3rd Seminar- Acute Inflmn

8/6/2019 3rd Seminar- Acute Inflmn

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-by Dr Shruthi B


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REFERENCES

1. Robbins & Cotron Pathological basis of diseases -7th edn.2. Walter, Hamilton & Israels Principles of pathology for dental

students 5th edn

3. Boyd text book of pathology 9th edn.

4. Text book of Pathology Rubin, John L.Farber 2nd edn.

5. Text book of oral pathology Shafer 4th edn.

6. Contemporary oral & maxillofacial surgery Peterson.

7. Textbook of medical pharmacology - tripathi

8. Google search

References


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Introduction

Inflammation

L.inflammatio; inflammare = to set on fire

Inflammation is a protective response intended to

eliminate the initial cause of cell injury as well as

the necrotic cells and tissues resulting from the

original insult.


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Definition

Acc to Robins

Inflammation is a complex reaction to injurious

agents such as microbes & damaged, usuallynecrotic, cells that consists ofvascular responses,

migration & activation of leukocytes, & systemic

reactions.


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Acc toJ. B. Walter & M. S. Israel

Inflammation is the reaction of the vascular and supporting

elements of the tissue to injury and results in the formation

of a protein rich exudates, provided the injury has not been

so severe as to destroy the area.


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Cardinal signs


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Historical highlights

Celsus (3000 BC) Roman writer listed 4

cardinal signs

Virchow 5th

clinicalsign, loss of function( functiolaesa )


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John Hunter(1793) Salutary effect

Julius Cohnheim (1839-1884)

-observed inflamed

blood vessels undermicrosco e


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Elie Metchnikoff(1880) Phagocytosis

Sir Thomas Lewis -Chemical

mediators


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Inflammatory cells


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Acute inflammation

Acute inflammationis a rapid responseto an injurious

agent that servesto delivermediators of hostdefenseleukocytes andplasma proteinsto the site of injury.


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Acute inflammation has threemajor components:

(1) alterations in vascular caliberthat lead to an increase in bloodflow

(2) structural changes in themicrovasculature that permit

plasma proteins and leukocytesto leave the circulation

(3) emigration of the leukocytesfrom the microcirculation, theiraccumulation in the focus of

injury, and their activation toeliminate the offending agent


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Stimuli for acute inflammation

Infections (bacterial, viral, parasitic) andmicrobial toxins

Trauma (blunt and penetrating)

Physical and chemical agents (thermal injury,e.g., burns or frostbite; irradiation; someenvironmental chemicals)

Tissue necrosis (from any cause)

Foreign bodies (splinters, dirt, sutures) Immune reactions (also called hypersensitivity

reactions)

Sti li f t


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Stimuli for acuteinflammation

Physical injuryInfection

(bacterial, viral, parasitic)Trauma

Tissue NecrosisForeign bodies(splinters, dirt, sutures)

Immune reactions


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VASCULAR CHANGESCELLULAR CHANGES*Vasoconstriction* Vasodilatation* Permeability

* Stasis* Transmigration

*Exudation of leukocytes* Phagocytosis

ACUTE INFLAMMATION


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Vascular changes

Alteration in the microvasculature is the earliestresponse to tissue injury

Two changes are

1. Changes in Vascular Flow and Caliber

2. Increased Vascular Permeability

(Vascular Leakage)


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Changes in thevascular flow

vasodilation

Permeability of

vasculature

viscosity

Stasis of blood

Transient vasoconstriction

Incr

ea

sedv

iscos

ity&s

tasiso

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bloo

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Normalaxia l

bloo

dflow


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Vascular leakage

IOP &HP

Outflow of

fluid

Edema

Loss of plasma protein

Hallmark of acute inflammation

Starlings Hypothesis


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Cellular changes

A critical function of inflammation is to deliverleukocytes to the site of injury and to activate theleukocytes to perform their normal functions inhost defense.

Two processes


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Extravasation

The sequence of events in the journey of leukocytesfrom the vessel lumen to the interstitial tissue, calledextravasation.

Events are1. Margination, rolling, and adhesion to Endothelium

2. Transmigration across the endothelium (diapedesis)

3. Migration in interstitial tissues toward a chemotactic

stimulus

Margination rolling and


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Margination, rolling, andadhesion

Blood flow slowsearlyin inflammation(stasis),

hemodynamicconditions change(wall shear stressdecreases), andmore white cells

assume aperipheral positionalong theendothelial

surface. This

Rows ofleukocytestumble slowlyalong the

endothelium andadheretransiently (aprocess calledrolling), finallycoming to rest atsome point wherethey adherefirmly

(resembling

The endothelium can be virtually linedby white cells, an appearance calledpavementing.


