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Good morning INFLAMMATION & CHEMICALMEDIATIORS 2Dr. Sharanprakash R S1st year MDS NPDCH, Visnagar.

INTRODUCTION - History General features of inflammation3CLASSIFICATION OF INFLAMMATIONACUTE INFLAMMATION Stimuli Vascular Events & Cellular Events Morphology of acute inflammation CHEMICAL MEDIATORS OF INFLAMMATIONCHRONIC INFLAMMATION causes featuresDENTAL ASPECTS OF INFLAMMATIONDENTAL ABSCESS4

CONCLUSIONREFERENCE

INTRODUCTION,, and. Hence in the importance of inflammation is that it can sometimes be, and is thus the cause of tissue injury in many disorders.

According to ROBINSINFLAMMATION is a complex reaction to injurious agent such as microbes and damaged , necrotic cells that consist of vascular responses , migration , and activation of leukocytes and systemic reaction5

Imagine suppose inflammation is not present

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HISTORICAL HIGHLIGHTS

Egyptian Papyrus , 3000 BC

CELSUS , Roman Writer - 1 AD - CARDINAL SIGNS

JOHN HUNTER , 1793 Inflammation is not a disease but a constructive effect on hostJULIUS CONHEIM-1st used microscope to observe inflamed blood vessels & cells6

Although clin f. of inflamm were describd in an egyptian papyrus 3000 BC , Celsus ..a roman writer 1st listed cardinal signs of inflammation1793 john Hunter a Scottish surgeon niticed that ..Julius Conheim

67SIGNS OF INFLAMMATIONGIVEN BY CELSUS

REDNESS

SWELLING

HEAT

PAINRuborTumorDolorCalor LOSS OF FUNCTION FUNCTIO LAESABY VIRCHOW

The five classical signs of inflammationAlthough Latin terms are still used widely in Western medicine, local language terms, such as English, are taking over. The traditional Latin based terms have been around for two thousand years:Dolor- Latin term for "pain Calor- Latin term for "heat"Rubor- which in Latin means "redness"Tumor- a Latin term for "swelling"Functio laesa- which in Latin means "injured function", which can also mean loss of function.

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EnglishGreek/LatinCaused ByRednessRuborHyperaemiaWarmthCalorHyperaemiaSwellingTumorIncreased permeabilityPainDolorLow pHLoss of function Functio laesa Pain, swellingThe five cardinal signs of acute inflammation - "PRISH"

An ingrown toenail with the five PRISH signs; pain, redness, immobility, swelling and heatPain- the inflamed area is likely to be painful, especially when touched. Chemicals that stimulate nerve endings are released, making the area much more sensitive.Redness- this is because the capillaries are filled up with more blood than usualImmobility- there may be some loss of functionSwelling- caused by an accumulation of fluidHeat- as with the reason for the redness, more blood in the affected area makes it feel hot to the touch.8

CLASSIFICATION99ACUTE INFLAMMATIONAnacutecondition is one with a rapid onset and/or a short course

INFECTIONS :Bacterial / viral / parasitic & microbial toxinsTrauma : Blunt / penetratingPhysical / chemical agents eg thermal injury Foreign body eg sutures / splinters Immune reactions / hypersensitivity reactions1010ACUTE INFLAMMATION

11ACUTE INFLAMMATIONVASCULAR CHANGES

HEMODYNAMIC CHANGES / Change in vascular flow & calibre

CHANGE IN VASCULAR PERMEABILITY12CHALIBER :-the level of their ability.12

Begin earlyDevelop at varying rates..severity13HEMODYNAMIC CHANGES / Change in vascular flow & caliberThese changes begin early after injury and develop at varying rates depending upon severity of injury. 13TRANSIENT VASOCONSTRICTION

Arterioles 3-5 sec. in mild injury5 minutes ; severe injury14Transient --- short lived Temporary vasoconstriction of arterioles 14PERSISTENT PROGRESSIVE VASODILATION

1st involves arteriole then other capillary bed seen in 1st 30 min. Results in, increase blood vol. in microvascular bed, which is responsible for redness and warmth at site Heat Redness

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16INCREASED PERMEABILITY OF MICROVASULATUREContraction of endothelial cells - Histamine

Retraction of endothelial cells -- cytokine IL 1 , TNF

Direct injury to endothelial cells

Endothelial injury mediated by leukocytes

Only venules affects (unknown reason ), where as arterioles and capillaries are unaffected > The temporary gaps

Re organization endothelial cell reversible retraction at the intercellular junction > 4-6 hrs of injury and last for 24 hrs TNF (tumor necrosis factor )

