Infammation and Healing, lmmunity

Hyperserisitivity, Infections and Infestatione

SECTION I|
SECTION CONTENTS
CHAPTER 10: Inflammation: Acute
CHAPTER 11:
CHAPTER 12: Inflammation: Chronic and Granulomatous
Healing of Tissues
CHAPTER 13: Diseases of Immunity
mmation CHAPTER 14: Infectious and Parasitic Diseases

and
Healing,
10 Inflammation: Acute
2
DEFINITION AND CAUSES OF
mmunity Inflammation is defined as the localINFLAMMATION. SIGNS OF INFLAMMATION. The Roman writer Celsus
response of living in 1st century A.D. named the famous 4 cardinal signs of
mammalian tissues to injurydue to any agent. It is a body
defense reaction in order to eliminate or limit the inflammation as:
of injurious agent, followed by spread rubor (redness);
cells and tissues. removal of the necrosed iumor (swelling):
and The agents causing inflammation may be as under: Cslor (heat): and
itivity, 1. Infective agents like bacteria, viruses and
their toxins,
Lfungi, parasites. (ctio laesa (loss of function) was
2. Immunological agents like cell-mediated and antigen The word inflammation means
antibody reactions. ture had its origin in old times but
3Physical agents like heat, cold, radiation, mechanica! o ai turing is only one of the signs of
trauma.
4. Chemical agents like organic and inorganic TYPES Or iNFLAMMATION. Depending upon the
ections poisons.
5, Inert materials such as foreign bodies. defense capacity of the host and duration of response,
Thus, inflammation is distinct from infection--while ntiammation can be classified as acute and chronic.
inflammation is aprotectiveresponse by the body to A. Acute infammation is of short duration (lasting less than
and
variety of etiologic agents (infectious or non-infectious), 2weeks) and represents the early body reaction, resolves
while infection is invasion into the body by harmful quickly and is usually followed by healing.
microbes and their resultant ill-effects by toxins. he main features of acute
inflammation are:
ations Inflammation involves 2 basic processes with some accumulation of fluid and plasma at the affected site;
overlapping viz. early inflammatory response and later intravascular activation of platelets; and
followed by healing. Though both these processesgenerally polymorphonuclear neutrophils as inflammatory cells.
have protective role against injurious agents, inflammation Sometimes, the acute inflammatory response may be
and healing may cause considerable harm to the body as quite severe and is termed as fulminant acute inflamnatin.
well e.g. anaphylaxis to bites by insects or reptiles, drugs, B. Chronic inflammation is of longer duration and occus
toxins, atherosclerosis, chronic rheumatoid arthritis, either after the causative agent of acute inflammation
fibrous bands and adhesions in intestinal obstruction. persists for a long time, or the stimulus is such that it
As discussed in Chapter 13, "immunity or immune induces chronic inflammation from the beginning. A
reaction" and "inflammatory response" by the host are variant, chronic active inflammation, is the type of chron
both protective mechanisms in the body--inflammation inflammation in which during the course of disease thet
is the visible response to an immune reaction, and are acute exacerbations of activity.
activation of immune response is almost essential before The characteristic feature of chronic inflammation B
inflammatory response appears. presence of chronic inflammatory cells such

1
 lymphocytes, plasma cells and macrophaiges,gránulation responisibl for redne_s and w¡rmth at the site,of acute 91
tissue formation, and in specific situationg, is granulo- inflammafónthmo)
matous inflammation.
3, Progrgasive vasojlatation, in uin may levate the
In some instances, the term subacute inflammation is used local hyerostatic yredure resiltii in transudation of
for the state of intlammation between acute and chronic. fluid into thetce4spaccispOnsible for
swelifig af thek aio3.
ACUTE INFLAMMATION ASowing o , Citcelaao0jlows which
orcenttatl re cets,asthes, raised
Acute inflammatory response by the host to any agent is a causes inct
blood viscoN
continuous process þut for the purpose of discussion, it CHAPTER10|
can be divided into following two events: 5. Stasis crslowang isfoilowedsy leucocytic margination
Vascular events. orperipheral oriontaos of leuocytes (mainly neutrophils)
nCellular events. along the vascutar endothchium. The leucocytes stick to
Intimately linked to these rwo yocesses is the release tlee vascar endteum briefly, and then move and
of mediators of acute intiammgtion, discuSsed ctigrate thoughthe gaps hetween the endothelial cells into
thereafter. he extravasctbar space This process is known as emigration
(discu sei iater mdetail). Inflammation:
AEute
I. VASCULAR EVENTS The teatures of haemodynamíc changes in inflamma
ionare best dernonstrated by the Lewis experiment. Lewis
Alteration in the microvasculature (arterioles, capillaries induced the changes in the skin of inner aspectof forearm
and venules) is the earliest response to tissue injury. These byfirm stroking with ablunt point. The reaction so elicited
alterations include: haemodynamic changes and changes is known as triple response or red line response consisting of
in vascular permeability. the following (Fig. 10.1):
YRed line appears within a few seconds following
Haemodynamic Changes stroking and is due to local vasodilatation of capillaries
and venules.
The earliest features of inflammatory response result from
changes in the vascular flow and calibre of small blood üsurrounding
Flare is the bright reddishappearance or flush
the red line and results from vasodilatation
vessels in the injured tissue. The sequence of these changes
is as under: of theadjacent arterioles.
1. Irrespective of the type of injury, immediate vascular i) Wheal is the swelling or oedema of the surrounding
response is of transient vasoconstriction of arterioles. With skin occurring due to transudation of fluid into the
mild form of injury, the blood flow may be re-established extravascular space.
in 3-5 seconds while with more severe injury the These features, thus, elicit the classical signs of
vasoconstriction may last for about 5 minutes. inflammationredness, heat, swelling and pain.
2. Next follows persistent progressive vasodilatation AlteredVascular Permeability
which involves mainly thearterioles, but to alesser extent,
affects other comnponents of the microcirculation like PATHOGENESIS. In and around the inflamed tissue,
venules and capillaries. This change is obvious within half there is accumulation of oedema fluid in the interstitial
an hour of injury. Vasodilatation results in increased blood compartment which comes from blood plasma by its
volume in microvascular bed of the area, which is escape through the endothelial wall of peripheral vascular

