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This is the normal appearance of the appendix against
the background of the cecum. The colonoscopic view of
the appendiceal orifice between the fork of two haustralfolds in the cecum is seen below.
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This appendix was removed surgically. The patient presented with abdominal
pain that initially was generalized, but then localized to the right lower
quadrant, and physical examination disclosed 4+ rebound tenderness in the
right lower quadrant. The WBC count was elevated at 11,500. Seen here is
acute appendicitis with yellow to tan exudate and hyperemia, including the
periappendiceal fat superiorly, rather than a smooth, glistening pale tanserosal surface.
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Microscopically, acute appendicitis is marked by
mucosal inflammation and necrosis.
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This is a normal esophagus with the usual white to tan smooth
mucosa seen at the left. The gastroesophageal junction (not an
anatomic sphincter) is at the center, and the stomach is at the
right. The upper GI endoscopic view of the transition from tan
squamous mucosa to pink columnar mucosa is seen below.
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Acute esophagitis is manifested here by increased
neutrophils in the submucosa as well as neutrophils
infiltrating into the squamous mucosa at the right.
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This is normal esophageal squamous mucosa at the left, with
underlying submucosa containing mucus glands and a duct
surrounded by lymphoid tissue. The muscularis is at the right.
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One consequence of acute inflammation is ulceration. This occurs
on epithelial surfaces. Here the gastric mucosa has been lost, or
ulcerated. A larger ulcer and several adjacent smaller ones withsurrounding erythema appear at the left of center.
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This example of a fluid collection, a friction blister of
the skin, is an almost trivial example of edema.
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The cardinal signs of inflammation are rubor (redness), calor
(heat), tumor (swelling), dolor (pain), and loss of function.
Seen here is skin with erythema, compared to the morenormal skin at the far right.
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This yellow-green exudate on the surface of an inflamed,
hyperemic (erythematous) bowel mucosa consists of many
neutrophils along with fibrin and amorphous debris fromdying cells.
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Here is an example of the fibrin mesh in fluid with PMN's that
has formed in the area of acute inflammation. It is this fluid
collection that produces the "tumor" or swelling aspect ofacute inflammation.
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INFLAMMATION
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INFLAMMATION
Reaction of cascularized conective tissue
to injury or stimuli
Protective mechanism
If goes unchecked
Tissue damage- scarring
Hypersensitivity- increased response
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COMPONENTS INVOLVED IN
INFLAMMATION Blood vessels: endothelium
Blood:
Cells:
NeutrophilsMonocytes
Lymphocytes
Eosinophils
Basophils
Platelets Plasma:
Serum
Clotting system
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COMPONENTS INVOLVED IN
INFLAMMATIONConnective tissue
Cells:
Mast cells
Fibroblasts
Macrophages
lymphocytes
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COMPONENTS INVOLVED IN
INFLAMMATION
Connective tissue
Extracellular matrix
Basement membrane
Proteoglycans
Adhesion glycoproteins Adhesion glycoproteins
Fibronectin
Laminin
Collagen type IV
Structural proteins Collagen
Elastin
Proteoglycans
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INFLAMMATION
Acute Short duration
Edema ( leakage of
proteins & fluids) Leukocyte migration
(PMNs mainly)
Chronic Long duration
Lymphocytes & macrophages
Blood vessel proliferation Fibrosis
Tissue necrosis
Terminate on removal of stimulus
Stimulus sends signals via chemical mediators
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Fig 3.1 (robins)
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DEFINITIONS
Exudation
Fluid rich in proteins and cells (exudate)
Secondary to increased vascular permeability
Specific gravity of 1.020 or more
Pus
Purulent exudate rich in PMN's and cell debris Transudation
Fluid with very little protein (mostly albumin)
From increased hydrostatic pressure in vessels
There is no increase in permeability Specific gravity 1.012 or more
Edema
Excess extravascular (interstitial ) accumulation of fluid
Could be either exudate or transudate
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This example of a fluid collection, a friction blister of the
skin, is an almost trivial example of edema.
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The arm at the bottom is swollen (edematous) and reddened
(erythematous) compared to the arm at the top.
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This yellow-green exudate on the surface of an inflamed,hyperemic (erythematous) bowel mucosa consists ofmany neutrophils along with fibrin and amorphous debrisfrom dying cells.
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Exudation of a protein-richfluid into a cavity leads to atransudate. The fibrin inthis fluid can form afibrinous exudate on thesurfaces. Here, the
pericardial cavity has beenopened to reveal a fibrinouspericarditis with strands ofstringy pale fibrin between
visceral and parietalpericardium.
