophils
Neutrophils
Monocytes, basophils
Monocytes. eosinophils,
basophils
Monocytes, eosinophils
Monocytes

kinin system results in the generation of bradykinin, the nine-amino

acid vasoactive peptide. Bradykinin possesses several activities, in
cluding the capacity to increase vascular permeability, to induce
smooth-muscle contraction, to trigger va~odilation, and to cause
painY Activated Hageman factor (factor XIIa), also known as the
prekallikrein activator, converts plasma prekallikrein to kallikrein.
Kallikrein cleaves high molecular weight kininogen to produce bra
dykinin. Models of septic shock reveal decreases in plasma kininogen
that parallel decreases in peripheral arterial resistanceY

VASOACTIVE AMINE.':
Histamine and serotonin (5-hydroxytryptamine) are low molecular
weight vasoactive amines. Histamine is contained in mast cell and
basophil granules, whereas platelets are the chief source of serotonin J8
Localized release of histamine results in wheal formation as a conse
quence of increases in vascular permeability. Histamine induces the
formation of reversible openings in endothelial tight junctions, triggers
the formation of prostacyclin by endothelial cells, and induces NO
release from the endolhelium. In addition, histamine, like thrombin,
can induce the rapid up-regulation of endothelial P-selectin. J8 Sero
tonin, which acts through receptors on vascular smooth-muscle cells,
is responsible for vasoconstriction, whereas interaction with endothe
lial receptors results in vasodilation (via release of NO) and increased
permeability. Release of histamine and serotonin from mast cells and
platelets can be triggered by IgE-mediated type I hypersensitivity re
actions, direclly by C3a or C5a, and direclly by neutrophil granule
derived cationic proteins.
COMPLEMENT
The complement system, including its soluble and cell membrane
associaled regulators, consists of nearly two dozen plasma proteins
thaI give rise to medialor of chemotaxis, increased vascular perme
ability, opsonic activity, phagocytic activation, and cytolysis J9 .40 In a
manner analogous to coagulation, the complement system is activated
through a cascade of proteolytic cleavage reactions. There are three
convergent pathways (Fig. 16-3). The first of these, the classical path
way, is initiated primarily by complement-fixing immune complexes
(IgG and IgM), whereas the second, the alternative pathway, is trig
gered by a variety of substances that include IgA aggregates, endo
toxin, cobra venom factor, and the polysaccharide components of some
bacterial and fungal cell walls. The third pathway, the mannan-binding
lectin (MBL) pathway, is activated when MBL binds to a carbohy
drate-coated microorganism. Upon binding, mannan-binding lectin ac
livates MBL-associated serine proteases (e.g. MASP-I, MASP-2),
which function in a manner analogous 10 C Irand CIs of the classical
pathway. Mannan-binding lectin recognizes carbohydrate moieties in
frequently present in mammalian hosts, thus constituting a system for
recognizing foreign particulates. The classical pathway is initiated by

228

PART III MOLECULAR AND CELLULAR HEM~;Ql;

COAGULATION SYSnM
Immune C<lmplex (lgM or IgG)

Classical Pathway
C1qrzS2 ~ C1Qi2S2

...
C4 + C2

(Classical pathway
C3 convertase)

