In Fla Mat Ion

8/6/2019 In Fla Mat Ion

1/77

Good Morning


2/77

INFLAMMATIONHemodynamic Changes in Inflammation


3/77

Contents

Definition Signs of inflammation Acute inflammation

Vascular eventsCellular events

Chemical mediators of inflammationCell derived mediatorsPlasma derived mediators

Morphology of acute inflammation Systemic effects of acute inflammation Fate of acute inflammation Chronic inflammation General features of chronic inflamation Systemic effects of chronic inflamation

Pulpal inflammationConclusionReferences


4/77

"Inflammation is one of the most important and most useful of our host defense mechanisms, and without an adequate inflammatory

response none of us or our patients would be living. Ironically it isalso one of the most common means whereby our own tissues areinjured." (Slauson and Cooper, 2002)


5/77

D efinition Literally, inflammation means burning. More specifically,

inflammation is the reaction of vascularized living tissues to localinjury.

Inflammation comprises a series of changes in the terminalvascular bed, in blood and in connective tissues to eliminate theoffending irritant and repair the damaged tissue.

Roles of Inflammation:- Protection: To contain and isolate the injury, and to destroy invading

organisms and inactive toxins- Achieve healing and repair


6/77

The agents causing inflammation are:

1. Physical agents like heat, cold, radiation, mechanical trauma.

2. Chemical agents like organic and inorganic poisons.3. Infective agents like bacteria, viruses and their toxins.

4. Immunological agents like cell-mediated and antigen-antibodyreactions.


7/77

S IGN S OF INFLAMMATION

The Roman writer Celsus in 1st century A.D. 4 cardinal signs of inflammation as:

Rubor ;Tumor ;

Calor ; and Dolor .

functio laesa was later added by Virchow.


8/77

TYPE S OF INFLAMMATION

Depending upon duration of response - classified

I. Acute inflammation

short and severe course It begins within 4-6 hours can last for 3-5 days

It represents the early body reaction and is followed by repair.

The main features of acute inflammation are:

1. accumulation of fluid and plasma at the affected site;

2. intravascular activation of platelets; and

3. polymorphonuclear neutrophils as inflammatory cells.


9/77

II. Chronic inflammation is of longer duration and occurs eitherafter the causative agent of acute inflammation persists for a long

time, or the stimulus is such that it induces chronic inflammationfrom the beginning.

The characteristic feature of chronic inflammation is presence of chronic inflammatory cells such as lymphocytes, plasma cells andmacrophages


10/77

ACUTE INFLAMMATIONACUTE INFLAMMATION

VASCULAR CHANGESVASCULAR CHANGES CELLULAR CHANGESCELLULAR CHANGESExudation of leukocytesPhagocytosis

Hemodynamic changesVasoconstrictionVasodilatationLocal hydrostatic pressureStasisLeucocytic margination

Vascular permeabilityContraction of endothelial cellsRetraction of endothelial cellsDirect injury to endothelial cellsEndothelial injury mediated by leucocytes

Neovascularisation


11/77

Haemodynamic Changes

Vasoconstrictiontime

Vasodilatationredness & warmth

Local hydrostatic pressuretransudation of fluid

Stasis Leucocytic margination

emmigration


12/77

Lewis experiment --- Triple response


13/77

Altered Vascular Permeability

PATHOGENESIS.

In and around the inflamed tissue, there accumulation of oedemafluid

In the initial stage - transudate in nature

Subsequently - inflammatory oedema, exudate


14/77

S tarlings law

The movement of fluid in andout of arterioles, capillaries, and

venules is regulated by the

balance between intravascular

hydrostatic pressure and

opposing effects of osmotic

pressure exerted by the plasma

proteins.


15/77


16/77

D ifference Between Transudate And Exudate

Transudate Filtrate of blood plasma withoutchanges in endothelial

permeability Non inflammatory oedema Low protein content ; mainly

albumin, low fibrinogen, doesnot coagulate

Glucose content same as plasma Few cells & cellular debris Eg : oedema in congestive heart

failure

Exudate Oedema of inflamed tissueassociated with increasedvascular permeability

Inflammatory oedema High protein content, readily

coagulates due to morefibrinogen & other coagulatingfactors

Glucose content low Many cells, inflamatory & parenchymal Eg : purulent exudate such as pus


17/77

MECHANI S M S OF INCREA S E D VA S CULAR PERMEABILITY

In acute inflammation, normally non-permeable endothelial layerof microvasculature becomes leaky.