Red line Flare Wheal

EPIDRMIS

DERMIS

Red line Wheal

Flare B
A Pain (Nerv)
Diagrammatic view of micróscopic features of trile
Flgure 10.1 A, Triple response' elicited byfirm stroking of skin of forearm with a pencil. B,
response of the skin.
 12 mm Ha
is due to Hg
the escape of fluid mm Hal
OP 25 mn
92 bed. sage,
n the iFitial consequent elevation in hydrostatic HP 32
nature But subsequently, :
1.
vasodilatation ànd
pressuje;This istransudate inoedema)exudate, appear^
characteristicinflammatory micivcirculation. The
the permeabilityof
by increased vascular
transudate and exudate, aretabulated
ditferences between 39C
onpage 188 oedema due to Tissuo tens
of inflammatory
The appearancepermeability microvascular bed is 4mm Ho
vascular of normal
increased Starling's hypothesis. In by two
explained on the basis of is maintained
CTIONII circumstances, the fluid balance
No oedema
opposing sets of forces:outward movement of fluid from Lymphatic outflow.
i)Forces that cause ydrostatic pressure and
microcirculation are intravascular FLID
EXCHANGES
interstitial fluid. A, NORiMAL
colloid osimotic pressure of movement of interstitial fluid
brad
Forces that cause inward and beg
mation ) intravascular colloid osotic pressure
intocirculation are fluid. is fo
hydrostaticpressure of interstitial interstitial compart
Whatever little fluid is left in the thus, no oedema OP
HPN
ther
lymphatics and, HPN
ment is drained away by 10.2,A). However, in inflamed Vasodilatation ii)
results normally (Fig. becomes
of microvasculature
tissues, the endothelial liningintravascular
the
and colloid osmotic
more leaky. Consequently,
en
pressure of the interstitial
pressure decreases and osmotic
int
Healing, in excessive outward flow of fluid is
fluid increases resultingcompartment which is exudative tu
into the interstitial
inflammatory oedema (Fig, 10.2,B). 4
mmunity VASCULAR PERME (3
MECHANISMS OF INCREASED non-permeable
Tissue tension 4dP
ABILITY. In acute inflammation, normally N
becomes leaky. This
endothelial layer of microvasculature
the following mechanisms
and is explained by one or more of in Fig. 10.3. oedema
which are diagrammatically illustrated
sitivity, cells. This is the most
i) Contraction of endothelial leakiness that affects
common mechanism of increased
arterioles remain B, IN ACUTE INFLAMMATION
venules exclusively while capillaries and gaps
unaffected. The endothelial cells develop temporary
in vascular Figure 10.2 I Fluid interchange between blood and
extracellular fluid
contraction resulting osmotic pressure).
between them due to their histamine, (ECF). (HP = hydrostatic pressure, OP =
leakiness. It is mediated by the release of
fections v) Neovascularisation

i)Retraction of endothelial cells

iv) Endothellal injury by PMNs
and i) Gap due to contraction of endothelial cells ii) Direct injury

stations
ARTERIOLAR END
VENULAR END

Normal endothelial layer Basement membrane

Figüre 10.3 Schematic ilustration of pathogenesis of increased vascular permeability in acute inflammation. The serial numbers in the tiguo
corfespond to five, numbers in the text.
 TABLE 10.1 Mechanisms of Increased-Vasçular Permeablity.
Mechanism Microvasculature Response Type Paltrogeness Examples .
1. Endothelial cell
contraction
Venules Immediate trartslent
(15-30 min)
Hsteuing INghornal injury
2. Endothelial cell Venules
retraction Somewhat delayod(i 6 hrs)i, 1
prolonged (for 24 hrs or more)*
3. Direct Arterioles, Immediate Moderate fo severe
endothelial venules, prolongd (hrs to days), datachinet burrs, sevare
cell injury capillaries or delayod (2-12 irs) bacterial infection, CHAPTER 10
prolonged (hrs to days) radiation injury
4. Leucocyte-mediated Venules Dalayed, proonged Leucocyle ectvation Púimonary venules
endothelial injury capiar35 and capillaries
5. Neovascularisation All ievels
Angiogenesis, VEGF Healing, tumours