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Adhesion moleculesAdhesionmolecules


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Selectins

E-selectin- endothelium P-selectin- endothelium

& platelets

L-selectin- leukocyte

The selectins are a family of three closely related proteinsthat differ in their cellular distribution

Selectins bind, through their lectin domain, to sialylatedforms of oligosaccharides (e.g., sialylated Lewis X), which

themselves are covalently bound to various mucin likeglycoproteins

various mucin-like glycoproteinsbinding of selectins to theirligands has a fast on rate but also has a fast off rate and isof low affinity; this property allows selectins to mediate

initial attachment and subsequent rolling of leukocytes onendothelium in the face of flowing blood


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Integrins

Integrins are transmembraneheterodimeric glycoproteins, made up of and chains, that are expressed on manycell types and bind to ligands onendothelial cells, other leukocytes, and the

extracellular matrix . The integrins LFA-1 and Mac-1

(CD11a/CD18 and CD11b/CD18) bind toICAM-1, and the integrins (such as VLA-4)

bind VCAM-1.


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molecules

The immunoglobulin family molecules include two

endothelial adhesion molecules:ICAM-1 (intercellular adhesion molecule 1)

VCAM-1 (vascular cell adhesion molecule 1)

Both these molecules serve as ligands forintegrins found on leukocytes

Mucin like glycoproteins Mucin-like glycoproteins, such as

heparan sulfate, serve as ligands for the leukocyte adhesion

molecule called CD44.

These glycoproteins are found in the

extracellular matrix and on cellsurfaces


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Process of migration ofthe leukocytes throughthe endothelium, calledtransmigration or

diapedesis.Chemokines stimulatethe cells to migratethrough interendothelialspaces toward thechemical concentrationgradient, i.e, towards the

site of injury or infection.


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The type of emigrating leukocyte varies with theage of the inflammatory response and with the

type of stimulus.

In most forms of acute inflammation, neutrophilspredominate in the inflammatory infiltrate during

the first 6 to 24 hours, then are replaced bymonocytes in 24 to 48 hours.


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Why neutrophils?

Neutrophils are more numerous in the blood

They respond more rapidly to chemokines

They may attach more firmly to the adhesion molecules thatare rapidly induced on endothelial cells, such as P- and E-

selectins

In addition, after entering tissues, neutrophils are short-lived;they undergo apoptosis and disappear after 24 to 48 hours,whereas monocytes survive longer

Schematic & histologic sequence of events following acute injury


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Schematic & histologic sequence of events following acute injury

Later (mononuclear) cellular InfiltratesEarly (neutrophilic) Infiltration


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Chemotaxis

It is the locomotion of leukocytesoriented along a chemical gradienttowards the site of injury

All granulocytes, monocytes and, to alesser extent, lymphocytes respond tochemotactic stimuli with varying rates

of speed.1. Exogenous- bacterial products

2. Endogenous


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Endogenous substances

(1)Components of the complement system,particularly C5a;

(2)Products of the lipoxygenase pathway, mainlyleukotriene B4 (LTB4); and

(3)Cytokines, particularly those of the chemokine

family (e.g., IL-8).


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Mechanism

hemotactic agents

Leukocyte receptors

Increase in cytosolic Ca

Polymerization & reorganization of actin

Linear assembly of actin polymers along filopo

Leukocyte moves by pulling back of the


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The functional responses that areinduced on leukocyte activation

include the following:

Production of arachidonic acid metabolites

Degranulation and secretion of lysosomal

enzymes Secretion of cytokines

Modulation of leukocyte adhesion molecules


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Phagocytosis

It is defined as the process ofengulfment of solid particulate

material by the cells( cell eating)

Phagocytosis and the release ofenzymes by neutrophils and

macrophages are responsible foreliminating the injurious agents


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Phagocytes

Neutrophil

Monocyte

Macrophage

3 steps


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3 steps


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1.RECOGNITION AND ATTACHMENT

Extensions of the


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Mannose receptors and

scavenger receptors are two

important receptors

microbes are opsonized by

specific proteins (opsonins)

major opsonins are IgG

antibodies, the C3b

breakdown product of

complement, and certain

plasma lectins

Extensions of thecytoplasm(pseudopods) flowaround the particle

to be engulfed,forms phagosome.The limitingmembrane of this

phagocytic vacuolethen fuses with thelimiting membraneof a lysosomalgranule, resulting indischarge of thegranule's contentsinto thephagolysosome

Phagocytosis is

Elimination of infectious agents and necroticcells is their killing and degradation withinneutrophils and macrophages


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Phagocytosis stimulates:

A burst in oxygen consumption,

Glycogenolysis, Increased glucose oxidation via the hexose-

monophosphate shunt, and

Production ofreactive oxygen intermediates

(ROIs, also called reactive oxygen species).

