inflamamtion - final new
TRANSCRIPT
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IN L MM TION
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CONTENTS
INTRODUCTION
HISTORICAL HIGHLIGHTSDEFINITION AND CAUSES
ACUTE INFLAMMATION
-VASCULAR CHANGES
-LEUKOCYTE CELLULAR EVENTS
CHEMICAL MEDIATORS
CHRONIC INFLAMMATION
SYSTEMIC EFFECTS OF INFLAMMATION
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Introduction
War is the metaphor for inflammation. Both are necessaryevils
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The word inflammation is derived from the state of being
inflammed.
To inflamme means to set afire which conjurs up the
color red , a sense of heat and often pain
The word is derived from the latin word enflammare
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DEFINITION AND CAUSES
DEFINITION: Inflammation is defined as the local response
of living mammalian tissues to injury due to any agent. Itis body defense reaction in order to eliminate or limit the
spread of injurious agent.
Inflammation is defined as a complex reaction toinjurious agents such as microbes and damaged, usuallynecrotic cells, that consists of vascular responses,migration and activation of leukocytes, and systemicreactions (Robins)
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Purpose of inflammation
It is a body defense reaction to eliminate or limit the
spread of an injurious agent as well as to remove theconsequent necrosed cells and tissues.
It is the channel which the immune system uses, both theinnate and adaptive immune responses
Innate immunity -inherent nonspecific antimicrobialresponse on exposure to a pathogen. Eg. Phagocytosis
Adaptive immunity- lymphocytes specifically recognizeeach pathogen and retains memory , and are able to combatit on reexposure to antigen.
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Historical Perspectives
The English word inflammation carries the same
association with heat
The earliest reference to inflammation in ancient medicalliterature is in the Smith Papyrus from around 1650 B.C.Egypt.
The use of a symbol of a flame as the determinant showsthat the ancient Egyptians associated inflammation withheat.
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HISTORICAL PERSPECTIVES
Ancient Greeks usedthe term flegmonh to
mean inflammation,
also indicating a hot
thing(flegein to burn).
The Greek term
persists in our word
phlegmon, used todescribe certain
internal inflammatory
lesions
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FOUR CARDINAL SIGNS
RUBOR(redness)
TUMOR(swelling)
CALOR(heat)
DOLOR(pain)
Signs of inflammation were first described in the Egyptian papyrus in 3000BC
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Fifth Cardinal Sign of Inflammation
Redness andSwelling with Heat
and Pain
...and Loss ofFunction
was added by the
famous 19th century
pathologist RudolfVirchow
...et Functio lsa
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The Cellular Theory of Inflammation
was advancedduring the mid-19th centurythrough works ofexperimentalistsJulius Cohnheim,who firstobserved
vasomotor effectsand leukocyteemigration in sitesof inflammation
and Elie11
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Contemporaneously, the
work of Paul Ehrlichdefining the role of
complements and
antibodies in hostdefenses gave rise to a.
Humoral Theory of
Inflammation Modern understanding
of inflammation admits
important roles for both
cellular and soluble12
Th t f t d h i
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The components of acute and chronic
inflammatory responses
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ACUTE INFLAMMATION
Acute inflammation is the immediate and early response to
injury,Short duration, lasting from a few minutes up to a few
days
Characterized by fluid and plasma protein exudation and
by a predominantly neutrophillic leukocyte accumulation.
It has three major components
a) Alteration in vascular caliber
b)Structural changes in microvasculature
c)Emigration of the leucocytes
These changes account for five classical signs of acute
inflammation. 14
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Signs of inflammation
Redness (rubor) caused by
hyperaemia
Swelling (tumor) caused by fluid
exudation
Heat (calor)caused by hyperaemia
Pain (dolor) resulting from release of
bradykinin and PGE2
Loss of function- due to combined
effects of the above
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STIMULI FOR ACUTE INFLAMMATION
Infections (bacterial, viral, parasitic) and microbial
toxins
Trauma(blunt and penetrating)
Physical and chemical agents (thermal injury, e.g.,
burns or frostbite; irradiation; some environmentalchemicals)
Tissue necrosis (from any cause)
Foreign bodies (splinters, dirt, sutures)
Immune reactions (also called hypersensitivity
reactions)
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TERMINOLOGIES
The escape of fluid, proteins, and blood cells from the
vascular system into the interstitial tissue or body cavitiesis known as exudation.