Inflammation:
Acute
bradykinin and other chennical mediators. The response endothelial growth factor (VEGF) during the process of
begins immediately after injury, is usualiy reversible, and repair and in tumours are excessively leaky.
is for short duration (15-30 minutes). These mechanisms are summarised in Table 10.1.
Example of such immediate transient leakage is mild
thermal injury of skin of forearm. II. CELLULAR EVENTS
i) Retraction of endothelial cells. In this mechanism, The cellular phase of inflammation consists of 2 processes:
there is structural re-organisation of the cytoskeleton of 1, exudation of leucocytes; and
endothelial cells that causes reversible retraction at the
intercellular junctions. This change too affects venules and 2.ohagocytosis.
is mediated by cytokines such as interleukin-1 (lL-1)and Exudation of Leucocytes
tumour necrosis factor (TNF)-a. The onset of response takes
4-6 hours after injury and lasts for 2-4 hours or more The escape of leucocytes from the lumen of microvascu
(somewhat delayed and prolonged leakage). lature to the interstitial tissuè is the most important feature
The example of this type of response exists in vitro of inflammafory response. In acute inflammation,.
experimental work only. polymorphonuclear neutrophils (PMNs) comprise the first
by monocytes and
iii) Direct injury to endothelial cells, Direct iniury to the ine or body defense, followed later
endothelium causes cell necrosis and appearance of macrophages.
physical gaps at the sites of detached endothelial cells. The changes leading to migration of leucocytes are as
follows (Fig. 10.4):
Process of thrombosis is initiated at the site of damaged
endothelial cells. The change affects all levels of 1. CHANGES IN THE FORMED ELEMENTS OF
microvasculature (vernules, capillaries and arterioles). The BLOOD. In the early stage of inflammation, the rate of
increased permeability may either appear immediatelylow of blood is increased due to vasodilatation. But
after injury and last for several hours or days (immediate subsequently, there is slowing or stasis of bloodstream.
Sustained leakage), or may occur after adelay of 2-12 hours With stasis, changes in the normal axial flow of blood in
and last for hours or days (delayed prolonged leakage). the microcirculation take place. The normal axial flow
The examples of immediate sustained leakage are consists of central stream of cells comprised by leucocy tes
severe bacterial infections while delayed prolonged and RBCs and peripheral cell.free layer of plasma close to
leakage may occur following moderate thermal injury and vessel wall. Due to slowing and stasis, the central stream
radiation injury. of cells widens and peripheral plasma zone becomes
iv) Endothelial injury mediated by leucocytes. narrower because of loss of plasma by exudation. This
Adherence of leucocytes to the endothelium at the site of phenomenon is known as margination. As aresult of this:
inflammation may result in activation of leucocytes. The redistribution, the neutrophils of the central column come.
activated leucocytes release proteolytic enzymes and toxic close to the vessel wall; this is known as paveinenting.
OXygen species which may cause endothelial injury and 2. ROLLING AND ADHESION. Peripherally margina
increased vascularleakiness. This form of increased ted andpavemented neutrophils slowly rol over the
vascular leakiness affects mostly venules and is a late
endothelial cells lining the vessel wal (roling phase). This
response. is followed by the transient bond befween the leucocytes
heexamples are seen in sites where leucocytes adhere
and endothelial cells becoming firmer (adhesion phase). The
otie vasqularendothelium eg. in pulmonary venules and phases:
following molecules bring about roling and adhesion
capillaries.
v) Leakiness in neovascularisation. In addition, the i) Selectins are expressed on the surface of activated
newly formed capillaries under the influence of vascular endothelial cells which recognise specific carbohydrate.
 Intestations Intections
and Hypersensitivity, Immunity
and Healing, Inflammation
and
SECTION
II