Contraction of endothelial cells

affects the venules

temporary gaps

It is mediated by the release of histamine, bradykinin and otherchemical mediators.

15-30 minutesExample - mild thermal injury of skin of forearm.


18/77

R etraction of endothelial cellsreversible retraction at the intercellular junctions

affects venules

mediated by cytokines such as interleukin-1(IL-1) and tumournecrosis factor (TNF).

4-6 hours after injury and lasts for 24 hours or more ( delayed and

prolonged leakage).Example - exists in vitro ex perimental work only


19/77

D irect injury to endothelial cells

cell necrosis and physical gapsthrombosis

All microvasculature

immediate sustained leakage,

delayed prolonged leakageexamples

severe bacterial infections

moderate thermal injury and radiation injury.


20/77

Endothelial injury mediated by leucocytes

activation of leucocytes

proteolytic enzymes and toxic oxygen species which maycause endothelial injury and increased vascular leakiness.

affects mostly venules

and is a late response.

Examples - in pulmonary

venules and capillaries.


21/77

N eovascularisation.

During the process of repair there is formation of new capillariesunder the influence of vascular endothelial growth factor (VEGF).

excessively leakyEg : occurring in tumours


22/77

Cellular Events

EXUDATION OF LEUKOCYTESChanges in the formed elements bloodRolling &AdhesionEmigrationChemotaxis

Leukocyte activation

PHAGOCYTOSISRecognition & attachmentEngulfmentDegranulationKilling &degradation


23/77

Ex udation of LeucocytesThe escape of leucocytes from the lumen of microvasculature tothe interstitial tissue is the most important feature of inflammatory response. In acute inflammation, polymorphonuclear neutrophils (PMNs) comprise the first line of bodydefense, followed later by monocytes and macrophages.


24/77

CHANGES IN THE FORMED ELEMEN TS OF BLOOD

Vasodilatation

stasis of bloodstream

normal axial flow

MarginationPavementing


25/77

R OLLING AND AD HES ION

adhesion molecules are :

i) Selectins

P-sclectin

E-selcctin (synthesised by cytokine activated endodothelial cells)

L-selectinii) Integrins

receptors for integrins on the neutrophils are also stimulated. .

iii) Immunoglobulin superfamily adhesion molecule such asintercellular adhesion molecule (ICAM-1,2) help in localisingleucocytes to the site of tissue injury and thus help intransmigration of PMNs.


26/77


27/77

EM IGR ATION

neutrophils throw out cytoplasmic pseudopodsemigration

24 hours, and monocyte-macrophages appear in the next 24-48hours.

Diapedesis - is a passive phenomenon

Diapedesis gives haemorrhagic appearance to the inflammatoryexudate.


28/77

CHEM OTAXIS

The transmigration of leucocytes after crossing several barriers(endothelium, basement membrane, peri-vascular myofibroblastsand matrix) to reach the interstitial tissues is called chemotaxis.

The concept of chemotaxis is illustrated by Boy den's chamber

experiment.a millipore filter (3 m pore size)

the test solution contains

chemotactic agent.


29/77

The agents acting as potent chemotactic substances for differentleucocytes called chemokines are as follows:

i) Leukotriene B 4ii) Platelet factor 4

iii) Components of complement system

iv) Cytokines (Interleukins 1L-1, IL-5, IL-6)v) Soluble bacterial products (such as formylated peptides)

vi) Monocyte chemoattractant protein (MCP-1)

vii) Chemotactic factor for CD 4+T cells

viii) Eotaxin chemotactic for eosinophils.


30/77

Phagocytosis

Phagocytosisphagocytes.

2 main types of phagocytic cells: PMNs also called as microphages . circulating monocytes and fixed tissue mononuclear phagocytes

called as macro phages. The process of phagocytosis involves 4 steps: recognition and attachment stage (opsonisation) Engulfment stage Secretion (degranulation) stage Digession or degradation stage.


31/77

RECOGNITION AN D ATTACHMENT S TAGE.

The phagocytic cells are recognised and attracted to a bychemotatic factors released by bacterial products as well as bytissue proteins.

micro-organisms get coated with o p sonins which occur in serum. The opsonins and their corresponding receptors are :

i) IgG o p sonin is the Fc fragment of immunoglobulin G; ii) C 3b o p sonin is the fragment of complement; iii) Lectins are carbohydrate-binding proteins in the plasma which

bind to bacterial cell wall.