Anexudateis an inflammatory extravascular fluid that has
a high protein concentration, cellular debris, and a specificgravity above 1.020.
Transudate is a fluid with low protein content (most of
which is albumin) and a specific gravity of less than 1.012.
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Edema denotes an excess of fluid in the interstitial or
serous cavities; it can be either an exudate or a transudate.
Pus,a purulent exudate, is an inflammatory exudate rich in
leukocytes (mostly neutrophils), the debris of dead cells
and, in many cases, microbes.
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VASCULAR CHANGES
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VASCULAR CHANGES
CHANGES IN VASCULAR FLOW AND CALIBER
Transient vasoconstriction(seconds)
Vasodilatation involving arteriole first
Local increase in blood flow
redness and warmth(erythema)
Increased permeability resulting in exudation of protein rich fluid into the extra vascular
tissues
Red blood cells become concentrated increasing the viscosity and slowing the
circulation(process called STASIS)
Leucocytes (neutrophils) accumulate along the vascular endothelial surface(process calledMARGINATION)21
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After adhering to endothelial cells the leucocytes squeeze between
them and migrate through the vascular wall into interstitialtissue(process called emigration)
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INCREASED VASCULAR PERMEABILITY
In earliest phase, vasodilatation and increased blood flow increase intra vascular
hydrostatic pressure
in filtration of fluid from the capillaries called Transudate.
flow of protein rich fluid and cells called Exudate into the interstitium
( reduces the intravascular osmotic pressure, while increasing the osmotic
pressure of the interstitial fluid.)
Net result is out flow of water and ions into the extra vascular tissues ,accumulation is
called Edema.
How does the normally non penetratable endothelial layer become leaky during acute
inflammation ? 24
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FIVE MECHANISM ARE KNOWN
Endothelial cellcontraction
-Immediate transient response
- Lasts for (15-30 min)
-Capillaries and arterioles are
unaffected
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Junctional retraction
-reversible mechanism
-occurs 4-6 hr after initial stimulus
-persists for 24 hr or more
-structural reorganization of cytoskeleton
-induced by cytokine mediator(TNF&IL-1)
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Direct endothelial injury
-vascular leakage by causing endothelial cell necrosis anddetachment
- reaction is called immediate sustained response
-direct injury may also induce a delayed prolonged leakage,
begins after a delay of 2-12hr.lasts for several hours or even days
-Attributed to apoptosis, and actions of cytokines.
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Leukocyte dependent endothelial injury
-due to leukocyte accumulation during inflammatory response
-leukocyte may be activated, releasing toxic oxygen species and proteolytic enzymes
which cause endothelial injury or detachment
-injury restricted to sites where leukocytes can adhere to the endothelium(venules,and
pulmonary capillaries)
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Increased transcytosis
-via an vesiculovacuolar pathway-augments venular permeability,f ollowing exposure to certain
mediators (vascular endothelial growth factor VEGF)
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Leakage from new blood vessels
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I n acute inf lammation, fluid loss from vessels with
increased permeabil i ty occurs in distinct phases: (1) an immediate transient response lasting for 30
minutes or less, mediated mainly by the actions of
histamine and leukotrienes on endothelium;
(2) a delayed response starting at about 2 hours and
lasting for about 8 hours, mediated by kinins, complement
products, and other factors; and
(3) a prolonged response that is most noticeable after
direct endothelial injury,for example, after burns.
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LEUKOCYTE CELLULAR EVENTS
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LEUKOCYTE CELLULAR EVENTS
Extravasation of leukocytes from vascular lumen to extravascular space is divided into
Margination and rolling
Adhesion and transmigration between endothelial cells
Miagration in interstial tissue toward a chemotactic stimulus
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MARGINATION AND ROLLING
In normal blood flow red and white blood cells travel along the central axis
As vascular permeability increases, fluid exits the vascular lumen and blood flowslows
As a result leukocytes settle out of central column, marginating to vessel periphery
Subsequently they tumble on the endothelium, transiently sticking along the way, a
process called rolling.
