General Pathology_SLIDES.ppt.............

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1. GENERAL PATHOLOGY
NCN 134
Shaviya Nathan

2. INTRODUCTION
Pathologyisthestudyofdiseasebyscientificmethods.
Diseasesaredefinedasanabnormalvariationinstructureorfunctionofanypartofthebody.Aspectsofthediseaseare
1)Etiology2)Pathogenesis3)Morphologicchangesand4)Functionalderangementsandclinicalsignificance.
1.Etiology
Etiologyofadiseasemeansthecauseofthedisease.
Ifthecauseofadiseaseisknownitiscalledprimaryetiology,unknownitiscalledidiopathic.
Therearetwomajorclassesofetiologicfactors:geneticandacquired(infectious,nutritional,chemical,physical,etc).
Etiologyleadstopathogenesis.
2.Pathogenesis
Aremechanismsthroughwhichthecauseoperatestoproducethepathologicalandclinicalmanifestations.
Thepathogeneticmechanismscouldtakeplaceinthelatentorincubationperiod.
Pathogenesisleadstomorphologicchanges.
3.Morphologicchanges
Arestructuralalterationsincellsortissuesthatoccurfollowingthepathogeneticmechanisms.
Structuralchangesintheorgancanbeseenwiththenakedeye(gross)ortheymayonlybeseenunderthemicroscope(microscopic).
Gross&themicroscopicmorphologicchangesmaybespecifictoadiseasehenceusedindiseasediagnosis.
Morphologicchangesleadtofunctionalalteration&totheclinicalsigns&symptomsofthedisease.

3. 4.Functionalderangementsandclinicalsignificance
Themorphologicchangesinfluencethenormalfunctionoftheorgan.
Theydeterminetheclinicalfeatures(symptomsandsigns),course,andprognosisofthedisease.
Diagnostictechniquesusedinpathology
a).HistopathologicalTechniques
Studiestissuesunderthemicroscope.
Tissuesforhisto-pathologicalexaminationareobtainedbybiopsy.
Biopsycanbeeitherincisionalorexcisionalandthetissuefixedin10%formaldehyde(10%formalin).
Thepurposeoffixationis:
1. To prevent autolysis and bacterial decomposition and putrefaction
2. To coagulate the tissue to prevent loss of easily diffusible substances
3. To fortify the tissue against the deleterious effects of the various stages in the preparation of sections and tissue processing.
4. To leave the tissues in a condition which facilitates differential staining with dyes and other reagents.
Then the tissue is processed to make it ready for microscopic examination.
The whole purpose of the tissue processing is to prepare a very thin tissue which can be clearly seen under the microscope. The tissue
is processed by putting it into different chemicals.
It is then embedded in paraffin, sectioned (cut) into thin slices, & is finally stained.
The stains can be Hematoxylin/Eosin stain or special stains such as PAS, Immunohistochemistry, etc...
Histopathology is usually the gold standard for pathologic diagnosis.

4. b).Cyto-pathologictechniques
Cytopathologyisthestudyofcellsfromvariousbodysitestodeterminethecauseornatureofdisease.
Applicationsofcytopathology:
Themainapplicationsofcytologyincludethefollowing:
1.Screeningfortheearlydetectionofasymptomaticcancer
2.Diagnosisofsymptomaticcancer
3.Surveillanceofpatientstreatedforcancer
Advantagesofcytologicexamination
Comparedtohistopathologictechniqueitischeap,takeslesstimeandneedsnoanesthesiatotakespecimens.
Itiscomplementarytohistopathologicalexamination.
Cyto-pathologicmethods
Therearedifferentcyto-pathologicmethodsincluding:
1.Fine-needleaspirationcytology(FNAC)
InFNAC,cellsareobtainedbyaspiratingthediseasedorganusingaverythinneedleundernegativepressure.
Theaspiratedcellsarethenstained&arestudiedunderthemicroscope.
Superficialorgans(e.g.thyroid,breast,lymphnodes,skinandsofttissues)canbeeasilyaspirated.
Deeporgans,suchasthelung,mediastinum,liverareaspiratedwithguidancebyfluoroscopy,ultrasoundorCTscan.
FNACischeap,fast,&accurateindiagnosingmanydiseases.
2.Exfoliativecytology
Referstotheexaminationofcellsthatareshedspontaneouslyintobodyfluidsorsecretions.
3. Abrasive cytology
Refers to methods by which cells are dislodged by various tools from body surfaces. E.g. Pap smears, can significantly reducethe mortality
from cervical cancer.

