1 &2. Acute Inflammation..

7/29/2019 1 &2. Acute Inflammation..

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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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INFLAMMATIONConnective tissue

Cells:

Mast cells

Fibroblasts

Macrophages

lymphocytes


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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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