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Th lti t f l k t i ti
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The multistep process of leukocyte migration
through blood vessels, for neutrophils
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L k t Adh i d T i ti
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Leukocyte Adhesion and Transmigration
Regulated largely by the binding of complementary
adhesion molecules on the leukocyte and endothelialsurfaces,
chemical mediators chemoattractants and certain
cytokinesaffect these processes by modulating the
surface expression or avidity of such adhesion molecules.
The adhesion receptors involved belong to four molecular
families
theselectins,
the immunoglobulin superfamily, the integrins,
and mucin-like glycoproteins.
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Selectins
E-selectin (on endothelium) P-selectin (on endothelium & platelets; is preformed and
stored in Weibel Palade bodies)
L-selectin (leukocytes) Ligands for E-and P-Selectinsare sialylated glycoproteins (e.g
Sialylated Lewis X) Ligands for L-Selectin are Glycan-bearing molecules such as
GlyCam-1, CD34, MadCam-1
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E selectin(ELAM 1)
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E-selectin(ELAM-1)-
Identified as cytokine-inducible
endothelial glycoprotein that binds toboth neutrophils and monocytes
Not found in uninflammed endothelium
Expressed within 30 mins of stimulation
Peak concn. - 2 - 4 hrs
Expressed for about 24 hrs.
Induced by IL-1 and TNF secreted by
macrophages
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P-SELECTIN
Platelet activation dependent granule to external membraneprotein (PADGEM)
P-selectin contains the largest number of complement
binding protein like sequences
P-selectin is found in platelets upon activation withthrombin, histamine etc and in activated endothelium.
Ligand lacto-n-fucopentaose III- sialyl LewisX
Bind to neutrophils and monocytes
Expressed within 10- 30 mins
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L-SELECTIN
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L SELECTIN
Leukocytes use it to interact with carbohydrate moleculescalled vascular addressins sialomucin CD34) on the luminalsurface of the endothelial cells. SYNONYMS: Lectin adhesion molecule-1 and Leu8 and is
believed to be intimately associated with lymphocyte binding
to endothelium
This molecule contains only 2 complement-bindingextracellular domains and is found on lymphocytes, PMNs,
and monocytes
The expression of this molecule is associated with leukocytecell activation and rolling.
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Following adhesion to endothelial cells
the expression of L-selectin isdiminished and other leukocytic
integrins that help in transendothelial
migration are increased
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INTEGRINS
Family of transmembrane glycoprotein cell surface receptor
adhesins with one alpha and one beta subunit Three domains- large extracellular domain
6 types of beta subunits and 11 different alpha subunits = 16
integrins
Beta 2 subunit is most important in leukocyte adhesion Other functions include helping in diapedesis, leukocyte
migration, T-cell macrophage interactions, clot formation,epithelial cell migration
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Integrins- and factors controlling their
expression in adhesion
C5a induces increased surface
expression of LFA-1, Mac-1 and P150-
95 (CD11/18) integrin complex on the
surface of leukocytes.
The ligand on endothelial cells for LFA
and MAC-1
is ICAM-1 molecule on endothelium.
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IL-1 stimulates leukocyte adhesion by
inducing synthesis or increasedsurface expression of adhesive
proteins onendothelialcells which can
then bind to receptors on leukocytes- anendothelium dependent defect.
TNF affects expression of both
leukocyte and endothelial molecules.
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Integrins(a+bchain)
Heterodimeric molecules VLA-4(b1 integrin) binds to VCAM-1
LFA1 and MAC1 (CD11/CD18) = b2
integrin bind to ICAM
Expressed on leukocytes
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Endothelial adhesion Receptor on leukocyte Function
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Endothelial adhesion
molecule
Receptor on leukocyte Function
ELAM-1 Sialyl Lewis X PMN adhesion
ICAM-1 Integrins LFA-1
Mac -1 (CD-
11a,b/CD18)
Neutrophil,
Lymphocyte
adhesion
VCAM-1 Integrin VLA-4 Lymphocyte and
monocyte adhesion
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Immunoglobulin family
Are expressed on activated
endotheliumLigands are integrins on leukocytes
Induction ICAM-1- 4-6hrs, max. 24hrs
Leukocytes binds to ICAM- flatten over
epithelium
ICAM-1 (intercellular adhesion
molecule 1)
VCAM-1 (vascular adhesion molecule
1)
ICAM-253
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ICAM-2-
33kd, binds to leukocyte integrin a12and a22
ICAM-1,2-localizes leukocytes to the site
of injury
ICAM-3-
87 kd, 5 domains forms Head-tail
arrangement
For T cell activation
VCAM-1 is induced on endothelial cells
b several inflammator c tokines54
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PECAM-1 (CD31)
cell surface glycoprotein of 130kdfound on platelets, endothelial cells,
monocytes and neutrophils and some T-
cell subsets Localized at endothelial cell junctions-
may provide means by which
endothelial cells may lose theiradhesiveness and permit emigration
Ligand is aVb3 integrin55
M i lik l t i
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Mucin-like glycoproteins
Heparan sulfate (endothelium)
Ligands for CD44 on leukocytes
Bind chemokines
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Rolling leukocytes become activated by
chemokinessuch as monocyte chemoattractant
protein 1 and RANTES, presented by
the activated endothelial surface. The activated leukocytes can bind to
other endothelial adhesion molecules,
such as ICAM-2, and starttransmigrating into the vascular intima.