3) Direct injury physical gap of venules capillaries and arterioles > thrombosis >>2-12 hrs to a days

4) Leukocytes releases proteolytic enzymes which causes endothelial cells gaps

16STASISIncreased vascular permeability leads to loss of fluid from microvasculatureConcentration of red cells in small vesselsSlower blood flowSTASIS

1717LEUCOCYTIC MIGRATION & EMIGRATION

Stasis is followed by peripheral orientation of leucocytes along vascular endotheliumLEUCOCYTIC MIGRATIONMovement of leucocytes in extracellular space through gaps b/w endothelium.EMIGRATION18Leucocytes are WBC- 1) polymorph {neutrophils} PNMs . 2) Eosinophil. 3) basophil/mast cells -- GRANULOCYTES 4) Monocytes/macrophage 5) Lymphocytes 6) Plasma cells 1819

CHANGE IN VASCULAR PERMEABILITY

Due to the changes of vascular flow, the collection of blood components around the inflamed tissue is seen 1920

The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation

Edema -Collection of exudate in the extravascular tissue Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate

Transudate is a fluid with low protein content. a transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity It is essentially an ultra filtrate of blood plasma & results, from hydrostatic imbalance across the vascular endothelium. In this situation, the permeability of the endothelium is normal.

The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation

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CELLULAR EVENTS21CELLULAR EVENTS

Deliver leukocytes to site of injuryTo perform their FUNCTIONACTIVATE Ingest offending bacteria

Kill bacteria & other microbes

Get rid of necrotic tissue & foreign substance

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Delivery of leukocytes to the site of injury and to activate the leukocytes to perform their normal function in host defense

(There are no free lunches in this world and the price for this defense by leukocytes is that some normal tissue damage also takes place)

2223CELLULAR EVENTSCHEMOTAXIS24 DELIVERY OF LEUKOCYTES TO SITE OF INJURY1 )Diapedasis transmigration 24CELLULAR EVENTSMARGINATION rollingAdhesionIN THE LUMENMARGINATION

25Normal blood flow consists of a central stream of cells contains of leukocytes & RBCs & plasma occupies periphery Due to slowing of blood flow & stasis taking place during inflammation ; central zone widens & plasma zone narrows since plasma is lost during exudation As a result of this , Leukocytes in central column now come close to vessel wall This is MARGINATION process of accumulation at the periphery of vessel 25Margination RollingAdhesionIN THE LUMENCELLULAR EVENTSROLLING Leukocytes now tumble along the endothelium Have a TRANSIENT adhesion with endothelium 26

26Migration RollingAdhesionIN THE LUMENCELLULAR EVENTSADHESION

27As said earlier. rolling is a form of transient adhesion. after rolling & transient adhesion , leukocytes come to rest at and adhere firmly in some time , endothelium gets lined by WBCs giving appearance of pavementing / pebbles over which stream runs without disturbing 27CELLULAR EVENTS TRANS acrossPSEUDOPODIASQUEEZE THROUGH INTER-ENDOTHELIAL JUNCTIONLIE B/W ENDOTH. CELLS & BASEMENT MEMBRANE

28across the endothelial wall..EMIGRATION

EMIGRATIONCELLULAR EVENTSDIAPEDESIS

EXTRA-VASCULAR SPLACE

29Red cells and b/w gaps of endothelial cells diapedesis wic gives haemorrhagic appearance to inflammatory 29CHEMOTAXISCELLULAR EVENTS

Along chemical gradient30After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by a process called chemotaxis1) Chemicals that cause movement of bacteria are called CHEMO-ATTRACTANTS2) After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by a process called chemotaxis

30CHEMO-ATTRACTANTSEXOGENOUS SUBSTANCESENDOGENOUS SUBSTANCESBacterial Products :Peptides N formyl methionine terminal amino acid LipidsLTB-4 (Lukotriene B-4)PF-4 (platelet factor-4)Components of complement system Cytokine : IL 1, 5 , 6Monocyte chemoattractant proteinChemotactic factor for CD-4 cells Eotaxin chemotactic factor for eosinophilsCELLULAR EVENTS31At the end of cellular events that leukocytes migrate toward the inflammatory stimulus in the direction of the gradient of locally produced chemo attractants.Exogenous the substance which comes out side the body Endogenous the substance present inside the body. Which activates on the demand needs 3132

CELLULAR EVENTS33Engulfing of solid particulate material by the cells (cell- eating) The performing this function are called phagocytosis