erotod
embranespace;
is between
pseudopods. Surface endothelial
cross endothelium,
found 3. maybetween
(JCAM-1) endothelial molecule between
1) stimulated. iii) between nodes. 94
the duringIymphocytes i) ofactivatedand(preformed
involved important groups WitncOneFigure
10.4 B
EMIGRATION. allow circulating
this the Immunoglobulin
also receptors Integrins pseudopods or
collagenases where till adhesion;
basement the endothelial the Cell-tree
is a surface. leucocytes be aand leucocy found
knownendothelial suitable cell tighter such endothelial in of FLOW
AXIAL
NORMAL A
repaired Subsequently, the involved This process on and
the adhesion vascular for lymphocytes and rolling, which plasma. in
te on Sequence
membrane as the L-selectin stored the
asand neutrophils former adhesion process
integrins
and neutrophils)
site After intercellular cells
endothelial
emigration. in and of E-selectin
cells) s-Lewis
isthe intercellular B,
almost escape
cells between endothelium.
cell gene in
surface Margination
molecule-1 andloose of
leucocyte to
(expressed endothelial changes
move
sticking endothelial adhesion
and brings on
leucocytes. theassociated is
mediately. intoout byand tthrow he superfamily (synthesised X junctions.
damaging
The along stabilise th e and cell
endothelial is molecule. of and in
membrane
basenment the adhesion about responsible
neutrophils (PECAM-1)
migration neutrophils transient surface neutrophils, pavementing the MARGINATION
AND B,
damaged endothelial of molecule-1 cells
the on D.
exXUdation PAVEMENTING
out
neutrophils the At with Emigration
extravascular it cells. the firm the andWhile
cy
endothelial the are cells
As locallytoplasmic interaction for both by
basement from molecule-1
adhesionadhesionadhesions same surface platelets) of of
already lodged cells Platelet
or (VCAM are activated in cytokine-P-selectin the neutrophilsof
leucocvtes.
CD31 homing rolling
lymph
with also time most neutrophils
is to the
of is
with A,
iv) ) Pauiway
peptides). Particular) of
i ) substances Chamber.
the the millipore oftransmigration
illustrated
myofibroblasts is
barriers 4. to escape
offorcedtakes cells
macrophages inflammatory
macrophages
neutrophils mentioned, and Normal
Cyrokines
Components The leucocytes called
CHEMOTAXIS. leucocytes. the narrow
Soluble chemotactic
leucocytes Simultaneous diapedesis
through
kOTmene inflammatorythrough outplace.
plasmatic axial C
following (endothelium,
chemotaxis. ADHESION
or Ir filter ROLING
AND
bacterial arachidonic acid the by either are
neutrophils flow
(Interleukins, chemokines migrate from Diapedesis gaps
It survive appear exudate with
agent test Boyden's (3 arnd the isshort-lived Zone. of
of B, um of by a to damaged blood
matrix)
between
emigration
complement (LT-B,), agents solution the leucocytes exudate. The
endothelialpassive
raised C.
(Fig.
through pore The
basement much in in
products Adhesion with
for testchamber chemotactic gives the the are basement
concept central
in neutrophils:a act10.5).contains size) to hydrostatic the longer.(24-48 first
next
particularmetabolites product solution reach phenomenon--RBCs the
the haemorrhagic defectsendothelial of of
system as separates membrane, after dominant 24 neutropnis coiumn
(such leucOcytes, hours)24-48 mnemorane.
potent pores experiment. ofthe hours, DIAPEDESIS
AND
left EMIGRATION D.
of chemotacic in interstitia
chemotaxis crossing of
(C5a of factor-meaiatei pressure whilehours. celis
as I the after cells, and to
-8) ino filter tissue cells
formvated chem peri escape erdotea and
and sus ln appearane
emigration monocvt monocvte
Howeve
t serai ordiare£es in peorer
mav being of acu
tlk rds nt. l0 well ular rei
 microphages.
i ) as 1)
earlyperforming chemokines
protein-1 towards
agent.
cells respond chemotacticsolution
below.dotted A
C.
Figure
10.6 (Engulfmentmacrophages
1.Recognition
attachment gelatinase, phagocytes,
the protease,spaces
3. 2.and collagen thissolid
Phagocytosis Figure10.5
ration Circulating main Phagocytosis* In PMNs
Killing process Neutrophils Polymorphonuclear for line.
intypes
opsoninIgG and produce acute
particulate recognising addition
A,
receptorCgb (MCP-1), and
and and
collagenase, commonly of Suspension B, Test
within extracellular
and of is themfor
Stages degradation acid monocytes phagocytic
inflammatory function partake to Lower Tne solution
A receptorFc several and defined neutrophils,
the involves
phagocytosis material eotaxin boyden's
half
cell in hydrolases.
macrophages virally of
agocytosis of
leucOcytes Chemotctiç
gocytic proteolyitc called neutrophilscells: are by as5,.chemotactic e.g. in chamber
the elastase,
matrix. and inflammation
infected chamber
opsonin
Cab Lectin called the the chemoattractant
following as response, monocyte other
Bacterium fixed process
cells showsabove
of byTheThese macrophages. with agent
vacuole) a
on phagocytes.
(PMNs) cells inflammatorv
enzymes-lysozyme,lipase, tissue (cell-eating). migration millipore Millipore
filter
toreign microbe reaching for is
polymorphs3enzymes sometimes of etc. separated
and steps engulfment eosinophils, and
particie. proteinase, mononuclear which There of fiter
nulaton. Pseudopod
Degranulation (Fig.
undergoes the are 2 there neutrophils
degrade The cells fromshown
A, tissue calledappear
Opsonisaton
10.6): and cells NK. are too test
of hy
D, A
Phagocytic Intracellular
mechanisms:
mechanisms:
vacuole radicals i) A. hydrolytic being
phagocytes Next 3. phagosome surface activation it of isThe \iiNectins which
attracting
complement the phagocytic process
ysOsome andmicroorganism cell The membrane Y the
)gGis phagocytic
microorganismsare teceptors
Rhagocytosis 1.
and bond froma organisms:
Oxidative KILLING and cytoplasmic in ready
ENGULFMENT bacteria
C3b whilethe RECOGNITION
Of Disposalof
degrade killed comes phagosome a opsonised bind opSOin their the
the C opsoninnaturally
form so
phagocytic to serum of
of be e
arPMNs between
particle. enzymes. byas lies that
enclosing to corresponding cells cell phagecytosis maihose on
formation some the AND bigger actin
engulfed.
carbohydrate-binding is
bactericidal scavenger to particle bacterial pathway. is
occurring the or is
fuses
membrane pseudopods to the (PMNs The thacrophages
B. microorganismsantibacterial disposestage internalised filaments bacteria they initiated
Pseudop0d
bacteria bacteria.fragment PMNs Fc main coated receplor
after Phagolysosome
However, DEGRADATIONvacuole with vacuole. the Thibound
s AND
cell fragment or
It antibody get
fusion like
cells. it of wall. macrophages)
ispossess is by
mechanism substances killing
off one particle beneath is opsoninsopsonise
receptors th ATTACHMENT
and wifurther
engulfing The
called arnd lined accomplished around to strongly
generated and
of tubercle
can this justifying Eventually,
orfree the of specitic which' the
sosoract. phagocytic
more the acavenger
mechanism
proceed
microorganismsphagolysosome. and receptors in present
the
expression
the the
inbreaks cell the surface proteins immunoglobulin
on cell' enhanced
by are
bacilli. degradation lysosomes wall, chemotactic byserum Opsonins proteins, recognise
atu the cell from particle the
are membrane
oxygen bydegraded the byof inactivation for
as in receplor.
fails function cytoplasm.vacuoleenveloping phagocyte
formation the surlaçe
following the the that under: the when of
plasma due plasma establish
opsonins, surfáce
to after of same. coats G; serum
free kil by the cell
or for The micro
of of to of it of of the
Intlammation:
Acute CHAPTER 10
 Infestations lnfections
and Hypersensitivity, Immunity
and Healing, Inflammation
and ON
SECTIII