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Here is an example of the fibrin mesh in fluid with PMN'sthat has formed in the area of acute inflammation. It is
this fluid collection that produces the "tumor" or swellingaspect of acute inflammation.
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Fig 3.2
Robins
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Fig 3.3
Robins
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Mechanism ofvascularleakage inacute
inflammation
Fig 3.4
Robins
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CLINICAL SIGNS OF ACUTE
INFLAMMATION Redness
Heat
Swelling
Pain
Loss of function
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CELLULAR EVENTSExtravasation
Journey of leukocytes from lumen to
interstitial tissue
Lumen
Margination Rolling
Adhesion
Wall
Diapedesis (transmigration across endothelium) Interstitial tissue
Migration towards stimuli
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Fig 3.5 Robins
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Fid 3.9 Robins
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Fig 3.7
Robins
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Fig 3.8 Robins
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LEUKOCYTE ACTIVATION
Induced by
Chemotactic agents
Phagocytosis
Ag-Ab complexes Includes
Production of AA metabolites
Degranulation & secretion of lysosomal enzymes &
activation of oxidative burst
Modulation of leukocyte adhesion molecule
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CHEMOTAXIS
Emigration of leukocytes toward the site of injury
along a chemical gradient
Chemotactic agentsSoluble bacterial products
Components of the complement system
Products of the lipoxygenae pathway ofarachidonic acid
Cytokines
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Biochemical events in leukocyte activationFig 3.11Robins
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PHAGOCYTOSIS
Steps include
Recognition & attachment
Opsonins (opsonization of particles)
Fc & IgG ______FcR C
3
b & C3
bi______CR1,2,3
Lectins ( carbohydrate binding proteins)
of plasma called collectins
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PHAGOCYTOSIS contd.
Engulfment Triggered by binding of opsonized particle to FCR Markedly enhanced in presence of complement receptors
Binding to CR alone: engulfment
Results in phagosome
Phagolysosome [ lysosome & phagosome] (degranulation)
Killing or degradation
Bacteria killed by O2 dependant mechanism
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PHAGOCYTOSIS contd
Killing or degradation
Phagocytosis causes
Increased O2 consumption
Glycogenolysis
Increased glucose oxidation
Production of reactive O2 metabolites
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PHAGOCYTOSIS contd
Mechanisms of killing
H2O2- MPO- Halide system: Most efficientbactericidal system in neutrophils
Others: Bactericidal permeability increases protein (BPI)
Lysozyme
Lactoferrin
Major basic protein (eosinophils); for parasites
After killing : degradation by acid hydrolases inazurophilic granules
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Phagocytosis ofa particle
Fig 3.11Robins
LEUKOCYTE INDUCED TISSUE
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LEUKOCYTE INDUCED TISSUE
INJURY
By Lysosomal enzymes
O2 derived active metabolites
Products of AA metabolism
Ways which these chemicals are released
Regurgitation during feeding Transient opening of phagosome before closure
Frustrated phagocytosis ? Surface phagocytosis
Cytotoxic release
After phagocytosis of membranolytic substance e.g. uratecrystals
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DEFECTS IN LEUKOCYTE
FUNCTIONS
IN
ADHESION: Defect in adhesion molecules
Recurrent bacterial infections
Phagocytosis
Chediak Higashi syndrome Decreased PMNs
Defective degranulation
Delayed killing
Giant granules Microbicidal activity
Chronic granulomatous disease
Bacterial infections
Defect in NADPH Oxidase
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Acute inflammation
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At medium power magnification, numerous neutrophils fillthe alveoli in this case of acute bronchopneumonia. Notethe dilated capillaries in the alveolar walls from
vasodilation with the acute inflammatory process.
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PMN's seen here are in alveoli, indicative of an acutebronchopneumonia of the lung. The PMN's form an
exudate in the alveoli
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PMN's that are marginated along the dilated venule wall(arrow) are squeezing through the basement membrane(the process of diapedesis) and spilling out into
extravascular space.
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The milky white fluid shown here in the peritoneal
cavity represents a chylous ascites. This is an
uncommon fluid accumulation that can be due to
blockage of lymphatic drainage, in this case by a
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This example of a fluid collection, a
friction blister of the skin, is an
almost trivial example of edema.
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This example of edema with inflammationis not trivial at all: there is marked
laryngeal edema such that the airway is
narrowed. This is life-threatening. Thus,
fluid collections can be serious depending
upon their location.