Oxygen-Dependent


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Oxygen DependentAntimicrobial Activity

O I d d t


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Oxygen-IndependentAntimicrobial Activity

Increased production of lactate &action of carbonic anhydrase

Lactoferrin

Lysozyme

Phagocytin, defensins, Major basic

protein, Bactericidal permeabilityincreasing protein


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Nitric oxide mechanism

NO is released from endothelial cells& macrophages

Fungicidal & antiparasitic action

Wh i th h t ll t


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Why is the host cell notaffected by the ROI?


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Defects in leukocytefunction

Disease Defect


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Disease Defect

Genetic

Leukocyte adhesion deficiency 1 chain of CD11/CD18 integrins

Leukocyte adhesion deficiency 2 Fucosyl transferase required for synthesis ofsialylated oligosaccharide (receptor for

selectin)

Chronic granulomatous disease Decreased oxidative burst

X-linked NADPH oxidase (membrane component)

Autosomal recessive NADPH oxidase (cytoplasmic components)

Myeloperoxidase deficiency Absent MPO-H2O2 system

Chdiak-Higashi syndrome Protein involved in organelle membranedocking and fusion

Acquired

T i ti


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Termination

mediators of inflammation have short half-lives

a variety of stop signals that serve to actively terminate thereaction

These active mechanisms include

A switch in the production of pro-inflammatory

leukotrienes to anti-inflammatory lipoxins fromarachidonic acid

The liberation of an anti-inflammatory cytokine,transforming growth factor- (TGF-), from macrophagesand other cells

Neural impulses (cholinergic discharge) that inhibit theproduction of TNF in macrophages

Chemical mediators of


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Chemical mediators ofinflammation


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General principles

Mediators originate either from plasma or from cells

production of active mediators is triggered bymicrobial products or by host proteins

perform their biologic activity by initially binding to

specific receptors on target cells

One mediator can stimulate the release of othermediators by target cells themselves


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Mediators can act on one or few target celltypes

Once activated and released from the cell,most of these mediators are short-lived

Most mediators have the potential to causeharmful effects.


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Vasoactive Amines


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Vasoactive Amines

1. HistamineReleased from mast cells , basophils and plateletsStimuli(1)Physical injury such as trauma, cold, or heat;

(2)Immune reactions involving binding ofantibodies to mast cells;(3)Fragments of complement called anaphylatoxins

(C3a and C5a);(4)Histamine-releasing proteins derived from

leukocytes, and(5)Neuropeptides (e.g., substance P); and (6)

cytokines (IL-1, IL-8).


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Actions

In humans, histamine causes dilation of the arterioles

and increases the permeability of venules.

It is considered to be the principal mediator of the

immediate transient phase of increased vascular

permeability, causing venular gaps.

Itching & pain mediator

Serotonin


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Serotonin

Released by platelets andenterochromaffin cells

Released when platelets aggregateafter contact with collagen,thrombin, adenosine diphosphate(ADP), and antigen-antibodycomplexes

Increases the vascular permeability


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Plasma Proteases

Plasma proteins that belong to threeinterrelated systems:

The complement,

Kinin, and

Clotting systems


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Complement system

20 component proteins (and theircleavage products)

found in greatest concentration in

plasma This system functions in both innate

and adaptive immunity for defense

against microbial agents. C3 and C5 are the most important

inflammatory mediators.

The Early Steps


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The classical pathway is triggered by fixation ofCl to antibody (IgM or IgG) that has combinedwith antigen, and proteolysis of C2 and C4, andsubsequent formation of a C4b2b complex thatfunctions as a C3 convertase.