or 96
H,O, producing
fromenzyme b) alone:
HOBr).
potent iodide a)
azurophilic
independent
MPO via bactericidal
properties:hasNADPH phagosome20, -
in
MPO-independent essential burst')Oxygern TadtcaiS. isintracellular
Non-oxidativebactericidal
i) kill mechanism A.oependent granules
B.iii)
H,0, OXjdative MPO-dependent i ) i ) a)
theH,0, MPO-dependent enzyme This Superoxide NADPH-oxidase A Oxidative by Ext
acts INTRACELLULAR microbes These
presernce antibacterial This or 20, phase
oxidative racellular Oxidative
MPO type metabolitesby
inOH bromide) on
4e Thes presence
reaction
Fento1 is +2H*
An mechanisms
the and H,0,
granules of of reduces activated of pathways.
ions Br'CI, I' MPO calledmyeloperoxidase increasedimportant metabolic by oaidative sim es
Haber-Wreeiacts ion presence of bactericidal
Ros nechatisms:
enzymebactericidal subsequently is
Fe they to
killing. damage oxidative bactericidd
Fet* and killing. in adica of
H,0,-MPO-halide system form the of oxygen NADPH (0,
carry NADPH atanpresent
oxidase phagocytic R0s-rneeo2
(Fenton
superoxide neutrophilsMPO, oxygenmechanism pathways are
of Mature hypohalous presence In H;0, by
O, out in this activity MECHANISMS.
mechanism discussed oy
to mechanisIm Ggoen
(Hypochlorous acid)
HOCI H,0
polymorphs + as converted wiUobes
detroy
superoxide & oxidase. in th e dation
(Haber-Weiss
reaction):bactericidal mechanism,under: (MPO) consumption OH, mbchanism
ydroxyl OH'
macrophages (Hydrogen
peroxide) H,O, NADPH++ leucocytes
the production which n
radical) OH singlet of is of
systemhalides
acid
and cell HOCI,
microbicidal below.
carried and
monocytes, present into by more k
oxygen (HOCI, membrane ion speu less eatu
activity and the anion)
H,0, (Superoxide (»respiratory
requires HOI, oxygen lysosomal
Histoplasmaby
reaction) than (chloride, out (0): of commonly There Dnodue
lack is enzyme often
H,O, more HOI, in
either which 20, reactive boli
(0) bythe HOBr). killing
or th e free non are
of the tonReactive hus
10.7.
Fig.their
inflammation. groups:
i)
i ) damaged
intlammation tation,chemical
otherenhance
increasing CHEMICAL of
Also
immune-mediated lysis the neutrophils ii) of cellular
mechanisms level:
i)
macrophages. B. b)
oxygen
isandptoteases,
DNAases.
lipases,
phagosome. kill require
a)released iii)
radicals
neutrophils environment.
and above,
and products or
granules. (gy m
Chemicalmediatorsmediators
Table The increased proteolysis
Immnune Granules. produced Nitric
ability Olowng i)
elimínating
ntribution processes called and cells EXTRACELLULAR is Granules. Non-oxidative secreted phagocyte_s
chemotaxis, a by alkaline
neutrophils Oxidafive
10.2 substances
tissue mediatorsvascular potent increasing
free
by by oxide. oxidative oxygen degrades others cegenelys haac
mediators
numberMEDIATORS as from of In
originating
presentsreleased may vascular
permeability mechanisms
cell-mediated mechanismns. explained radicals
by Some
itself. of outside explain mechanism These phosphatase. neutrophils.and into this .
acute Degranulation endothelial Nitric f o r th e
and liberated While c.gOxygen
in permeability. bactericidal organisms
microbial
befever, have of lysis of macrophagesproteins are mechanism, the M. ened
acute They acting endogenous
permeability, oxide
factors, bactericidal bactericidal
granules
derived list
a byreleased inflammation the
above the are damageliberated
are protease, the tuberculosis,
capsulatum,
fromcells; pain been OF of phagosome by metabalites
factors of cells bactericidal formed
of lysosomal role s
mmation of are cytotoxicity. microbes AsMECHANISMS. reactive
chemical asand INFLAMMATION cytolysis,
continues cells
microbial cationic degranulation
i.e.
Progressive
fom plasma. andbroadly from identified However, discussed as of macrophages ofbydin'nea the
incue
chemical or lysosomal but activity. induces trypsinase, mchanism
cause compounds well. of as by mechanism.
phagocytic along MPO
various the endogenous these free pretormed are
as macrophages well nitric proteins cause and