There are 2 types cells

Polymorph nuclear neutrophils (PNMs) also called as microphages 2) Circulating monocytes & fixed tissue mononuclear phagocytes called ,macrophages

PHAGOCYTOSIS33CELLULAR EVENTSPHAGOCYTOSIS34123434CELLULAR EVENTSRECOGNITION AND ATTACHMENT OF PARTICLE 1

CHEMO-TACTIC AGENTS OPSONINS Ig G

C3b Opsonin

Lectins MANNOSE RECEPTOR

SCAVENGER RECEPTOR

35But to establish a bond b/w bacteria and cell membrane of phagocytic cell micro-org get coated with opsonins.Now , there should be receptors on leukocyte surface also to recognise these opsonins. these include35ENGULFMENT WITH FORMATION OF PHAGOCYTIC VESICLE2CELLULAR EVENTS

Fig 10.6 harsh mohan pg 101

36PHAGO-LYSO-SOMEAfter a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a vesicle (phagosome) that encloses the particle.36DEGRANULATION STAGE3CELLULAR EVENTSDuring this stage the PMNs (ploymorphonuclear neutrophils)

&

Mononuclear phagocyte secrete enzymes eg IL-2 , 6-TNF Arachidonic acid metabolites (Prostaglandin , leukotriene , platelet activating factor Oxygen metabolites

are released into phagolysosome37KILLING & DEGRADATION STAGE4CELLULAR EVENTS

OXYGEN DEPENDENT BACTERICIDALMECHANISMOXYGENINDEPENDENT MECHANISM38If this mechanism fails to kill and degrade some bacteria like TUBERCLE BACILLI THEN KILLING & DEGRADATION STAGEOXYGEN DEPENDENT MECHANISM39Production of reactive oxygen metabolites is necessary to kill the micro organism & Increased oxygen consumption by the phagocytic leucocytes (respiratory brust ) 2o2NADPH oxidase

(superoxide anion )NADPHNADP + H(PLUS ION )Increased oxygen consumption by the phagocytic leucocytes (respiratory brust ) requires the essential presence of NADPH oxidase

NADPH Oxidase present in cell membrane of phagosome reduces oxygen to superoxide ion

Superoxide is subsequently converted in to hydrogen peroxide, which have the bactericidal activity

39OXYGEN INDEPENDENT MECHANISMCELLULAR EVENTSFollowed by :

Lysosomal hydrolases

Permeability increasing factors

Defensing

Cationic proteins404041

CHEMICAL MEDIATORS OF INFLAMMATION MEDIATOR : one that reunites differences b/w disputantsCHEMICAL MEDIATORS : chemical substances that mediate the process of inflammation..421.Onethatmediates,especiallyonethatreconcilesdifferences betweendisputants.2.PhysiologyAsubstanceorstructurethatmediatesaspecific responseinabodilytissue.Aftr although injury starts the inflammatory response , these chemical factors bring about various vascular & cellular changes.

42CHEMICAL MEDIATORS OF INFLAMMATION

PLASMA DERIVED

CELL DERIVED Present in plasma in precursor form

Must be activated to acquire biologic properties Pr. In intracellular granules

Major cellular sources Platelets Neutrophil Monocyte / macrophage 43CHEMICAL MEDIATORS OF INFLAMMATIONCELL DERIVED MEDIATORS

VASO ACTIVE AMINES44HISTAMINE

SOURCE : 1) Mast cells in C.T adjacent to blood vessels 2) Blood basophils 3) Platelets STIMULI : Injury Immune reactions SEROTONIN

SOURCE : 1) Platelets 2) Enterochromaffin cells

STIMULI : Platelet aggregation after contact with collagen , thrombin

ROLE IN INFLAMMATION

45Dilation of arteriolesPermeability of vasculatureRole : dil. Of arterioles incr permeability of vasculature45CHEMICAL MEDIATORS OF INFLAMMATION

ARACHIDONIC ACID METABOLITESA fatty acid with 2 main sources : Directly through diet

Through conversion of essential fatty acid

CYCLO OXY- GENASE PATHWAY Prostaglandin - PGD2 , E2 , F2 Thromboxane A2

Prostacyclin

LIPO OXY GENASE PATHWAY

5 HETE( hydroxy eico-satetraenoic acid)

Leukotrienes46Chemotactic and cell adherence

CHEMICAL MEDIATORS OF INFLAMMATIONLYSOSOMAL COMPONENTS

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CHEMICAL MEDIATORS OF INFLAMMATIONCYTOKINES proteins produced mainly by- activated lymphocytes & macrophages , also from endothelium, epithelium & connective tissue cells.