5. c).Hematologicalexamination
Thisisamethodbywhichabnormalitiesofthecellsofthebloodandtheirprecursorsinthebonemarrowareinvestigatedtodiagnosethe
differentkindsofanemia&leukemia.
d).Immunohistochemistry
Thisisamethodisusedtodetectaspecificantigeninthetissueinordertoidentifythetypeofdisease.
e).Microbiologicalexamination
Thisisamethodbywhichbodyfluids,excisedtissue,etc.areexaminedbymicroscopical,culturalandserologicaltechniquestoidentify
micro-organismsresponsibleformanydiseases.
f).Biochemicalexamination
Thisisamethodbywhichthemetabolicdisturbancesofdiseaseareinvestigatedbyassayofvariousnormalandabnormalcompoundsin
theblood,urine,etc.
g).Clinicalgenetics(cytogenetics),
Thisisamethodinwhichinheritedchromosomalabnormalitiesinthegermcellsoracquiredchromosomalabnormalitiesinsomaticcellsare
investigatedusingthetechniquesofmolecularbiology.
h).Moleculartechniques
Differentmoleculartechniquessuchasfluorescentinsituhybridization,Southernblot,etc...canbeusedtodetectgeneticdiseases.
i).Autopsy
Autopsyisexaminationofthedeadbodytoidentifythecauseofdeath.Thiscanbeforforensicorclinicalpurposes.

6. THECAUSESOFDISEASE
Diseasescanbecausedbyeitherenvironmentalfactors,geneticfactorsoracombinationofthetwo.
a).Environmentalfactors
1.Physicalagents
Theseincludetrauma,radiation,extremesoftemperature,andelectricpower.
2.Chemicals
Ever-increasinguseofchemicalagentssuchasdrugs,chemicallyinducedinjuryhasbecomeverycommon.E.g.theeffectofparacetamoland
alcoholonliver.Manytoxicchemicalsaremetabolizedinliverandexcretedinkidney,asaresult,theseorgansaresusceptibletochemical
injury.
3.Nutritionaldeficienciesandexcesses.
Nutritionaldeficienciesmayariseasaresultofpoorsupply,interferencewithabsorption,inefficienttransportwithinthebody,ordefective
utilization.Ontheotherhand,dietaryexcessplaysanimportantroleindiseases.
4.Infectionsandinfestations
Viruses,bacteria,fungi,protozoa,andmetazoaallcausediseases.
5.Immunologicalfactors
a).Hypersensitivityreaction
b).Immunodeficiency
c)Autoimmunity
6.Psychogenicfactors
Thementalstressesimposedbyconditionsoflifeareprobablycontributoryfactorsinsomegroupsofdiseases.
b). Genetic Factors
These are hereditary factors that are inherited genetically from parents.

7. COURSEOFDISEASE
Thecourseofdiseasecanbesimplifiedasfollows.

8. OUTCOMEANDCONSEQUENCESOFDISEASE
Followingclinicalonset,diseasemayfollowanyofthefollowingtrends:
a)Resolutioncanoccurleavingnosequelae,
b)Thediseasecansettledown,butsequelaeareleft,or
c)Itmayresultindeath.
Clinical&Biologicdeath
Clinicaldeath
Clinicaldeathisthereversibletransmissionbetweenlifeandbiologicdeath.Clinicaldeathisdefinedastheperiodofrespiratory,circulatory
andbrainarrestduringwhichinitiationofresuscitationcanleadtorecovery.Clinicaldeathbeginswitheitherthelastagonalinhalationorthe
lastcardiaccontraction.
Signsindicatingclinicaldeathare
•Thepatientiswithoutpulseorbloodpressureandiscompletelyunresponsivetothemostpainfulstimulus.
•Thepupilsarewidelydilated
•Somereflexreactionstoexternalstimulationarepreserved.Forexample,duringintubations,respirationmayberestoredinresponseto
stimulationofthereceptorsofthesuperiorlaryngealnerve,thenucleusofwhichislocatedinthemedullaoblongataneartherespiratory
center.
•Recoverycanoccurwithresuscitation.
BiologicalDeath
Biologicaldeath(suresignofdeath),whichsetsinafterclinicaldeath,isanirreversiblestateofcellulardestruction.Itmanifestswith
irreversiblecessationofcirculatoryandrespiratoryfunctions,orirreversiblecessationofallfunctionsoftheentirebrain,includingbrainstem.

9. CELLULARREACTIONSTOINJURY
Cellinjuryunderliesalldiseasesandiskeytounderstandingdiseases.Whenacellisexposedtoaninjuriousagentthepossible
outcomesare:
1.Thecellmayadapttothesituationor
2.Theycellmayacquireareversibleinjuryor
3.Thecellmayobtainanirreversibleinjury&maydie.Thecellmaydieviaoneoftwoways:eitherbynecrosisorbyapoptosis.
Typesofcellularadaptation
a).Hypertrophy:Istheincreaseinthesizeofcells.Increasedworkloadleadstoincreasedproteinsynthesis&increasedsize&number
ofintracellularorganelleswhich,inturn,leadstoincreasedcellsize.
b).Hyperplasia:Isanincreaseinthenumberofcells.Itcanleadtoanincreaseinthesizeoftheorgan.Itisusuallycausedby
hormonalstimulation.
c).Atrophy:Isadecreaseinthesizeofacell.Thiscanleadtodecreasedsizeoftheorgan.
Atrophycanbecausedby:
1.Disuse2.Under-nutrition3.Decreasedendocrinestimulation4.Denervation(lossofnervesupply)5.Oldage
d.Metaplasia
Metaplasiaisthereplacementofonedifferentiatedtissuebyanotherdifferentiatedtissue.Therearedifferenttypesofmetaplasia.
Examplesinclude:
1.Squamousmetaplasia:Thisisreplacementofanothertypeofepitheliumbysquamousepithelium.Forexample,thecolumnar
epitheliumofthebronchuscanbereplacedbysquamousepitheliumincigarettesmokers
2.Osseousmetaplasia:Thisreplacementofaconnectivetissuebybone,forexampleatsitesofinjury.