32/77

ENGULFMENT S TAGE

The opsonised particle is engulfed. cytoplasmic pseudopods Cytoplasmic processes meet, and fuse membrane lined phagocytic vacuole lies free in the cell cytoplasm The lysosomes of the cell fuse with the phagocytic vacuole and

form phagolysosome or phagosome .


33/77

D EGRANULATION S TAGE

During this process, the preformed granule stored products of PMNs are discharged or secreted into the phagosome and theextracellular environment.

In particular, the specific or secondary granules of PMNs aredischarged (e.g. lysosomes) while the azurophilic granules arefused with phagosomes. .


34/77

K ILLING OR D EGRA D ATION S TAGE

scavenger cells degraded by hydrolytic enzymes fails to kill and degrade some bacteria like tubercle bacilli.

The antimicrobial agents act by either of the followingmechanisms:

Oxygen-dependent bactericidal mechanism; Oxygen independent bactericidal mechanism


35/77

Oxygen-dependent bactericidal mechanism Microbicidal killing occurs by the production of reactive oxygenmetabolites (O' 2 H20, OH', HOCl, HOI, HOBr). A phase of increased oxygen consumption ('respiratory burst') by

activated phagocytic leucocytes requires the essential presence of NADPH oxidase.


36/77

bactericidal activity occurs with or without enzymemyeloperoxidase (MPO) present in neutrophils and monocytes :MPO- de pendent killing (H 202-MPO- halide system).

MPO- inde pendent killing. Mature macrophages lack the enzymeMPO and they carry out bactericidal activity by producing OH -

ions


37/77

ii) Oxygen-independent bactericidal mechanism. Some agentsreleased from the granules of phagocytic cells do not requireoxygen for bactericidal activity. These include lysosomalhydrolases, permeability increasing factors, defensins and cationic

proteins.


38/77

CHEMICAL ME D IATOR S OF INFLAMMATION

permeability factors or endogenous mediators enhance vascular permeability The substances acting as chemical mediators of inflammation may

be released from t he cells, t he plasma, or damaged tissue itself.


39/77

1. VASOACTIVE AMINES.- early inflammatory response (first one hour) are histamine and 5-hydroxytryptamine (5-HT) or serotonin i) Histamine. It is stored in the granules of mast cells, basophils

and platelets. Stimuli e.g. heat cold, irradiation, trauma, irritant chemicals.

immunologic reactions etc Anaphylatoxins like fragments of complement C 3a and C 5awhichincrease vascular permeability and cause oedema in tissues.

histamine releasing proteins from leukocytes. neuropeptides ( subs. P ) & cytokines ( IL-1, IL-8 ). Interleukins.


40/77

actions of histamine are:

vasodilatation, increased vascular (venular) permeability, itching and pain.

ii) 5-Hydroxytryptamine (5-HT or serotonin). It is present in tissues like chromaffin cells of GIT, spleen,nervous

tissue, mast cells and platelets. actions - increased vascular permeability and vasodilatation Eg ; carcinoid tumour is a serotonin-secreting tumour.


41/77

2. ARACHIDONIC ACID METABOLITES Arachidonic acid is a fatty acid, and its 2 main sources are: from diet directly; and conversion of essential fatty add, linoleic acid to arachidonic acid. Arachidonic acid is activated by stimuli or mediators like C 5a to

form arachidonic acid metabolites by 2 pathways: i) Metabolites via cyclo-oxygenase pathway (prostaglandins,

thromboxane A2, prostacyclin).


42/77

Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes).

The enzyme, lipo-oxygenase, acts on activated arachidonic acid toform hydroperoxy compound, 5-HPETE (hydroperoxy eico-satetraenoic acid)


43/77

APPLIE D AS PECTI. Cyclooxygenase inhibitors

1. Nonselective Cox inhibitors Salicylates -aspirin Pyrazolone derivatives - phenylbutazone Indole derivatives - indomethacin Propionic acid derivatives - ibuprofen Anthronilic acid derivatives mephenamic acid Aryl-acid derivatives - diclofenac Oxicam derivatives - piroxicam Pyrrolo-pyrrole derivatives - ketorolac

2. Preferential Cox-2 inhibitors

Nimesulide


44/77

3. Selective Cox-2 inhibitors

Celecoxib, Rofecoxib, Valdecoxib.II. Lipoxygenase inhibitors

I. Zileuton

II. zafirlukost

III. Broad spectrum inhibitors

I. Glococorticoids


45/77

3 . LY S O S OMAL COMPONENT S

Neutrophil granules Lactoferrin Lysozyme Alkaline phosphatese Collagenase Myeloperoxidase Acid hydrolases