Prolonged endothelial stimulation
results in more of ICAM-157
Diapedesis
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p
Neutrophils and monocytes create a passage between the
endothelial cells.
Diapedesis typically occurs in venules and is mediated by
PECAM-1(CD31)
A leukocyte leading edge process rich in F-actin, catenin
and LFA-1 interacts with endothelial cell surface in
creating this channel
The endothelial zonula adherens junction undergoes rapid
assembly and disassembly during the process
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Emigration
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g
Adherent neutrophils throw out cytoplasmic pseudopodsand cross the basement membrane by damaging it with
secreted collagenases and escapes into the extravascularspace.
First 24 hours- PMNs escape
24-48 hours- monocytes and macrophages
Neutrophils are shortlived.
Monocyte migration is sustained
Chemotactic factors for neutrophils and monocytes areactivated at different phases of the response
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I t ti ith ll f i t ll l t i
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Interaction with cells of intercellular matrix
After crossing endothelium leukocytes have to interact
with cells of intercellular matrix using VLA molecules of
the 1 integrin group
VLA-2,3 for collagen
VLA-3,6 for laminin
VLA-3,4,5 for fibronectin
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CHEMOTAXIS AND ACTIVATION
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After extravasation leukocyte emigrate toward the site of injury along
a chemical gradient in a process called chemotaxis
Both endogenous and exogenous substances can act as chemotactic
agent for leukocyte including:
-soluble bacterial products, paricularly peptides with N-formyl
methionine termini-components of complement system, particularly C5a
-products of lipoxygenase pathway of arachidonic acid
(AA)metabolism, leukotrieneB4 (LTB4)
-cytokines
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Leukocyte activation
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Leukocyte activation
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Biochemical events in leukocyte activation
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Biochemical events in leukocyte activation
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PHAGOCYTOSIS
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PHAGOCYTOSIS
Process of engulfment of solid particulate material by the
cells of the size visible to light microscope
Cells performing phagocytosis are microphages (PMN)
and macrophages
Results in the eventual containment of the pathogen in a
within a membrane- delimited structure -phagosome
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Timed sequential events in the formation of
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a phagosome
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STEPS
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STEPS
Recognition and attachment
(opsonisation) Engulfment stage
Secretion (degranulation)
Digestion (degradation)
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Recognition and attachment
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Recognition and attachment
Phagocytes are recognized and attracted to bacteria by
chemokines released by bacteria and tissue proteins
Opsonized by serum complement, immunoglobulin (C3b,
Fc portion of IgG)
Corresponding receptors on leukocytes (FcR, CR1, 2, 3)
leads to binding
Microorganisms get coated with opsonins from the serum
to make a bond between bacteria and cell membrane of the
phagocytes as phagocyte possesses receptor for opsonin
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O i i
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Opsonization- coating the pathogen with a few recognizableligands which enable the pathogen to bind to and ingest the pathogen
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OPSONINS
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OPSONINS
IgG-Fc fragments
C3bgenerated by complement pathway
Lectins-carbohydrate binding proteins in
plasma
binding to bacterial cell wall
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The activation of the neutrophils makes
them more efficient at phagocytosis andkilling. Opsonisation of bacteria by
complement and immunoglobulins
renders them more readilyphagocytosed.