10. Reversible cellular changes & accumulations
Therearemanydifferentkindsofreversiblecellularchanges&accumulations,wewillmainlydealwithfattychangeandaccumulationof
pigments.
1.Fattychange
•Istheaccumulationoftriglyceridesinparenchymalcells.
•Itiscausedbyanimbalancebetweentheuptake,utilization,&secretionoffat.
•Fattychangeisusuallyseenintheliver,heart,orkidney.
•Fattylivermaybecausedbyalcohol,diabetesmellitus,malnutrition,obesity,&poisonings.
Theseetiologiescauseaccumulationoffatinthehepatocytesbythefollowingmechanisms:
a.Increaseduptakeoftriglyceridesintotheparenchymalcells.
b.Decreaseduseoffatbycells.
c.Overproductionoffatincells.
d.Decreasedsecretionoffatfromthecells.
2.Theaccumulationsofpigments
Pigmentscanbeexogenousorendogenous.Endogenouspigmentsincludemelanin,bilirubin,hemosiderin,&lipofuscin.Exogenous
pigmentsincludecarbon.Thesepigmentscanaccumulateinsidecellsindifferentsituations.
a.Melanin
Melaninisabrownish-blackpigmentproducedbythemelanocytesfoundintheskin.Increasedmelaninpigmentationiscausedbysun-
tanning&certaindiseasese.g.nevus,ormalignantmelanoma.Decreasedmelaninpigmentationisseeninalbinism&vitiligo.

12. b.Bilirubin
Bilirubinisayellowishpigment,mainlyproducedduringthedegradationofHg.
Excessaccumulationofbilirubincausesyellowishdiscolorationofthesclerae,mucosae,&internalorgans.
Suchayellowishdiscolorationiscalledjaundice.Jaundiceismostoftencausedby;
1.Hemolyticanemia-CharacterizedbyincreaseddestructionofRBCs.
2.Biliaryobstruction-Thisisobstructionofintrahepaticorextra-hepaticbileducts.Itcanbecausedbygallstones.
3.Hepatocellulardisease-Thisisassociatedwithfailureofconjugationofbilirubin.
c.Hemosiderin
•Hemosiderinisaniron-containingpigmentderivedfromferritin.
•Itappearsintissuesasgoldenbrownamorphousaggregates&isidentifiedbyitsstainingreaction(bluecolor)withthe
Prussianbluedye.
•Hemosiderinexistsnormallyinsmallamountswithintissuemacrophagesofthebonemarrow,liver,&spleenas
physiologicironstores.
•Itaccumulatesintissuesinexcessamountsincertaindiseases.Thisexcessaccumulationisdividedinto2types:
1.Hemosiderosis;Whenaccumulationofhemosiderinisprimarilywithintissuemacrophages&isnotassociatedwithtissue
damage,itiscalledhemosiderosis.
2.Hemochromatosis;Whenthereismoreextensiveaccumulationofhemosiderin,oftenwithinparenchymalcells,which
leadstotissuedamage,scarring&organdysfunction,itiscalledhemochromatosis.

13. Cell Death
Cellscandieviaoneofthefollowingtwoways:
1.Necrosis
2.Apoptosis
1.Necrosis
Innecrosis,excessfluidentersthecell,swellsit,&rupturesitsmembranewhichkillsit.Afterthecellhasdied,intracellular
degradativereactionsoccurwithinalivingorganism.Necrosisdoesnotoccurindeadorganisms.Indeadorganisms,autolysis
&heterolysistakeplace.Necrosisoccursbythefollowingmechanisms:
A.Hypoxia
B.Freeradical-inducedcellinjury
C.Cellmembranedamage
D.Increasedintracellularcalciumlevel
A.Hypoxia
Hypoxiaisdecreasedoxygensupplytotissues.Itcanbecausedby:
1.Ischemia:Ischemiaisdecreasedbloodflowtoorfromanorgan.Ischemiacanbecausedbyobstructionofarterialblood
flow–themostcommoncause,orbydecreasedperfusionoftissuesbyoxygen-carryingbloodasoccursincardiacfailure,
hypotension,&shock.
2.Anemia:Anemiaisareductioninthenumberofoxygen-carryingredbloodcells.
3.Carbonmonoxidepoisoning:COdecreasestheoxygen-capacityofredbloodcellsbychemicalalterationof
hemoglobin.
4.Pooroxygenationofbloodduetopulmonarydisease.Thecellinjurythatresultsfollowinghypoxiacanbedividedintoearly
&latestages:

14. 1.Early(reversible)stagesofhypoxiccellinjury
Atthisstage,hypoxiaresultsindecreasedoxidativephosphorylation&ATPsynthesis.
DecreasedATPleadsto:
a.FailureofthecellmembraneNa–Kpump,whichleadstoincreasedintracellularNa&water,whichcausecellular&
organelleswelling.Cellularswelling(hydropicchange)ischaracterizedbythepresenceoflargevacuolesinthecytoplasm.The
ERalsoswells.Themitochondriashowalowamplitudeswelling.Alloftheabovechangesarereversibleifthehypoxiais
corrected.
b.Disaggregationofribosomes&failureofproteinsynthesis.
2.Late(irreversible)stagesofhypoxiccellinjury.
Thisiscausedbysevereorprolongedinjury.Itiscausedbymassivecalciuminflux&verylowpH,whichleadtoactivationof
enzymes,whichdamagethecellmembrane&organellemembranes.Irreversibledamagetothemitochondria,cell
membranes,&thenucleusmarkthepointofnoreturnforthecell,thatisafterthisstage,thecellisdestinedtodie.
Releaseofaspartateaminotransferase(AST),creatinephosphokinase(CPK),&lactatedehydrogenase(LDH)intothebloodis
animportantindicatorofirreversibleinjurytoheartmusclefollowingmyocardialinfarction.
B.Freeradical-inducedinjury
Freeradicalisanymoleculewithasingleunpairedelectronintheouterorbital.Examplesincludesuperoxide&thehydroxyl
radicals.Freeradicalsareformedbynormalmetabolism,oxygentoxicity,ionizingradiation,drugs&chemicals,&reperfusion
injury.
Theyaredegradedbyspontaneousdecay,intracellularenzymessuchasglutathioneperoxidase,catalase,orsuperoxide
dismutase,&endogenoussubstancessuchascerulo-plasminortransferrin.Whentheproductionoffreeradicalsexceeds
theirdegradation,theexcessfreeradicalscausemembranepumpdamage,ATPdepletion,&DNAdamage.

16. Thesecancausecellinjury&celldeath.
C.Cellmembranedamage;Directcellmembranedamageasinextremesoftemperature,toxins,orviruses,orindirectcell
membranedamageasinthecaseofhypoxiacanleadtocelldeathbydisruptingthehomeostasisofthecell.
D.Increasedintracellularcalciumlevel;Increasedintracellularcalciumlevelisacommonpathwayviawhichdifferent
causesofcellinjuryoperate.Forexample,thecellmembranedamageleadstoincreasedintracellularcalciumlevel.The
increasedcytosoliccalcium,inturn,activatesenzymesinthepresenceoflowpH.Theactivatedenzymeswilldegradethe
cellularorganelles.
Typesofnecrosis
Thetypesofnecrosisinclude:
i.Coagulativenecrosis
ii.Liquefactivenecrosis
iii.Fatnecrosis
iv.Caseousnecrosis
v.Gangrenousnecrosis
i.Coagulativenecrosis;mostoftenresultsfromsuddeninterruptionofbloodsupplytoanorgan,especiallytotheheart.It
is,inearlystages,characterizedbygeneralpreservationoftissuearchitecture.Itismarkedbythefollowingnuclear
changes:Pyknosis(whichischromatinclumping&shrinkingwithincreasedbasophilia),karyorrhexis(fragmentationof
chromatin),&karyolysis(fadingofthechromatinmaterial).
ii.Liquefactivenecrosis;Liquefactivenecrosisischaracterizedbydigestionoftissue.Itshowssoftening&liquefactionof
tissue.ItcharacteristicallyresultsfromischemicinjurytotheCNS.Italsooccursinsuppurativeinfectionscharacterizedby
formationofpus.

17. iii.Fatnecrosis;canbecausedbytraumatotissuewithhighfatcontent,suchasthebreastoritcanalsobecausedbyacute
hemorrhagicpancreatitisinwhichpancreaticenzymesdiffuseintotheinflamedpancreatictissue&digestit.Thefattyacids
releasedfromthedigestionformcalciumsalts(soapformationordystrophiccalcification).Inaddition,theelastaseenzyme
digeststhebloodvessels&causethehemorrhageinsidethepancreas,hencethenamehemorrhagicpancreatitis.
iv.Caseousnecrosis;Caseousnecrosishasacheese-like(caseous,white)appearancetothenakedeye.Anditappearsasan
amorphouseosinophilicmaterialonmicroscopicexamination.Caseousnecrosisistypicaloftuberculosis.
v.Gangrenousnecrosis;Thisisduetovascularocclusion&mostoftenaffectsthelowerextremities&thebowel.Itiscalled
wetgangreneifitiscomplicatedbybacterialinfectionwhichleadstosuperimposedliquefactivenecrosis.Whereasitis
calleddrygangreneifthereisonlycoagulativenecrosiswithoutliquefactivenecrosis.Necrosiscanbefollowedbyreleaseof
intracellularenzymesintotheblood,inflammationordystrophiccalcification.
2.Apoptosis
Apoptosisisthedeathofsinglecellswithinclustersofothercells.(Notethatnecrosiscausesthedeathofclustersofcells.)In
apoptosis,thecellshowsshrinkage&increasedacidophilicstainingofthecell.Thisisfollowedbyfragmentationofthecells.
Thesefragmentsarecalledapoptoticbodies.Apoptosisusuallyoccursasaphysiologicprocessforremovalofcellsduring
embryogenesis,menstruation,etc…Itcanalsobeseeninpathologicalconditionscausedbymildinjuriousagents.
Apoptosisisnotfollowedbyinflammationorcalcification.Theabovementionedfeaturesdistinguishapoptosisfrom
necrosis.