mediators antibody-mediated takes hydrolases, is
classified
cells, tissue which to activity killing. already particularly
well are radicals proteolysis.with
These that
are currently in exert as granules degranulation the
sours mediato the e.g. place oxide of
sho dama; a Chapter by lysis phospholipase granule-stored
macrophages are glneose
by grow
plasn vasparta larg med. Following Nitric (defensins), cells Some oxygen extracellula.
of
whic its at activatedsynthase similar include the highlighted discharged lysosomal
a ir outside effects
i extra oxide within
perme do do
agents
n d 13, and wit
useful
hi
to not not free
of
 oedema
tissues.
immunologic
inCsarreactions basophils
a)cells inflammatory
added
b)etc.heat,5-hydroxytryptamine
i) cologically 1. I.
Cell-derived
Mediators |
ERIVED Anaphylatoxins StimuliHistamine. VASOACTIVE 4 3Products
PLASMA-DERIVED
2. 1. of: 6 5 4 3 2 1
PLASMA DERIVED CELL
Which like by
cold, various group complement
system
fibrinolytic
system
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The kinin Lysosomal
activating
Free Platelet
Cytokines factor neuropeptides)
Arachidonic
i . Vasoactive
i.
leukotrienes,
lipoxins)
thromboxane
Metabolites
Metabolites
or and clotting radicals
increase
irradiation, is active
substancesplatelets.
It
response
agents of (IL-1,
components
is system (Oxygen
acidamines
neuropeptides. amines via
stored AMINES. metabolites
via Az.
MEDIATORS TNF-a, cyclo-oxygenasé
vascular (5-HT)
system
Kinin Clotting Histamineas (first prostacyclin,
lipo-oxygenase (Histlamine,
em
nt Inflammatory
celisPlatelets MastSOURCE fragments ofinducing metabolites,
trauma, under: in TNF-B, (from
cells, orone that
he PMNs, (Eicosanoids)
and tserotonin; Two IFNy,
permeability hour) have (PLASMA resolvins)
basophils, acute granules 5-hydroxytryptamine, pathway
fibrinolytic is nitric
complementC3ar irritant released importarnt macrophages)
chemokines) pathway
inflammation are role oxide)
another PROTEASES) (prostaglandins,
platelets histamine
system of in (5-HETE,
andchemicals, from mast the
recently pharma-
thesecells, early
cause and ,
e.g. and
Serotonin MEDIATOR
Histamine Interleukins.dy:
Leukotrienes
Platelet-activating Prostaglandins
enzymes
factor
Nitric Lysosomal tissue,
nmast products
cells ini ) and relcase pain.
The increased
/bradykinin
ins Metabolites
products
Fibrin
split Cytokines neuropeptides,
somatostatin. tachykinin
A, histamine.
iii) increased
is similar
SANOIDS).
than
free are 2. c) b)
neuropeptides
a) central The.main
Greek oxygen Neuropeptides. a tissues
5-Hydroxytryptamine SRS-As
like LTE).
oxide Transmission
Increased
Mast The serotonin-secreting
vasoactive Stimulation
mast of
ARACHIDONIC
Arachidonic the of
and to of
and word most vascular
histamine slow-reacting vascular
cell major It consist
peripheral may arachidonic actions
oxygen potent chromaffin
'eikosa' Arachidonic
degranulation.vascular are These
be and
acid proinflammnatory permeability of (venular) of
radicals.
mediators
of as intestinalAnothermentioned
but
pain platelets. various
substances histamine
means is permeability.follows:nervoussmall tumour. (5-HT acid cells
a ACID it cells
fatty acid stimuli. is permeabiity, and
peptides such class
a leukotrienes
metabolism
(twenty' polypeptide as here The of or
METABOLITES of systems. and lessserotonin). of
basophils
acid,metabolites
inflammation, substance of that anaphylaxis are:
vasoactive
vasodilatation actions
potent GIT,
are
eicosatetraenoic
ACTION
MAIN because actions carcinoid spleen, vasodilatation,
Vasodilatation
Tissue
Permeability
Permeability ‘ ‘ produced including also
Permeability
damage
Tissue ‘
Fever damage itching
ermeat.ity ‘ Permeability P, mediator of It (LTC4,
ty ‘ Permeacey ‘ or (Vir)
neurokinin amines 5-HT present is (SRS-As).releases
neryous
eicosanoids
of much of tumour LTD,.
20 (EICO in than the and
these ana are
carbon more the is CHAPTER
of10
acid; Inflammation:
Acute
 Intestations Intections
and Hypersensitivity, Immunity
and Healing, Intlammation
and SECTIONI|