TNF and IL - 1 major cytokines that mediate inflammation.

Produced mainly by activated macrophagesSTIMULI : Immune reactions, physical injury & variety of inflammatory stimuli.endotoxins & other microbial products

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NITROUS OXIDECHEMICAL MEDIATORS OF INFLAMMATIONReleased by activated neutrophils and macrophages,such as Superoxide , hydrogen peroxide , hydroxyl ion

ACTION : Endothelial cell damage- inc. vascular permeability

496OXYGEN METABOLITES

mediates in vascular dilation

CHEMICAL MEDIATORS OF INFLAMMATIONPLASMA DERIVED MEDIATORSKININ SYSTEMCLOTTING SYSTEMCOMPLEMENT SYSTEM50FACTOR XII51PLASMA DERIVED MEDIATORSFACTOR XII(Hageman factor)FACTOR XIIaComplement system CLOTTING SYSTEMKININ SYSTEMAnaphylatoxins FIBRINBRADYKININ

FATE OF ACUTE INFLAMMATIONACUTE INFLAMMATIONRESOLUTIONHEALING BY SCARRINGPROGRESSION TO SUPPURATIONPROGRESSION TO CHRONIC INFLAMMATION521)Resolution tissue changes are slight and cellular changes are reversible 2)Healing by scar 3)Suppuration - tissue necrosis suppuration (pus) contamination cavity formation (abscess) in not drained may get fibrous tissue and calcified mass 4)Chronic inflamatiion progression of inflammation and healing side by side 52CHRONIC INFLAMMATIONInflammation of prolonged duration (weeks to months) in which inflammation , tissue destruction and attempts at repair are proceeding simultaneously. CAUSES Following acute inflammation

Begin insidiously as a low grade inflammation Persistent inf. By micro-organisms : Eg-tubercle bacilli

Prolonged exposure to toxic agents Auto - immunity 53FEATURES OF CHRONIC INFLAMMATION :54CHRONIC INFLAMMATIONInfiltration with mononuclear cells macrophages ,lymphocytes , & plasma cellsTissue destructionHealing by Proliferation & connective tissue replacement of damaged tissueProliferation of small blood vessels (ANGIOGENESIS)

Mononuclear -

54INFILTRATION WITH MONO-NUCLEAR CELLS55

Mononuclear cells arise from precursors in bone marrow which give rise to blood monocytesmonocytes then start emigrating into extravascular tissue i.e out of blood and reach various tissues and form predominant cell type in 48hrs of inflamm.When monocyte reaches extravascular tissue..it transforms to form macrophages.( in liver- kupper cells}, {in lungs -alvelor macrophages}, {nerves system microglial cells}

55 Incr. lysosomal enzymes

Greater ability to phagocytose 56ACTIVATION OF MACROPHAGE

Cytokine IFN - Endotoxin , fibronectin chemical mediatorsBlood monocytes on reaching extravascular space get transformed into macrophages.

Macrophage have capacity of phagocytosis, inc cell size, inc content of lysosome enzyme, greater ability of kill ingested organism. 56MACROPHAGEIN ACUTE INFLAMMATION IN CHRONIC INFLAMMATION* Irritant eliminated macrophage disappearsPersistent macrophage accumulation by following mechanisms :

1)Recruitment from circulation Chemotactic stimuli include :

Platelet derived growth factor Transforming growth factor

2.) Local proliferation of macrophages

3.) Immobilization of macrophages57

58TISSUE DESTRUCTION OR NECROSISCENTRAL feature ACTIVATED MACROPHAGES Elastase Protease Collagenase Reactive oxygen radical Cytokine IL-1,859Part 2 Dental aspect

Cont60

DENTAL ASPECTSINFLAMMATION OF PULP & PERIAPICAL TISSUEPULPITIS

DEEP DENTAL CARIESTOOTH FRACTURECRACKED TOOTH SYNDROMECHEMICAL CHANGESTHERMAL CHANGES61Like other tissue throughout the body , pulp reacts to bact. Infection or other stimuli thru inflamm process k/a PULPITIS61

62Involves enamelProgresses to dentinInvade pulp

REACTIONS OF PULP TO BACTERIAL INVASION

Vascular changes take place inside blood vessels.

PMNLs reach the area of inflammation

ANATOMICAL FEATURES OF PULP THAT TEND TO ALTER THE RESPONSEEnclosure of pulp in rigid calcified walls - PREVENTS EXCESSIVE SWELLING thus more painful.