18. Pathologic calcification
Pathologic calcification is divided into 2 types:
1. Metastatic calcification
This is caused by hyper-calcemia, resulting from hyperparathyroidism, milk-alkali syndrome, sarcoidosis etc…
2. Dystrophic calcification
This occurs in previously damaged tissue, such as areas of old trauma, tuberculous lesions, scarred heart valves, &
atherosclerotic lesions.
Unlike metastatic calcification, it is not caused by hypercalcemia.
Typically, the serum calcium level is normal.

19. INFLAMMATION
Topic 3

20. INTRODUCTION
Definition: Inflammation is a local response (reaction) of living vasculaized tissues to endogenousand exogenous stimuli. The
term is derived from the Latin "inflammare“ meaning to burn. Inflammation is fundamentally destined to localize and
eliminate the causative agent and to limit tissue injury.
Thus, inflammation is a physiologic (protective) response to injury, an observation made by Sir John Hunter in 1794
concluded: “inflammation is itself not to be considered as a disease but as a salutary operation consequent either to some
violence or to some diseases”.
Causes:
Causes of inflammation are apparently causes of diseases such as
Physical agents -mechanical injuries, alteration in temperatures and pressure, radiation injuries.
Chemical agents-including the ever increasing lists of drugs and toxins.
Biologic agents (infectious)-bacteria, viruses, fungi, parasites
Immunologic disorders-hypersensitivity reactions, autoimmunity, immunodeficiency states etc
Genetic/metabolic disorders-examples gout, diabetes mellitus etc…
Nomenclature:
The nomenclatures of inflammatory lesion are usually indicated by the suffix 'itis'. Thus, inflammation of the appendix is
called appendicitis and that of meninges as meningitis, etc.… However, like any rule, it has its own exceptions examples
pneumonia, typhoid fever, etc….###appendicitis, cellulitis, arthritis, colitis, mastitis, hepatitis, encephalitis…
Classification:
Inflammation is classified crudely based on duration of the lesion and histologic appearances into acute and chronic
inflammation.

21. ACUTE INFLAMMATION
Acute inflammation is an immediate and early response to an injurious agent and it is relatively of short duration, lasting for
minutes, several hours or few days.
It is characterized by exudation of fluids and plasma proteins and the emigration of predominantly neutrophilic leucocytes to
the site of injury.
The five cardinal signs of acute inflammation are;
Redness (rubor) which is due to dilation of small blood vessels within damaged tissue as it occurs in cellulitis.
Heat (calor) which results from increased blood flow (hyperemia) due to regional vascular dilation
Swelling (tumor) which is due to accumulation of fluid in the extravascular space which, in turn, is due to increased vascular
permeability.
Pain (dolor), which partly results from the stretching & destruction of tissues due to inflammatory edema and in part from
pus under pressure in as abscess cavity.
Some chemicals of acute inflammation, including bradykinins, prostaglandins and serotonin are also known to induce pain.
Loss of function: The inflammed area is inhibited by pain while severe swelling may also physically immobilize the tissue.
Events of acute inflammation:
Acute inflammation is categorized into an early vascular and a late cellular responses.

22. 1) The Vascular response has the following steps:
a) Immediate (momentary) vasoconstriction in seconds due to neurogenic or chemical stimuli.
b) Vasodilatation of arterioles and venules resulting in increased blood flow.
c) After the phase of increased blood flow there is a slowing of blood flow & stasis due to increased vascular permeability
that is most remarkably seen in the post-capillary venules. The increased vascular permeability oozes protein-rich fluid into
extravascular tissues. Due to this, the already dilated blood vessels are now packed with red blood cells resulting in stasis.
The protein-rich fluid which is now found in the extravascular space is called exudate. The presence of the exudates
clinically appears as swelling. Chemical mediators mediate the vascular events of acute inflammation.
2) Cellular response
The cellular response has the following stages:
A. Migration, rolling, pavementing, & adhesion of leukocytes
B. Transmigration of leukocytes
C. Chemotaxis
D. Phagocytosis
Normally blood cells particularly erythrocytes in venules are confined to the central (axial) zone and plasma assumes the
peripheral zone. As a result of increased vascular permeability (See vascular events above), more and more neutrophils
accumulate along the endothelial surfaces (peripheral zone).