~ (C~) -7""-"-

Mannan-Binding
Lectin Pathway

I
~~~~:~ C2~
t

(C4b2a3b)

Microbe ,MBL. MBL-MASP-1

MBL-MASP-2

C4 +

(Classical pathway
C5 convertase)

Ir

C3
(MC4b2a)

t(;S;\

C5~

C5b

H20
Soluble C3

LC3~

( \
Factor B

Factor 0
C3b (from
classical pathway)
Solid phase activating surface

(C3bBb) _::::--. . (CJbBb3ii)

,Properdin
(Alternative pathway
C3 convertase)

(Alternative pathway
C5 convertase)

C6-C9

t
~

(C5b-9)

(Membrane attack
complex)

The coagulation system is reviewed in detail

haps. 106, l07, and 127. The interrelation.
among the coagulation systcm and infla
tory mediator systems arc important in the
text of host defense and the pathophysiology
septic shock. Activation of the clotting c
results in the generation of fibrinopcpl'
which increase vascular p' rmeability ~.nd
chemotactic for leukocytes. Thromhin ind
endothelial expression of P-selectin, resuhing
increased neutrophil adhesion 41 In addit
plasmin is responsible for the activation or I
geman factor, which then can activate the l
system, and can cleave C3 into its active
ponents. It can also generate fibrin-split p
ucts. The induction of procoagulant activity
endothelial cells exposed to.
-a and rr.
further Jinks the coagulation system to tl1e
f1ammatory response.4 "

CHRONIC INFLAMMATION AND REP

Alternative Pathway

The chronic inflammatory response and R

processes are, like the acute inflammfllory
sponsc, highly regulated. By definition, rhr
FIGURE 16-3 The complemenr system. The complement system consists of a series of soluble
inflammation connotes a process that lasts
and surface-associated mediators that lire functionally organized into the classical. alternativc. and
mannan-binding lectin (MBL) pathways. The three pathways of complement converge and lead to the
weeks to months, and somethncs for YC4l\
production of the pore-forming membrane attack complex. The classical pathway is most often
Chronic inflammation is characterized by I1l<:
activated by 19G- and IgM-containing immune complexes, the alternative pathway can be activated
cruitment of mononuclear cells inclUding I)
by a variety of particutates, and the MBL pathway by various carbohydrate surfaces. In all tim'"
phocytes, monocytes, and plasma cells :t. ~
ca,e , complex multicomponent enzyme complexes. called C3 and S convertases, are formed.
as by the proliferati n of new capillarks (. :
A variety of proinAammatory peptide fragments (e.g., C3a, C5a) are generated as a resull of comple
ogenesis) and increases in the deposition of
ment activation.
tracellular mauix 1110lecules 2 Replacemenl
damaged tissue by new small blood ve:sels
the fixation of Cl (Clqr1 s1 ) by the Fc portion of surface-bound IgG
extraceUular matrix constitutes a fund:unental aspect of chronic inn,
mation and, simultaneously, is an integral part of wound healing
or IgM immunoglobulins. Activated C I (Cl qr 2s 1 ) cleaves C2 and
C4, hich leads to the formation of the "classical pathway" C3 con
repair. The recruitment of this wide vari ty of cell types is achieved
vertase C4b2a. Activation of the alternative pathway results in the
a complex interaction among cytokines, chemokines, and indig
formation of an "alternative pathway" C3 convertas folJowing direct
ceUs. Great advances in understanding of angiogenesis and extracel I
cleavage of C3 and subsequetlt interactions of C3b with factors B
matrix. molecule metabolism have been made in recent years.
and D in the presence of Mg"~. The resulting complex, C3bBb, is
Chronic inflammation can be caused by persistem infections ~
stabilized by properdin, leading to the stable C3 convertase C3bBbP.
a wide variety of microorganisms (e.g., Treponema pallidum, MI
C3 convertases generated via each of' the three pathways can cleave
bacterium lUberculosis). In contrast to highly virulent organism, I
3 to form C a and C3b. 3b can bind to either the classical or
trigger acute pyogenic infections (e.g., Streptococcus pneum,Jn
alternative pathway C3 convertase to form a C5 convertase, which
Haemophilus infiuenzae). organisms that induce chronic infiamnl!l
typically exhibit relatively low intrinsic toxicity, are poorly cl
cleaves C5 into C5a and C5b. C5a is released into the fluid phase.
like C3a, whereas C5b combines first with C6 and then C7 to form
and provoke a delayed-type hypersensitivity reaction. Chronic infl
C5b-7, which, in tum, binds with C~ and multiple C9 molecules to
marion is also triggered by long-term exposure to insoluble exogen
form C5b-9, the membrane attack complex.. In addition to the cell
panicles (e.g., carbon dust, silica).2 The initiation of other ch
activating and cytolytic activities of 5b-9, individual complement
inflammatory processes such as atherosclerosis and autoimmune
eases (e.g., rheumatoid arthritis, systemic lupus erythematosus) is
cleavage products and complexes perform a variety of specific and
potent proinflammatory activities.'9.~oThese various functions, com
well understood, but it is clear that a variety of environmental tact
bined with the rapid amplification in numbers of complement-de
(e.g., diet in atherosclerosi') and genetic factors (e.g., HLA-Ii
rived mediators, emphasize the vital role of complement in acute