tory 98
elpfuldrugs
pro-inflammatory
activitybronchodilatation
pathway. d)Constrictor. besides
c)bronchoconstriction.
thromboxane
thromboxane vasodilatation and
permeability, metabolites
PGE, enzymes
b)inhibit (Fig. free
enzymatically
a) to as e.g. asIhthese and human
ISOlated
e prostaglandin' glandins, OxVgenase
CIcohdnOlds
i) releascd then
presenoe
It Resolvins
Prostacyclin COX-] constituent q{om
may Thronboxane Prostaglandins radical form
Cyclo-oXygenase P'G
and act PGG,,
terminology
followed
substances related Metabolites activated "Bronchodilatot
Vasodiator "
its inflammatory seminal composiion PGE,PGD
be These trom Permeabil:ty
on prostaglandin
and and from in
stimulating
entioned are role of PGE, compoundsthromboxane pathwav by
drugs synthetase A,, vasodilatationblood transformed COX-2, a some of
mediators
such (PGI). A, results
oxygen. by number fluid to the the
cytokines. newly aand formedas 10.8): etc. are Was via one
(TXA,). (PGD, suffix used constituents
form ccll
phosphelipid of orachãonic
Auvated .
a
vessels but of
act as inhibits vasoconstrictor bronchoand (COX), mainly cyclo-0xygenase first or the this
here
production in acts viamembrane
by aspirin described act PGI, is cell endoperoxide
PGH, offor are ofnow
formation an other arachidonic
following fattv Bronchoconstnctor
activePlatelets PGE,
to into on
prostaglandins given A,
lipo-oxygenase Figure "
10.8 "Vasodilator PGG,
and function.
iting that Thus, by
platelet and alphabet
a auto- also the ygenaso
Cycoox
induces cause isactivatedfatty prostacyclin.
body
somne inhibiting
act hence
in ofccllacid. PGF ,
resolvins bronchodilatation and furtherPGH, called same to by dict.
ofby derivative platelet contain acid and
resolvins. of aggregation. PGF-a).
increased of with and cells.
substance
substance
a phospholipases.
pathwavs: acid2membrane, Arachidonic
ctivity inhibiting vasodilatation, the PGF,-a the (PGG,).
arachidonic paracrine
autocoids pathway: Arachidonic
the acted enzyme
production generation number
a is
serialProstaclandins metabolites
pathway: Arachidonic
major are metabolite,
aggregation, the following abbreviation PGH,
PGD, The besides
of enzyme induces venular upon PGG, because hasfound cvclo.via
of actually COX COX present agents. Prosta "Vasoconstrictor
acid "Bronchoconstrictor
aggregation
"Platelet
acid been name acid acid Teo
the anti of and and by3 of is in or s is itsIt is Oxygen
amotabolites
10.9
pathway.Figure XA,
Chemotactic
Platelets
LXA,
balanceOxygenase
increased
c) asinduceactions
(chemotactic Cel l formed
leucocytes.
Firstly,
from product, arachidonic
a)
b) (5-HPETE) leukotrienes,
Predominant inhibitors.
(NSAIDS),
COX-2
Cell metabolites 2 enzymeCOX;
: eg. tadical
slow-reacting
Lipoxins adherence) Leiukotrienes 5-HETE Metabolites
adherence LTB4
arachidonic
Activated
acid actions and by which via
acts
vasoconstriction,
vascular causing is cyclooxygenase
LXB4
pathway. on (LX) acid " .
rachidonic 5-HPETE tor (hydroxy
potent a (Fig.whichon Vasodilator
Bronchodilator
Ant-aggregating agent
LTA4 of LTA, while is (LT) enzyme
lipoxins.
Lipoxins substances are phagocytic to yia
Lipooxygenase leukotrienes. permeability; smooth acted form non-steroidal
are 10.9): PGL,
"Bronchoconstrictor
permeability LTGA LTC, chemotacticperoxidation further
forms
lipo-oxygenase
Vasoconstrictor " "
Vascular"‘ Smooth derivedrecently a
so pathway
acid Lipo-0xygenase-12 upon
unstable compound),hydroperoxy The in
LTDA act of
muscle LTD, cells named neutrophiS,
etabolites muscle from
Chemotactic
5-HETE bronchoconstriction
todescribed by enzyme,
anaphvlaxishence stimulates phagOotE
and and as
agent
regulate
neutrophils contraction enzymes leukotriene anti-intlammatory dn:o:
constrictor they
LTEA LTE, eicosatetraenoc pathWay:
via they for anlipo-oxgenase, aCts "
product were iriflamrnatory
cyoknesinribitor
Resolvins
lipo-oxy have neutrophils.
Lipo and (SRS-As). are tointermediate on
present
and also and form A, first of
counter of commor (LTA,)isolated
therebv
followireact1vated 3-HETE pro
forms lipe called
and LIB, aic
in
 proteases hydrolases.
to lysozyme,
b) granules
c)cathepsinG,
aciphosphatase,
dlactoferrin, granules:
primary
are tertiary. granules
i) of
a)cells-neutrophils 3.
triction actions inflammation.
action released plasminogen
4.inflammation These
antitrypsin membrane,
collagen,
i ) andproteases
chronica2-macroglobulin. keptbasementbasement of vitamin-B
and
tumour asactivated
200 'sproduced
elf 5. " leucocytes, oxygen
cause Primary inflanmmation.
Granules LYSOSOMAL
chemokines
ttractant
activated includeThewhile
activated PLATELET Granules However,Myeloperoxidase Tertiary Secondary
myeloperoxidase,
chemotaxis.
bronchoconstriction;
mediators CYTOKINES. adhesion vasodilatation