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Here is simple edema, or fluid collection within
tissues. This is "pitting" edema because, on physical
examination, you can press your finger into the skin
and soft tissue and leave a depression.
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The arm at the bottom is swollen (edematous)
and reddened (erythematous) compared to the
arm at the top. Click to determine which areas
are painful to touch.
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At medium power magnification,numerous neutrophils fill the alveoli in
this case of acute bronchopneumonia in a
patient with a high fever. Pseudomonasaeruginosa was cultured from sputum.
Note the dilated capillaries in the
alveolar walls from vasodilation with theacute inflammatory process.
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Acute bronchopneumonia
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The PMN's seen here are in alveoli, indicative
of an acute bronchopneumonia of the lung.
The PMN's form an exudate in the alveoli.
This patient had a "productive" cough becauselarge amounts of purulent sputum were
produced. The source, the neutrophilic
alveolar exudate, is seen here.
exudate
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exudate
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Fibrinous Exudate (pericardium)
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At higher magnification, vasculitis with arterial wall necrosis is seen. Note the fragmented
remains of neutrophilic nuclei (karyorrhexis). Acute inflammation is a non-selective process that
can lead to tissue destruction.
necrosis
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Inflammation with necrosis
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The vasculitis shown heredemonstrates the destruction that can
accompany the acute inflammatory
process and the interplay with the
coagulation mechanism. The arterialwall is undergoing necrosis, and
there is thrombus formation in the
lumen.
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Migration of neutrophils
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As in the preceding diagram, here PMN's that are marginated along the dilated venule wall
(arrow) are squeezing through the basement membrane (the process of diapedesis) and
spilling out into extravascular space.
Pleural effusion
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H i l f fl id ll i i b d
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Here is an example of fluid collection into a body
cavity, or an effusion. This is a right pleural effusion
(in a baby). Note the clear, pale yellow appearance ofthe fluid. This is a serous effusion. Extravascular fluid
collections can be classified as follows:
Exudate: extravascular fluid collection that is rich inprotein and/or cells. Fluid appears grossly cloudy.
Transudate: extravascular fluid collection that is
basically an ultrafiltrate of plasma with little protein
and few or no cells. Fluid appears grossly clear.
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Effusions into body cavities can be further
described as follows:
Serous: a transudate with mainly edema fluidand few cells.
Serosanguinous: an effusion with red blood
cells.Fibrinous (serofibrinous): fibrin strands are
derived from a protein-rich exudate.
Purulent: numerous PMN's are present. Also
called "empyema" in the pleural space.
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A purulent exudate is seen beneath the
meninges in the brain of this patient
with acute meningitis from
Streptococcus pneumoniae infection.The exudate obscures the sulci.
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The abdominal cavity is opened at autopsy here to reveal
an extensive purulent peritonitis that resulted fromrupture of the colon. A thick yellow exudate coats the
peritoneal surfaces. A paracentesis yielded fluid with the
properties of an exudate: high protein content with many
cells (mostly PMN's).
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Here is a purulent exudate in which the exuded fluid also
contains a large number of acute inflammatory cells.
Thus, the yellowish fluid in this opened pericardial
cavity is a purulent exudate.
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INFLAMMATIONS
Definition
A protective response of
vascularized connective tissue to injurious
stimuli, leading to the accumulation of
fluid and leukocytes in the E/V tissues.
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PURPOSE
1.destroy
2.dilute
3.wall off
h ill h i h
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What will happen without
inflammation 1.Infections would go un-checked
2.wounds would never heal
O CO S O
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OUTCOMES OF
INFLAMMATION 1.REGENERATION
2.SCARRING
3.HARM DONE BY THE RESPONSEITSELF
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TYPES
1.ACUTE
SHORT-LIVED (MIN. TO FEW
DAYS) ASSOCIATED WITHEXUDATION AND NEUTROPHIL
EMIGRATION
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TYPES
2. CHRONIC:
LONGER-DURATION
ASSOCIATED WITH NECROSISFIBROSIS,PROLIFERATION OF
BLOOD-VESSELS AND
ACCUMULATION OF LYMPHOS ANDMACROPHAGES
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COMPONENTS/AFFECTORS
OF THE RESPONSE
1.PLASMA
2.CIRCULATING CELLS--NEUTRO
EOSINO
BASO
LYMPHOS
MONOS ANDPLATELETS
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AFFECTORS CONTD
3.BLOOD VESSELS
4.CELLS/EXTRACELLULAR
CONSTITUENTS OF CT:mast cells,histiocytes,fibroblasts
and
collagen,elastin,fibronectin,laminin
etc.