23. A) Margination, rolling, pavementing, and adhesion of leukocytes
Marginationisaperipheralpositioningofwhitecellsalongtheendothelialcells.
Subsequently,rowsofleukocytestumbleslowlyalongtheendotheliuminaprocessknownasrolling
Intime,theendotheliumcanbevirtuallylinedbywhitecells.Thisappearanceiscalledpavementing
Thereafter,thebindingofleukocyteswithendothelialcellsisfacilitatedbycelladhesionmoleculessuchasselectins,
immunoglobulins,integrins,etcwhichresultinadhesionofleukocyteswiththeendothelium.
B).Transmigrationofleukocytes
Leukocytesescapefromvenulesandsmallveinsbutonlyoccasionallyfromcapillaries.Themovementofleukocytes
byextendingpseudopodiathroughthevascularwalloccursbyaprocesscalleddiapedesis.
Themostimportantmechanismofleukocyteemigrationisviawideningofinterendothelialjunctionsafter
endothelialcellscontractions.Thebasementmembraneisdisruptedandresealedthereafterimmediately.
C).Chemotaxis
Aunidirectionalattractionofleukocytesfromvascularchannelstowardsthesiteofinflammationwithinthetissue
spaceguidedbychemicalgradients(includingbacteriaandcellulardebris)iscalledchemotaxis.
Themostimportantchemotacticfactorsforneutrophilsarecomponentsofthecomplementsystem(C5a),bacterial
andmitochondrialproductsofarachidonicacidmetabolismsuchasleukotrieneB4andcytokines(IL-8).All
granulocytes,monocytesandtolesserextentlymphocytesrespondtochemotacticstimuli.
Howdoleukocytes"see"or"smell"thechemotacticagent?Thisisbecausereceptorsoncellmembraneofthe
leukocytesreactwiththechemoattractantsresultingintheactivationofphospholipaseCthatultimatelyleadsto
releaseofcytosoliccalciumionsandtheseionstriggercellmovementtowardsthestimulus.

24. D) Phagocytosis
Phagocytosisistheprocessofengulfmentandinternalizationbyspecializedcellsofparticulatematerial,whichincludes
invadingmicroorganisms,damagedcells,andtissuedebris.
ThesephagocyticcellsincludePMNleukocytes(particularlyneutrophiles),monocytesandtissuemacrophages.
Phagocytosisinvolvesthreedistinctbutinterrelatedsteps.
1).Recognitionandattachmentoftheparticletobeingestedbytheleukocytes:Phagocytosisisenhancedifthematerial
tobephagocytosediscoatedwithcertainplasmaproteinscalledopsonins.Theseopsoninspromotetheadhesionbetween
theparticulatematerialandthephagocyte’scellmembrane.Thethreemajoropsoninsare:theFcfragmentofthe
immunoglobulin,componentsofthecomplementsystemC3bandC3bi,andthecarbohydrate-bindingproteins–lectins.
Thus,IgGbindstoreceptorsfortheFcpieceoftheimmunoglobulin(FcR)whereas3cband3biareligandsforcomplement
receptorsCR1andCR2respectively.
2).Engulfment:Duringengulfment,extensionofthecytoplasm(pseudopods)flowaroundtheobjecttobeengulfed,
eventuallyresultingincompleteenclosureoftheparticlewithinthephagosomecreatedbythecytoplasmicmembraneof
thephagocyticcell.Asaresultoffusionbetweenthephagosomeandlysosome,aphagolysosomeisformedandthe
engulfedparticleisexposedtothedegradativelysosomalenzymes.
3)Killingordegradation;Theultimatestepinphagocytosisofbacteriaiskillinganddegradation.Therearetwoformsof
bacterialkilling
a).Oxygen-independentmechanism:
ThisismediatebysomeoftheconstituentsoftheprimaryandsecondarygranulesofPMNleukocytes.
Theseinclude:
Bactericidalpermeabilityincreasingprotein(BPI),Lysozymes,Lactoferrin,Majorbasicprotein,Defenses.

25. It is probable that bacterial killing by lysosomal enzymes is inefficient and relatively unimportant compared with the
oxygen dependent mechanisms. The lysosomal enzymes are, however, essential for the degradation of dead organisms
within phagosomes.
b) Oxygen-dependent mechanism:
There are two types of oxygen-dependent killing mechanisms
i) Non-myeloperoxidase dependent
The oxygen -dependent killing of microorganisms is due to formation of reactive oxygen species such as hydrogen
peroxide (H2O2), super oxide (O2) and hydroxyl ion (HO-) and possibly single oxygen (1O2). These species have single
unpaired electrons in their outer orbits that react with molecules in cell membrane or nucleus to cause damages. The
destructive effects of H2O2in the body are gauged by the action of the glutathione peroxidase and catalase.
ii) Myloperoxidase–dependent
The bactericidal activity of H2O2involves the lysosomal enzyme myeloperoxidase, which in the presence of halide ions
converts H2O2to hypochlorous acid (HOCI). This H2O2–halide -myeloperoxidease system is the most efficient
bactericidal system in neutrophils. A similar mechanism is also effective against fungi, viruses, protozoa and helminths.
Like the vascular events, the cellular events (i.e. the adhesion, the transmigration, the chemotaxis, & the phagocytosis)
are initiated or activated by chemical mediators.