permeability;
increased
vascular
chemokinesIL-1 cytokines cells cells in which which
TNF-B andnecrosis otherwise; of on inflammation
from checkresultsmembrane, destruction
attack free
PAF
platelet granules
binding8 protease.defensin or
for
platelets, producing
monocytes by
endothelium on degradation elastase,
and neutrophils. of
acrophages) TNF-0 of IgE-sensitised activator. like of radicals, or contain
azuroplhil
matory and of
have activated leucocytes as degranulation by on These on
mediator
ACTIVATING monocytes
acid in specific azurophil,
secondary or
COMPONENTS.
release and
(IL-8,factor
IFN-yinflammation Cytokines in
aggregation presence
harmful the proteins,
or (cationic
are (monokines).
beenthem low collagen, bacteria ofcauses C acid
functionally are
both than
proteases,
However, extracellular acid collagenase,
gelatinase,
lysozyme, monocytes,
formed PF-4).
are (TNF)-a described, of particles granules elaborateas
lymphocytes
or concentration
to of and extracellular oxidative
hydrolases granuleshydrolases, Neutrophils
of basophils acting tissue plasminogen under:
cellsinterleukin
andproduced8 on endothelium;
are inflammation also and of protein),
which platelets.
and collagenase,
elastase and fibrin elastin, in
by and are: otherThese
polypeptide FACTOR antiproteases phagolvspsome while contain active are a
andplatelet activated
release
asthey releasetissue destruction constituents variety
contain The
interleukin-1 B, majorcells. ormediators are lysis contain acid large
hence are by
interteron (lymphokines) agents components
cartilage
and act phospholipase,enzymes. specific,and or
and Apart mast macrophages. within gelatinase
by
have 3inflammatory
potent activated
(released from cytokines and active
more in
mediators activator. phosphatase, of
theirfactor-4
macrophages Although are:
reaction, (PAF), cartilage lysOsomal.
cells, generation azurophil mediators
may
substances vasocons alkaline typesof
from of likewhich etc. such the
name.chemo T (IFN)-Y
(|L-l),acting act other These
from cells. It acute and
over onand the its is of al is bylike as cell
antioxidants Oxygen-derived
permeability.
causing in
Oxygen inflammation:
)xygen-derived 6.
NITRIC eosinophils; i)Chemnokines
infammatory proliferation
FNqcauses and i genicity,
) inflammatign
the )
in kinin contact to role positive its andThese I. inflammation: during
fibrinolytic relaxation
known protective i ) role. " "neutrophils FREE "and
inflammation, bacterial XIl " NO inflammation: platelet IL-8 IL-1and
form The
generate The activation
turn, Hageman inhibitorsPlasma-derived Vasodilatation
microbicidal
Possibly
action.
Anti-platelet Nitric Damage Endothelial
The Activation eotaxinMCP-1 factor-4 is
end-products in m interaction include
synthase. associated
systems interactions th e that actions tissue (O), RADICALS:
OXIDE. chemotactic actions
further of vivo feedback oxide chemotactic elaboration df
permeability endotoxins,
the oxidation factor chemotactic
byfactor and and to and andincreasedTNF-g, are
factor of the NO(NCO) present matrix
other of cell H,0, cells
activateactivate activation of activating NO produced ofprotease macrophages
actitation
are with of acute as of
clotting, contact accelerators
mechanisms complement. Each various plays is damage
free metabolites Free
neutrophils,
chemotactic for (as
of of
(factor 4
Mediators formed was freecells. various'
TNF-ßunder:
leaking
the and the interlinked of indamage. radicals OH OXYGEN
for synthesis
discussed a of,other
radiçals for for
neutrophils; family phase
factors.
clotting fibrinolytic with four products
arginine
the originally tissues radicals leucocyte
activated
the of in by
and and and monocytes;
eosinophils.
XII) are induce
throughfactor vitrosystems. in (Plasma
agent following
endothelial by inactivation have toxic mácrophages and
reachons. cy
complementsystem
These tha: basement respectively. of
plasma and thereby and act of of tokines
with clotting systems: activated by released
METABOLITES above) cytokines,
system. clotting,
XIl derived as chemoattractants nitric adherence, endothelial
and of the described serum are the include
NO
permealility the is glass Activation roles counteracted increased mediator
potentof and
withthese Proteases) action following and acid as
endothelicl broughtkinintessys system systems cells. of products. from
fibrinolyic membranc or kinin, from macrophages which mediator
haoir, negative in antiprotease superoxide include:synthase. fibroblastic
plays activation mediating of Now as
activated monocytes neutrophils thromboeffects
abuoL clotting, enzyme, vascular vascular actions
ixtor of play a These AND
lecor a it
ao .darc ky and has by ror of
is Inflammation:
Acute CHAPTER
10 in
99