Pressure leads to deceased blood supply and ischemia does not get corrected since collateral circulation cannot develop through tiny apical foramina 63Will be discussed in comparison to injury due to sharp object on skin.Loss of collateral circulation .also another reason why analgesics become ineffective in relieving pain of pulpal origin.63HISTOLOGIC FEATURES OF PULPITIS64

VASCULAR EVENTSCELLULAR EVENTS MONONUCLEAR CELLS PREDOMINATE - chiefly plasma cells & lymphocytes.

Fibroblastic activity is evident

collagen fibres seen in bundles Continued vascular dilation

Accumulation of oedemal fluid in connective tissue

Pavementing Of PMNLs along endothelial wallUNTREATED PULPITISACUTECHRONICPULPITIS

UNTREATEDAPICAL PERIODONTITISPERIAPICAL ABSCESSPERIAPICAL GRANULOMA65UNTREATED PULPITISAPICAL PERIODONTITISInflammation of periodontal ligament around root apex..

INITIALLYChanges localised around root apex..since richly vascular

LATER if irritant presentResorption of bone ABSCESS FORMATION66

Consists of Vascular changes , infiltration of PMNLs , and exudate accumulation6667TYPES OF ABSCESSPYOGENIC ABSCESSPYAEMIC ABSCESSCOLD ABSCESS Commonest type

mostly found in soft tissues eg periapical abscess occurs due to circulating bacterial emboli in bloodAbscess without signs of inflammationEg Tubercular abscessABSCESS FORMATION / SUPPURATIONAcute bacterial inf. + intense neutrophillic infiltrateTISSUE NECROSIS Cavity is formed called an ABSCESS Contain purulent exudate called as PUSSUPPURATION68

PERIAPICAL ABSCESS

MICRO-ABSCESSRise in pressure with inflammatory exudateLocal tissue hypoxia Localised destruction .breakdown of leucocytes , bacteria & tissueABSCESS FORMATION PERIAPICAL ABSCESS69Periapical abscess formn is not a sudden and rapid process..begins with formation of micro abscessAfter microabscessthis process keeps progressing towards remaining pulp..until reaches apex and causes apical p.dtis & periapical abscess.69PERIAPICAL ABSCESS70PERIAPICAL ABSCESS( DENTO-ALVEOLAR ABSCESS / ALVEOLAR ABSCESS )

Tender on percussionWill feel slightly extruded from socket

Fever & regional lymphadenitis71INFLAMED PERIODONTIUMPRESENTS WITHfeatures of BOXChronic per abscess mild well circumscr area of suppuration that shows little tendancy to spread.7172ACUTE PERIAPICAL ABSCESSCHRONIC FORMPERIAPICAL ABSCESS

Takes the path of least resistance in tissues

SINUSFISTULA / PARULIS / GUM BOILBLIND TRACT leading from surface and down to tissues Lined by GRANULATION TISSUE

7273STAGES

DAYS BLOOOD VESSELSJN & SULCULAR EPITHELIUM PREDOMINANT IMMUNE CELLSCLINICAL FINDINGS INITIAL LEASION 2-4 Vas-Dil VasculitisInfiltration of PNMsPNMsGingival fluid flow EARLY LEASION 4-7Vas- proliferation Same as stage 1 & Rete pegs, atrophic areasLymphocytesErythemaBleeding on probingESTABLISHED LEASION 14-21 Same as stage 2Blood stats seen Same as above, but advanced Plasma cellsChanges seen in color,size,texture etc.The sequence of events in the development of gingivitis is analyzed in three different stages

GINGIVAL INFLAMMATION 74CLINICAL FEATUARES75Conclusion.Destroy, dilute and wash off any injurious agent & constitutes the repair. Without inflammation, infections would go unchecked, wounds would never heal, and injured organs may remain as permanent decaying lesions.

In our day to day lives we come across many cases starting from gingivitis to oral cancer wherein inflammation exerts a direct or an indirect effect.

So understanding inflammation helps us to know the various vascular and cellular changes, mediators involved and therefore help us to evaluate the significance of various antibiotics and anti-inflammatory drugs that we do prescribe, for controlling the same.

Thank You . . .I choose a lazy person to do a hard job.Because a lazy person will find an easy way to do it.

Bill Gates

References..77Essential pathology for dental students- Harsh Mohan -3rd edn.Pathologic basis of disease- Robbins & Cotran 7th edn .Shafers text book of oral pathology 5th edn.Newman, Takei, Klokkevold, Carranza. Carranzas clinical periodontology. 12th ed, 2013

78THANK YOU