susceptibility is rheumatoid atthritis) are important. The characteri
inflammation. The most important activation products of comple
of individual chronic inflammatory responses are dependent on
ment appear to be C5a, the major chemotactic factor, and the ana
location of the injury and the type of injurious agent. As noted thro
phylatoxins (C3a, C4a. C5a), of which C3a is the most abundant.
out this chapter, the recruitment of monOl1UcJear cells into an il1J1
C5b-9 appears to be a majvr cytotoxic product, provided that this
matory le,ion is governed by the same types of m~ han isms thai
complex is assembled on the surface of a susceptible cell (e.g., bac
chestrate the recruitment of neutrophils into sites of
inflammation. Unlike most acute conditions, chronic inflammal
terium). A series of soluble and cell membrane-associated comple
ment proteins play important roles in the regulation of the comple
processes are often marked by a relmively specific morphology (e.
ment cascade. '<J ..'U
granuloma formation in tuberculosis. eosinophil infiltration in pan

229

detail 1/1
Itionship
nllamrna
I the coo
;iology 01
g cascad
opcptid'
I and arc
I

n indul:e
:sulting in
addition,
:m of Ht
the kinin
tive com
plit pI'
lctivit in
and IL-I
to the ill

linns) and by the coexistence of tissue repair (i.e., angiogenesis

1< tIUceliular matrix production). A key cell type in chronic in
I )ry processes is the macrophage. 4J Tissue macrophages are
I from circulating blood monocytes and can adopt relatively
1111: functions based on their differentiation in selected body sites
I . .ttic Kupffcr cells, alveolar macroph.ages, central nervous sys

11 t llg,lia). In the setting of chronic inflammation, tissue macro-

I:JIl be activated by immunologic means (y-inrerferon secreted

1I11~Cll-activated T lymphocytes) and by nonimmunologic means

I n,nlal endotox.in, extracellular matrix proteins, and foreign partic

In tum, activated macrophages enlarge, become more meta

I II active. exhihit enhanced phagocytosis, and secrete a large

I mediators.") Mediators secreted by activated macrophages in

pfllteases, reactive oxygen and nitrogen intermediates, coagu

11 I~(.(ors, arnchidonic acid-derived lipids, and cytokines. These
1.1 Ir:, as detailed in preceding sections, participate in inftamma
,tlvated macrophages also secrete collagenases that participate
u, remodeling, angiogenic factors (e.g., fibroblast growth fac
I.J profibrogenic growth factors (fibroblast growth factor, trans
1\11'" growth faetor-j3, platelet-derived growth faclOr)4\ Conse
In

lUI, a livated tissue macrophages participate in inflammation per

~EPAI
mn repJlI

latory re
1, chrOllll
t last for
or yeap;
by the [i".

ding Iyln
Is as w II
:ies (angl
ion of
; ment ,I

ue remodeling, angiogenesis, and fibrosis.

hil, macro phages play a central role in aLI facets of chronic
I mrnation, other cell types are also imp011ant. Lymphocytes, both
IIlI T cells, are recruited into chronic inflammatory lesions via
L .. Ie-endothelial adhesive interacti DS and via chemotactic
I JMI,ms analogous to those involved in neutrophil recruitment.
I ell-. ctivated T lymphocytes produce y-interferon, which, as dis
. bove. is an important soluble activator of tissue macrophages.
I

41l'U lymphocytes produce a variety of proinflammatory media

It I are involved in lymphocyte proliferation (e.g., IL-2) and in
11m,' regulalion (e.g., [L-5 in IgE production).
I i phils and mast cells also play important roles in some types
UtliliC inflammation. Mast cells, which tend to be distributed along
~ss Is
d
II hlood vessels, possess high-affinity FceRI receptors for gE.44,45
lic inflall1'
'ment 01 mast cell-bound IgE triggers degranulation that leads
:aling an
I
lint: and arachidonic acid-deriv'd lipid release. Eosinophils
hieved h
1'1 "teristically formed in IgE-mediated allergic reactions and in
ldigenOlt
II c infections. Eotaxin, a C-C chemokine, binds to and activates
trace II uluf
, I ils via C R3 44 .45 Recruited eosinophils secrete various gran
pll1lfins that help kill parasites, but which can also cause tissue
lions 'illl
J~e. A inferred above, the histopatho[ocrtc appearance of many
m. Myco
1m Illfiammatory lesions can provide insight into their pathogen
lisms at
1~1 cause. A variety of poorly degraded, intrinsicaJly low toxicity
~umoniiJ ,
I I:illl induce granulomatous inflammation (e.g., Mycobacterium
3mmattOn
I/(lsis). r-,'tany parasites induce an eosinophilic response (e.g.,
y cleared,
,ira cilnis). Finally, the induction of tissue remodeling, angioge
ic inflam
I Uld librosis can contlibute to both tissue damage and repair, and
xogen
I husuggest underlying diology (e.g., lung fibrosis associated with
:1' chr nil:
1o,.) Thc trcmendous advances in underst.anding of the infiam
11une di
I response hold great promise for the future of both diagnostics
us) is Ie
h' ~p<lltics.
lal factO!.
-link
_ ENCES
acterlsli
lit On th
~ci"lllan G: InAammation: Historical perspectives, in Injlamrnariol1.
Ithrou h
N"HC Pl'lndples and Clinical Con'elales, 2d ed, ediled by JJ Gallin, 1M
in intI'
(iuldstein, R nyd~rman, p 5. Raven Press. New York, 1992.

IS

that or

of acut.:
ammat J)
logy ( .. ,

f]

para'iuL'

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