This entire process is orchestrated by a
plethora of chemical mediators derivedfrom injured tissues, bacteria, plasma
proteins and leucocytes
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Engulfment stage
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Engulfment stage
Opsonized particles bonded to the
phagocyte is engulfed by formation ofcytoplasmic pseudopods around the
particle due to activation of actin
filaments beneath the cell wall,enveloping it in a phagocytic vacuole.
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Degranulation stage
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Degranulation stage
Preformed granule stored products of PMN
azurophilic granules are fused to phagosomes phagocytosistriggers an oxidative burst engulfment and formation of
vacuole which fuses with lysosomal granule membrane
(phagolysosome)
Granules discharge within phagolysosome and
extracellularly (degranulation)
Lysosomes discharged into intercellular space
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Killing/degradation
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Killing/degradation
Killing byHydrolytic
enzymes
Oxygen-
DependentBactericidal
enzymes
Oxygen-
independentBactericidal
enzymes
Nitric oxide
Mechanismsenzymes
After the
microorganisms are
killed by antibacterial
substances they are
degraded by
hydrolytic enzymes
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Oxygen-dependent bactericidal mechanisms
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Require oxygen & redox potential of -160mv
Within seconds of stimulation the neutrophils sharplyincrease their oxygen uptake (RESPIRATORY BURST)
because of two biochemical events-
One electron reduction of molecular oxygen to superoxideradical
oxidation of glucose via HMP shunt with resultantproduction of NADPH and reduced glutathionine (GSH)
A respiratory burst oxidase is activated that catalyzes thetransfer of electrons from NADPH to oxygen through anelectron transport chain consting of a flavin and
cytochrome 558 to create superoxide.
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Extracellular superoxide is also converted to hydrogenperoxide using plasma protein ceruloplasmin
H2O2 diffuses across cell membranes and is utilized byMPO enzyme as substrate with halide ions to form HOClions
Microbicidal activity by forming toxic, reduced oxygenmetabolites such as superoxide anion O2- & H2O2.iscomparitively weaker than that of HOCl.
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Detoxification of hydrogen peroxide
Reduced glutathionine(GSH) is acted upon byenzyme glutathione peroxidase to detoxify H2O2.
It is also detoxified in the cytoplasm by catalase to
water and oxygen.
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Oxygen-Independent Antimicrobial Activity
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Oxygen Independent Antimicrobial Activity
Bactericidal permeability increasing protein (BPI) causes
phospholipase activation, phospholipid degradation and
increased membrane permeability
Lysozyme causes degradation of bacterial coat
oligosaccharides
Major basic protein (MBP) is cytotoxic component of
eosinophil granules- parasites
Defensinsare pore-forming antibacterials. alpha defensins
are small antimicrobial peptides( eg.HNP-1,2,3) ,rendering
them susceptibile to cathepsins and ROS esp. for bacteria
and fungi.
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Inhibition of locomotion--- serum of certain patients,
drugs- corticosteroids and phenylbutazone.
Deficiencies in generation of chemotactic signals---
complement system
Disorders of phagocytosis- Opsonin deficiencies
complement or IgG sickle cell disease failure of
alternate pathway activation.
Defects of engulfment- morphine analogues, diabetic
ketoacidosis
Disorders of lysosomal fusion steroids, colchicine,
Chediak-Higashi syndrome
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Chemical Mediators
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Mediators- in plasma or at local site of inflammation
Induce effect by binding to specific receptors on target
cells.
Stimulate target cells secondary effector molecules
amplify a particular response or have an opposing
function Act on only one or very few targets, or widespread
activity.
Function is tightly regulated
Quickly decay-----AA metabolites Eliminated -------antioxidants scavenge toxic O2
metabolites
Inhibited------complement inhibitory proteins.83
Chemical mediators of inflammation
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Vasoactive amines
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Histamine- tissues- in mast cells adjacent to vessels
( basophils, platelets)
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Neuropeptides
small peptides, such as substance P andneurokinin A,
Transit pain signals, regulate vessel tone and
modulate vascular permeability
Nerve fibres secrete neuropeptides
Commonly seen in lung & GIT
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Plasma proteases
Three interrelated plasma derived factors- kinins,clotting system, complement activation of
Hageman factor
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Increased vascular permeability
and leukocyte emigration
Increased
permeabili
ty,
arteriolar
dilation,
leukocyte adhesion
vascular
permeability and