Monocyte granules Acid protease Collagenase Elastase Plasminogen activator


46/77

4. PLATELET ACTIVATING FACTOR

Increased vascular permeability Vasodilatation Broncho constriction Chemotaxis

5. CYTOKINES

1. Interleukins 1(IL-1)

2. Tumour necrosis factor (TNF)-alfa & beta

3. Interferon (IF)-gama

4. Chemokines (IL-8, PF-4)


47/77


48/77

6. NITRIC OXIDE & OXYGEN METABOLITES

NO-Derived from activated macrophases

O2- derived from activated neutrophils & macrophases

They include-superoxide oxygen

-hydrogen peroxide

-hydroxyl ion


49/77

Plasma derived mediators

1) The kinin system

2) The clotting system

3) The fibrinolytic system

4) The complement system


50/77

THE K ININ S YS TEM.

Bradykinin acts in the early stage of inflammation and its effectsinclude:

smooth muscle contraction; vasodilatation; increased vascular permeability; and pain


51/77

THE CLOTTING S YS TEM

Factor Xlla initiates the cascade of the clotting system resulting information of fibrinogen which is acted upon by thrombin to formfibrin and fibrinopeptides .The actions of fibrinopeptides in inflammation are:

increased vascular permeability; chemotaxis for leucocyte; and anticoagulant activity.


52/77

THE FIBRINOLYTIC S YS TEM.

This system is activated by plasminogen activator


53/77

The actions of plasmin in inflammation are:activation of factor XII to form prekallikrein activator thatstimulates the kinin system to generate bradykinin;splits off complement C 3 to form C 3a which is a permeabilityfactor; anddegrades fibrin to form fibrin split products which increasevascular permeability and are chemotactic to leucocytes.


54/77

THE COMPLEMENT S YS TEM.

The activation of complement system can occur by antigen-antibody complexes or by bacterial toxins, cobra venoms and IgA.

Complement system on activation by either of these two pathwaysyields anaphylatoxins C 3a, C 5a and C 4a.

The actions of ana ph ylatoxins in inflammation are:release of histamine from mast cells and basophils;increased vascular permeability causing oedema in tissues;C 3b augments phagocytosis; and

C 5a is chemotactic for leucocytes.


55/77

MORPHOLOGY OF ACUTE INFLAMMATION

Inflammation of an organ is usually named by adding the suffix-itis to its Latin name e.g. appendicitis, hepatitis, meningitis etc.

morphologic varieties

P S EU D OMEMBRANOU S INFLAMMATION.It is inflammatory response of mucous surface (oral, respiratory)

denudation of epithelium, so plasma exudes on the surface where itcoagulates, and together with necrosed epithelium, forms falsemembrane.


56/77

ULCER.

local defects on the surface of an organ produced by inflammation. Common sites are the stomach, duodenum, intestinal ulcers in

typhoid fever, intestinal tuberculosis, bacillary and amoebicdysentery, ulcers of legs due to varicose veins etc.

S UPPURATION (AB S CE SS FORMATION). When acute bacterial infection is accompanied by intense

neutrophilic infiltrate in the inflamed tissue, it results in tissuenecrosis.

A cavity is formed which is called an abscess and contains purulent exudate or pus and the process of abscess formation isknown as suppuration.

The bacteria which cause suppuration are called pyogenic.


57/77

pus is creamy or opaque in appearance and is composed of numerous dead as well as living neutrophils, some red cells,fragments of tissue debris and fibrin.

An abscess may be discharged to the surface due to increased pressure inside or may require drainage by the surgeon. Due to

tissue destruction, healing occurs by fibrous scarring.

Some of the common examples of abscess formation are as under:i) B oil or furruncle which is an acute inflammation via hair follicles in the dermal tissues.

ii) Carbuncle is seen in untreated diabetics and occurs as aloculated abscess in the dermis and soft tissues of the neck.


58/77

CELLULITI S .

It is a diffuse inflammation of soft tissues resulting from spreadingeffects of substances like hyaluronidase released by some bacteria.

5. BACTERIAL INFECTION OF THE BLOO D .

This includes the following 3 conditions:i. Bacteraemia is defined as presence of small number of bacteriain the blood which do not multiply significantly.

They are commonly not detected by direct microscopy. Bloodculture is done for their detection e.g. infection with S almonellaty phi, Esc heric hia coli, S tre ptococcus viridans.