The alternative pathway can be triggered bymicrobial surface molecules (e.g., endotoxin, or

LPS), complex polysaccharides, and cobra venom.It involves a distinct set of plasma components(properdin, and factors B and D). In this pathway,the spontaneous cleavage of C3 that occursnormally is enhanced and stabilized by a complexof C3b and a breakdown product of Factor Bcalled Bb; the C3bBb complex is a C3 convertase

In the lectin pathway, mannose-binding lectin, aplasma collectin, binds to carbohydrate-containing proteins on bacteria and viruses and

directly activates Cl

The Early Steps

The Early Steps of Complement


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The Early Steps of ComplementActivation

the classical pathway, which is triggered by fixation of Cl to antibody (IgM orIgG) combined with antigen The classical pathway is triggered by fixation ofCl to antibody (IgM or IgG) that has combined with antigen, and proteolysis ofC2 and C4, and subsequent formation of a C4b2b complex that functions as aC3 convertase.

The alternative pathway can be triggered by microbial surface molecules

(e.g., endotoxin, or LPS), complex polysaccharides, and cobra venom. Itinvolves a distinct set of plasma components (properdin, and factors B andD). In this pathway, the spontaneous cleavage of C3 that occurs normally isenhanced and stabilized by a complex of C3b and a breakdown product ofFactor B called Bb; the C3bBb complex is a C3 convertase

The lectin pathway, in which plasma mannose-binding lectin binds tocarbohydrates on microbes and directly activates Cl.In the lectin pathway,

mannose-binding lectin, a plasma collectin, binds to carbohydrate-containingproteins on bacteria and viruses and directly activates Cl

The Late Steps of Complement


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The Late Steps of ComplementActivation

The C3b that is generated by any of thepathways binds to the C3 convertase andproduces a C5 convertase, which cleavesC5. C5b remains attached to the complex

and forms a substrate for the subsequentbinding of the C6C9 components.

Polymerized C9 forms a channel in lipidmembranes, called the membrane attack

complex, which allows fluid and ions toenter and causes cell lysis.

The Late Steps


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The Late Steps

C3b binds to the C3 convertaseand produces a C5 convertase,which cleaves . C5b forms asubstrate for the subsequent

binding of the C6C9

Polymerized

C9 forms achannel inlipidmembranes,called themembraneattack

complex,which allowsfluid and ionsto enter and

causes cell


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Actions

Vascular phenomenaAphylatoxins (C3a, C5a)- increase vascular

permeability & vasodilation

C5a also activates the lipoxygenase pathway of

arachidonic acid (AA) metabolism Leukocyte adhesion, chemotaxis, and activation

C5a is a powerful chemotactic agent for neutrophils,monocytes, eosinophils, and basophils

Phagocytosis.

C3b-opsonin

Kinin system


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Kinin system

Factor XIIa

Plasmaprekallikrein

Kallikrein

High-molecular-weight

kininogen Bradykinin

The kinin system generates vasoactive peptides fromplasma proteins, called kininogens, by the action ofspecific proteases called kallikreins

Activation of the kinin system results in the release ofthe vasoactive nonapeptide bradykinin.


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Actions

Bradykinin increases

vascular permeability

causes contraction of smooth muscle,pain when injected into the skin

dilation of blood vessels


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Clotting system

The clotting system and inflammation are intimately

connected processes.

Factor XII initiates clotting cascade as it encounters

collagen or basement membrane or activated platelets

The protease thrombin formed from its precurses

prothrombin provides the main link between thecoagulation system and inflammation


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Thrombin binds to receptors that are calledprotease-activated receptors (PARs)

It causes

1.mobilization of P-selectin

2.production of chemokines

3.expression of endothelial adhesion molecules for

leukocyte integrins

4.induction of cyclooxygenase-2

5. production of Prostaglandins

6. production of PAF and nitric oxide

7.changes in endothelial shape

Fibrinolytic system


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Fibrinolytic system

Plasminogen

activator

Plasminogen

Plasmin

Fibrin split productsC3C3a

Actions:1.Stimulates the kinin system to generatebradykinin.2.Splits off complement C3 to form C3a .3.Fibrin products : Increases vascular

permeability


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Arachidonic Acid


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Metabolites

Arachidonic acid (AA) is derived from dietarysources or by conversion from the essential fattyacid linoleic acid

It does not occur free in the cell but is normally

esterified in membrane phospholipids

It is released from membrane phospholipidsthrough the action of cellular phospholipases

mechanical chemical and


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mechanical, chemical, andphysical stimuli or by othermediators (e.g., C5a)

increase in cytoplasmic Ca2+

and activation of variouskinases

activation of phospholipase A2


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Inflammatory actions of


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Inflammatory actions ofeicosanoids

Action Metabolite

Vasoconstriction Thromboxane A2, leukotrienes

C4

, D4

, E4

Vasodilation PGI2, PGE1, PGE2, PGD2

Increased vascular permeability Leukotrienes C4, D4, E4

Chemotaxis, leukocyte adhesion Leukotriene B4, HETE, lipoxins


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Pl t l t ti ti f t


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Platelet activating factor

PAFis another bioactive phospholipid-derivedmediator.