MEDIATORS OF THE
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MEDIATORS OF THE
RESPONSE CHEMICALS DERIVED FROM:
1.PLASMA
2.CELLS:
BLOOD
CT
ENDOTH
NECROTIC CELLS ALSO
TERMINATION OF THE
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TERMINATION OF THE
RESPONSEREMOVAL OF THE CAUSE
OR
INHIBITION/DISSIPATION OF THEMEDIATORS
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Inflammation vs immunity
1.SPECIFICITY
2.MEMORY
3.AMPLIFICATION
4.TYPE OF STIMULUS
physical/chemical:inflammation
infectious:combined
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Acute inflammation------events
Vascular events
a.changes in calibre
b.changes in structure Cellular events
occuring in the
a.lumenb.wall and outside the wall
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Vascular events
Changes in the calibre
a.trasient VC (arterioles)
b.VD (arterioles/capillaries)
Outcome of calibre changes
a.increased blood flow
b.increased hydrostatic pressure
St t l h
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Structural changes
(increased permeability,leakage) Vessels involved:arterioles,capillaries and
venules
Outcome:exudation Mechanisms:1.endothelial contraction
2.endothelial retraction
3.transcytosis
4.endothelial injury
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Mechanisms contd
5.WBC-mediated
6.new blood vessels
Mechanism 1 endothelial
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Mechanism 1-endothelial
contraction1.vessels involved:- venules
2.type of response:- immediate/trasient
3.cause:- chemical mediators
4.mechanism:- cells shrink,so I/C
junctions open up
Mec an sm 2-en ot e aretraction(cytoskeletal
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retraction(cytoskeletal
reorganization)1.vessels involved:-capillaries/venules
2.type of response:-delayed/prolonged
3.cause:-mediators and sublethal injury to
endothelial cells
4.mechanism:-rearrangement of cytoskeleton
such that cells retract from
each other at I/c junctions
Mechanism 3 increased
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Mechanism 3-increased
transcytosis1.vessels involved:- venules
2.cause:- mediators
3.mechanism:- increased transport across the
cell cytoplasm,through small,
inter-connected vesicles
Mechanism 4
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Mechanism 4-
direct endothelial injury1.vessels involved:-all levels of microcirc
2.type of response:-immediate/sustained
3.cause:-moderate to severe injury
4.mechanism:-necrosis and detachment of
cells
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Mechanism 6
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Mechanism 6-
leaky new blood vesselsDuring the process of healing,new blood
vessels are formed(angiogenesis);these are
leaky due to poorly developed I/c junctions
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Outcome of vascular events
EDEMA formation
edema is defined as excess fluid in the
interstitium or in the body cavities.It can
either be:
a transudate
or
an exudate
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Exudate vs transudate
Feature exudate transudate
1.permeab increased normal
2.protein 1.5-6g/dl 0-1.5g/dl
3.prot.type all albumin
4.fibrin yes no
5.sp.grav 1.015-1.027 1.010-1.015
6.cells inflammatory none
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Cellular events
1.margination role of WBC in
2.rolling inflammation
3.adhesion 1.ingest
4.transmigration 2.kill
5.chemotaxis 3.degrade
6.activation 4.prolong inflam
7.phagocytosis 5.tissue damage
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Adhesion/transmigration
Two factors are important:
1.complementory adhesion molecules on
endothelium and white cells eg
a. selectins on endoth/glycoproteins on wbc
b.ICAM/VCAM on endoth/integrins on wbc
2.modulation by chemical mediators
Adhesion molecules role of
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Adhesion molecules------role of
chemical mediators They cause:
1.redistribution on surface
2.induction of production
3.increase affinity
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chemotaxis
Unidirectional movement of wbc towards a
chemical gradient or
locomotion oriented along a chemical
gradient
agents classified:
1.exogenous: bacterial peptides and lipids
2.endogenous:LT,cytokines,complement
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mechanism
Chemotactic agent
cell p.lipase-c activated
PIP-2 IP-3 + DAG
Ca released
stimulates contractile apparatus
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phagocytosis
3 steps involved:
1.recognition/attachement of particle
opsonization opsonins
2.engulfment into vacoule 1.Fc of IgG
3.killing/degradation: 2.C3b
oxygen-dependant 3.collectins
oxygen-independant
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Oxygen dependant mechanisms
Non-specific:over-production of free
radicals due to increased metabolism
specific:hydrogen peroxide-MPO-halidesystem in the azurophil granules;HOCl
produced is bactericidal
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Oxygen-independant