59/77

ii) Septicaemia means presence of rapidly multiplying, highly pathogenic bacteria in the blood e.g. pyogenic cocci, bacilli of plague etc.

iii) Pyaemia is the dissemination of small septic thrombi in the blood which cause their effects at the site where they are lodged.

This can result in pyaemic abscesses or septic infarcts.


60/77

a) P yaemic abscesses are multiple small abscesses in various

organs resulting from very small emboli fragmented from septicthrombus.

b) S e ptic infarcts result from lodgement of larger fragments of septic thrombi in the arteries.


61/77

S YS TEMIC EFFECT S OF ACUTE INFLAMMATION

1. Fever occurs due to bacteraemia. It is thought to be mediatedthrough release of factors like prostaglandins, interleukin-1 andtumour necrosis factor in response to infection.

2. Leucocytosis 15,000-20,000/ l A leukocyte count above is termed a leukemoid reaction in bacterial infections there is neutrophilia; in viral infections lymphocytosis; and in parasitic infestations, eosinophilia.


62/77


63/77

OUTCOME OF ACUTE INFLAMMATION

INJURY

Acute inflmn

Chronic inflmn

RESOLUTION

ABSCESS FORMATION

HEALING


64/77

CHRONIC INFLAMMATION

Chronic inflammation is defined as prolonged process in whichtissue destruction and inflammation occur at the same time.

caused by one of the following 3 ways:1. Chronic inflammation following acute inflammation.2. Recurrent attacks of acute inflammation.3 . Chronic inflammation starting de novo.


65/77

GENERAL FEATURE S OF CHRONIC

INFLAMMATION1. MONONUCLEAR CELL INFILTRATION.

mononuclear inflammatory cells - phagocytes and lymphoid cells. Phagocytes - circulating monocytes, macrophages, epithelioid cells

and sometimes, multinucleated giant cells. These appear at the site of chronic inflammation from: chemotactic factors local proliferation of macrophages and longer survival of macrophages at the site of inflammation. Other chronic inflammatory cells include lymphocytes, plasma

cells, eosinophils and mast cells.


66/77

2. TI SS UE D E S TRUCTION OR NECRO S IS .

Tissue destruction and necrosis are central feature of chronicinflammatory lesions which occurs by activated macrophageswhich release a variety of biologically active substances e.g.

protease, elastase, eollagenase, lipase, reactive oxygen radicals,cytokines (TL-1, IL-8, TNF), nitric oxide, angiogenesis growthfactor etc.

3. PROLIFERATIVE CHANGE S . As a result of necrosis, proliferation of small blood vessels and fibroblasts is stimulated

resulting in formation of inflammatory granulation tissue.Eventually, healing by fibrosis and collagen laying takes place.


67/77

S YS TEMIC EFFECT S OF CHRONICINFLAMMATION

Fever. Anaemia Leucocytosis ESR Amyloidosis occurs in long-term cases of chronic suppurative

inflammation.


68/77


69/77

Inflammatory changes caused by severe injury can lead to necrosisof the pulp and subsequent pathologic changes in the periradicular tissues.

portals of entry The vascular response causes the aggregation of red blood cells in

the vessels.

metabolic changes waste products spread inflammation total necrosis of the pulp


70/77

K im Hypothetical Model


71/77

Periradicular Manifestations

the root canal will serve as a pathway to the periradicular area for the noxious products of tissue necrosis.

noxious products produce bone resorption and granulation tissue


72/77

Tissue Changes Following Inflammation

Tissue changes following inflammation are either degenerative or proliferative.

Degenerative Changes Degenerative changes in the pulp may be one of the following: Fibrous Resorptive Calcific Another form of degeneration is su ppuration. Three requisites are necessary for suppuration: 1. Necrosis of tissue cells 2. A sufficient number of polymorphonuclear leukocytes 3. Digestion of the dead material by proteolytic enzymes


73/77

Proliferative Changes Proliferative changes are produced by irritants mild enough to act

as stimulants. Within the same area, a substance may be both anirritant and a stimulant, such as calcium hydroxide and its effect onadjacent tissue.


74/77

Endodontic Implications

The reaction of the periradicular tissues was described by Fish. foci of infection in the jaws of guinea pigs 4 well defined zones of reaction were found: (i) zone of infection; (ii) zone of contamination; (iii) zone of irritation; and (iv) zone of stimulation.


75/77


76/77

Conclusion Inflammation has a protective role as well as may harm the body.

Thus proper treatment is to be devised and implemented for optimum health to be achieved.


77/77

References Harsh Mohan pathology Robbins Internet sources

Documents

In Fla Mat Ion