A variety of cell types, including platelets,basophils (and mast cells), neutrophils,

monocytes/macrophages, and endothelial cells,can elaborate PAF.

PAF mediates its effects via a single G-protein-coupled receptor, and its effects are regulated

by a family of inactivating PAF acetylhydrolases


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In addition to platelet stimulation, PAF causes

Vasoconstriction and bronchoconstriction, and induces vasodilation and increased venular

permeability at extremely low concentrations

increased leukocyte adhesion to endothelium (byenhancing integrin-mediated leukocyte binding),chemotaxis, degranulation, and the oxidative burst

- boosts the synthesis of other mediators,particularly eicosanoids, by leukocytes andother cells.

C t ki


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Cytokines

Cytokines are proteins produced by manycell types (principally activatedlymphocytes and macrophages, but alsoendothelium, epithelium, and connectivetissue cells) that modulate the functions ofother cell types

TNF and IL-I are two of the major cytokines

that mediate inflammation. They areproduced mainly by activatedmacrophages


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CHEMOKINES


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CHEMOKINES

Chemokines are a family of small (8 to 10 kD)proteins that act primarily as chemoattractants forspecific types of leukocytes.

About 40 different chemokines and 20 different

receptors for chemokines have been identified.

Chemokines stimulate leukocyte recruitment ininflammation and control the normal migration of

cells through various tissues.

f j


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four major groups


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Some chemokines are produced transiently inresponse to inflammatory stimuli and promote therecruitment of leukocytes to the sites ofinflammation.

Other chemokines are produced constitutively intissues and function in organogenesis to organize

different cell types in different anatomic regions ofthe tissues.

Nitric Oxide


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Nitric Oxide NO, a pleiotropic mediator of inflammation, was discovered as a

factor released from endothelial cells that caused vasodilation by

relaxing vascular smooth muscle and was therefore calledendothelium-derived relaxing factor.

NO is a soluble gas that is produced not only by endothelial cells,but also by macrophages and some neurons in the brain.

NO acts in a paracrine manner on target cells through induction of

cyclic guanosine monophosphate (GMP), which, in turn, initiates aseries of intracellular events leading to a response, such as therelaxation of vascular smooth muscle cells.


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Since the half-life of NO is only seconds, the gas actsonly on cells in close proximity to where it is produced.

In addition, NO reduces platelet aggregation andadhesion, inhibits several features of mast cell-inducedinflammation, and serves as an endogenous regulator ofleukocyte recruitment.

Thus, production of NO is an endogenous compensatorymechanism that reduces inflammatory responses.


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NO and its derivatives are microbicidal,and thus NO is also a mediator of hostdefense against infection

High levels of NO production by a varietyof cells appear to limit the replication ofbacteria, helminths, protozoa, and viruses(as well as tumor cells).


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-Radicals


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Radicals Oxygen-derived free radicals may be released extracellularly

from leukocytes after exposure to microbes, chemokines, andimmune complexes, or following a phagocytic challenge.

Superoxide anion, hydrogen peroxide (H2O2), and hydroxylradical (OH) are the major species produced within the cell,and these metabolites can combine with NO to form otherreactive nitrogen intermediates.

Extracellular release of low levels of these potent mediators

can increase the expression of chemokines (e.g., IL-8),cytokines, and endothelial leukocyte adhesion molecules,amplifying the cascade that elicits the inflammatory response.


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The physiologic function of these reactive oxygenintermediates is to destroy phagocytosed microbes. At

higher levels, release of these potent mediators can bedamaging to the host.

Serum, tissue fluids, and host cells possess antioxidantmechanisms that protect against these potentially harmfuloxygen-derived radicals.

Thus, the influence of oxygen-derived free radicals in anygiven inflammatory reaction depends on the balancebetween the production and the inactivation of thesemetabolites by cells and tissues

Lysosomal Constituents


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Lysosomal Constituents

Neuropeptides


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Neuropeptides

Morphologic forms


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Morphologic forms

Outcome of acute


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inflammation

Resolution of acute


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inflammation

3rd Seminar- Acute Inflmn

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