26. Chemical mediators of inflammation
Chemical mediators account for the events of inflammation. Inflammation has the following sequence:
Cell injury Chemical mediators Acute inflammation (i.e. the vascular & cellular events).
Sources of mediators:
The chemical mediators of inflammation can be derived from plasma or cells.
a) Plasma-derived mediators:
i) Complement activation
Increases vascular permeability (C3a,C5a)
Activates chemotaxis(C5a)
Opsoninization(C3b,C3bi)
ii) Factor XII (Hageman factor) activation
Its activation results in recruitment of four systems: the kinin, the clotting, the fibrinolyticand the complement systems.
b) Cell-derived chemical mediators:
Cell-derived chemical mediators include:

28. Most mediators perform their biologic activities by initially binding to specific receptors on target cells. Once activated and
released from the cells, most of these mediators are short lived. Most mediators have the potential to cause harmful
effects.
Morphology of acute inflammation
Characteristically, the acute inflammatory response involves production of exudates. An exudate is an edema fluid with high
protein concentration, which frequently contains inflammatory cells.
A transudate is simply a non-inflammatory edema caused by cardiac, renal, under-nutritional, & other disorders.

29. There are different morphologic types of acute inflammation:
1)Serous inflammation
This is characterized by an outpouring of a thin fluid that is derived from either the blood serum or secretion of
mesothelialcells lining the peritoneal, pleural, and pericardial cavities.
It resolves without reactions
2) Fibrinousinflammation
More severe injuries result in greater vascular permeability that ultimately leads to exudation of larger molecules such as
fibrinogensthrough the vascular barrier.
Fibrinousexudate is characteristic of inflammation in serous body cavities such as the pericardium (butter and bread
appearance) and pleura.
Course of fibrinousinflammation include:
Resolution by fibrinolysis
Scar formation between perietaland visceral surfaces i.e. the exudates get organized
Fibrous strand formation that bridges the pericardial space.
3) Suppurative(Purulent) inflammation
This type of inflammation is characterized by the production of a large amount of pus. Pus is a thick creamy liquid,
yellowish or blood stained in colour and composed of
A large number of living or dead leukocytes (pus cells)
Necrotic tissue debris
Living and dead bacteria
Edema fluid
There are two types of suppurativeinflammation:

30. A) Abscess formation:
An abscess is a circumscribed accumulation of pus in a living tissue. It is encapsulated by a so-called pyogenic membrane,
which consists of layers of fibrin, inflammatory cells and granulation tissue.
B) Acute diffuse (phlegmonous) inflammation
This is characterized by diffuse spread of the exudate through tissue spaces. It is caused by virulent bacteria (eg.
streptococci) without either localization or marked pus formation. Example: Cellulitis (in palmar spaces).
4) Catarrhal inflammation
This is a mildand superficial inflammation of the mucous membrane. It is commonly seen in the upper respiratory tract
following viral infections where mucous secreting glands are present in large numbers, eg. Rhinitis.
5) Pseudomembranous inflammation
The basic elements of pseudomembranous inflammation are extensive confluent necrosis of the surface epithelium of an
inflamed mucosa and severe acute inflammation of the underlying tissues.
The fibrinogens in the inflamed tissue coagulate within the necrotic epithelium. And the fibrinogen, the necrotic epithelium,
the neutrophilic polymorphs, red blood cells, bacteria and tissue debris form a false (pseudo) membrane which forms a
white or colored layer over the surface of inflamed mucosa.
Pseudomembranous inflammation is exemplified by Dipthetric infection of the pharynx or larynx and Clostridium dificille
infection in the large bowel following certain antibiotic use.

31. Effects of acute inflammation:
A. Beneficial effects
Dilution of toxins: The concentration of chemical and bacterial toxins at the site of inflammation is reduced by dilution in
the exudate and its removal from the site by the flow of exudates from the venules through the tissue to the lymphatics.
Protective antibodies: Exudation results in the presence of plasma proteins including antibodies at the site of
inflammation. Thus, antibodies directed against the causative organisms will react and promote microbial destruction by
phagocytosis or complement-mediated cell lysis.
Fibrin formation: This prevents bacterial spread and enhances phagocytosis by leukocytes.
Plasma mediator systems provisions: The complement, coagulation, fibrinolytic, & kinin systems are provided to the area
of injury by the process of inflammation.
Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen and other nutrients to meet the metabolic
requirements of the greatly increased number of cells. It also removes their solute waste products via lymphatic channels.
Promotion of immunity: Micro-organisms and their toxins are carried by the exudates, either free or in phagocytes, along
the lymphatics to local lymph nodes where they stimulate an immune response with the generation of antibodies and
cellular immune mechanisms of defence.
B. Harmful effects
Tissue destruction Inflammation may result in tissue necrosis and the tissue necrosis may, in turn, incite inflammation.
Swelling: The swelling caused by inflammation may have serious mechanical effects at certain locations. Examples include
acute epiglottitis with interference in breathing; Acute meningitis and encephalitis with effects of increased intracranial
pressure.
Inappropriate response: The inflammatory seen in hypersensitivity reactions is inappropriate (i.e. exaggerated).