BPI factor(bacterial permeability
increasing)
lysozyme lactoferrin
MBP(major basic protein)
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Chemical mediators of
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Chemical mediators of
inflammationstimuli
plasma: cells:
precursors activated released from gran1.bind to receptors or syn
2.act as enzymes
3.oxidative damage
4.stimulate release of mediators from targets
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Cell derived
Pre-formed in the granules:
histamine/serotonin
lysosomal enzymes newly synthesized:
a. prostaglandins b. leukotrienes
c. platelet-activating factor
d. reactive oxygen e.cytokines f.NO
ll l f di
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Cellular sources of mediators
1.Platelets 2.neutrophils
3.monocytes/ 4.mast cells
macrophages 5.endothelium6.smooth muscles 7.fibroblasts
8.epithelia
l d i d di
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Plasma derived mediators
factor-xii
activated
kinin system clotting cascadefibrinolytic
cascade
complement cascade
C l
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Complement system
20 proteins in plasma: stimulus activation:
C1-C9 i. classic pathway: MAC(C5-9),
AA reaction by-products:ii. alternate pathway: a.vascular:
a.endotoxins C3a,C5a
b.aggregated Ig b.cells:
c.polysacch/venom C5a,C3b,
Ki i
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Kinin system
Kininogens kallikrein vaso-active pep
in plasma 1.chemotactic esp.bradykinin
2.convert c5 a.VD/permeabto c5a b.pain
c.SM contract
action terminated by:kininase in plasma and
ACE in lungs
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Fib i l i
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Fibrinolytic system
plasmin cleaves C3
C ll d i d
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Cell-derived
Pre-formed:
1.Vaso-active amines:
serotonin/histamine: tissue distribution:mast
cells,basophils,platelets(in the granules)
actions: a.dilatation of arterioles
b.increased permeability of venules
A i td
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Amines contd
Stimuli for degranulation:
1.physical:trauma,heat,cold
2.immune reactions3.complement components,c3a and c5a
4.cytokines /other mediators
P f d l l
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Preformed---lysosomal enzymes
Neutrophils have:
specific granules containing:
lysozyme,collagenases,lactoferrin,plasminogen activator
secrete extracellularly
azurophil granules containing:
MPO,acid hydrolases,neutral proteases
C td
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Contd.
Termination:
decay or enzymatic
check/balance:anti-proteases
N l th i d
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Newly synthesized
Arachidonic acid metabolites:
.AA is a polyunsaturated fatty acid
.derived from diet or synthesized fromlinoleic acid
.exists in esterified form in memb PL
.released by phospholipases through:
physical,chemical stimuli or mediators
C td
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Contd.
Products are also called Eicosanoids;they
are:
prostaglandinsleukotrienes
lipoxins
thromboxanes
AA t b li
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AA metabolism
membrane phospholipids
p.lipases x steroids
AA NSAIDsLOX COX
LT PG
(A4 toE4 ) ( D2 toI2)
increase permeab pain,fever
PAF
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PAF
PL-derived
sources:mast
cells,basophils,platelets,endoth actions:platelet and leukocyte activation
increase in permeability
chemotaxis smoking
generates it
Nit i id
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Nitric oxide
Nature:gas
source:neurons,macrophages,endothelium
actions:paracrinesmooth muscle relaxation through
GMP production,antimicrobial activity
VD,neutrophil activation,plt.aggregation
enzymes in synthesis:NO synthetase
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Contd
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Contd.
Prototypes IL-1 and TNF
secrete in response to:endotoxins,AA comp.
And physical injury actions:1.acute phase reactions
2.on endothelium TNF controls
3.on white cells body mass
4.on fibroblasts
Most likely mediators of
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y
inflammation
Vasodilatation:protaglandins,NO
increased permeability:amines,c3a c5a,LT,
and bradykinin
chemotaxis:chemokines,c5a,LT
fever:PG,cytokines(IL-1,IL-6,TNF)
pain:PG,bradykinin
tissue damage:NO,oxygen,lysosomal enzymes
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Contd
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Contd.
Fever:IL-1
IL-6 hypothalamus PG
TNF VM centresympathetic
hyperactivity
skin vc less heat loss
FEVER
Contd
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Contd.
Leukocytosis:count is beyond 15 to 20,000
neutrophilia:bacterial infections
lymphocytosis:viral
eosinophilia:allergic/helminthic conditions
leukopenia:typhoid,overwhelming
leukemoid reaction:very high counts that
resemble leukemias can be seen in infections
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