32. Course of acute inflammation
Acute inflammation may end up in:
Resolution: i.e. complete restitution of normal structure and function of the tissue, eg. lobar pneumonia.
Healing by fibrosis (scar formation).
Abscess formation {Surgical law states -Thou shalt ( you should ) drain all abscesses.} However, if it is left untouched, it
may result in
-Sinus formation -when an abscess cavity makes contact with only one epithelial lining.
-Fistula formation: when an abscess tract connects two epithelial surface. Or very rarely to septicemia or Pyemiawith
subsequent metastatic abscess in heart, kidney, brain etc.
CHRONIC INFLAMMATION
Definition: Chronic inflammation can be defined as a prolonged inflammatory process (weeks or months) where an active
inflammation, tissue destruction and attempts at repair are proceeding simultaneously.
Causes of chronic inflammation:
1. Persistent infections; Certain microorganisms associated with intracellular infection such as tuberculosis, leprosy,
certain fungi etccharacteristically cause chronic inflammation.
These organisms are of low toxicity and evoke delayed hypersensitivity reactions.
2. Prolonged exposure to non-degradable but partially toxic substances either endogenous lipid components which result
in atherosclerosis or exogenous substances such as silica, asbestos.
3. Progression from acute inflammation: Acute inflammation almost always progresses to chronic inflammation following:
a. Persistent suppuration as a result of uncollapsedabscess cavities, foreign body materials (dirt, cloth, wool, etc),
sequesterumin osteomylitis, or a sinus/fistula from chronic abscesses.
4. Autoimmunity. Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosisare chronic
inflammations from the outset.

33. Morphology:
Cells of chronic inflammation:
Monocytes and Macrophages are the prima Dona (primary cells) in chronic inflammation. Macrophages arise
from the common precursor cells in the bone marrow, which give rise to blood monocytes. These cells are then
diffusely scattered in various parts of the body, in the liver (Kupffer cells), spleen, lymph nodes (sinus
histiocytes), lungs (alviolar macrophages), bone marrow, brain (microglia), skin (Langerhan’s cells), etc…. These
cells constitute the mononuclear-phagocytic system.
Macrophages are scavenger cells of the body.
Other cells in chronic inflammation:
1. T-Lymphocytes are primarily involved in cellular immunity with lymphokine production, and they are the key regulator
and effector cells of the immune system.
2. B-lymphocytes and Plasma cells produce antibody directed either against persistent antigen in the inflammatory site or
against altered tissue components.
3. Mast cells and eosinophilsappear predominantly in response to parasitic infestations & allergic reactions.
Though neutrophils are hallmarks of acute inflammatory reactions, large numbers of neutrophils may be seen in some
forms of chronic inflammation, notably chronic osteomylitis, actinomycosis, & choric lung diseases induced by smoking
and other stimuli.

34. Classification of chronic inflammation:
Chronic inflammation can be classified into the following two types based on histologic features:
1)Nonspecific chronic inflammation: This involves a diffuse accumulation of macrophages and lymphocytes
at site of injury that is usually productive with new fibrous tissue formations. E.g. Chronic cholecystitis.
2) Specific inflammation (granulomatous inflammation):
Definition: Granulomatous inflammation is characterized by the presence of granuloma. A granuloma is a microscopic
aggregate of epithelioidcells. Epithelioidcell is an activated macrophage, with a modified epithelial cell-like appearance
(hence the name epithelioid). The epitheloidcells can fuse with each other & form multinucleated giant cells. So, even
though, a granuloma is basically a collection of epithelioidcells, it also usually contains multinucleated giant cell & is usually
surrounded by a cuff of lymphocytes and occasional plasma cells. There are two types of giant cells:

35. a.Foreignbody-typegiantcellswhichhaveirregularlyscatterednucleiinpresenceofindigestiblematerials.
b.Langhansgiantcellsinwhichthenucleiarearrangedperipherallyinahorse–shoepatternwhichisseentypicallyin
tuberculosis,sarcoidosisetc…Giantcellsareformedbyfusionofmacrophagesperhapsbyaconcertedattemptof
twoormorecellstoengulfasingleparticle.
Pathogenesis:
Therearetwotypesofgranulomas,whichdifferintheirpathogenesis.
A.Foreignbodygranuloma
Thesegranulomasareinitiatedbyinertforeignbodiessuchastalc,sutures(non-absorbable),fibers,etc…thatarelarge
enoughtoprecludephagocytosisbyasinglemacrophageanddonotinciteanimmuneresponse.
B.Immunegranulomas
Antigenpresentingcells(macrophages)engulfapoorlysolubleincitingagent.Then,themacrophageprocessesand
presentspartoftheantigen(inassociationwithMHCtype2molecules)toCD4+Thelper1cellswhichbecomeactivated.
TheactivatedCD4+T-cellsproducecytokines(IL-2andinterferongamma).TheIL-2activatesotherCD4+Thelpercellsand
perpetuatestheresponsewhileIFN-γisimportantintransformingmacrophagesintoepitheloidcellsandmultinucleated
giantcells.Thecytokineshavebeenimplicatednotonlyintheformationbutalsointhemaintenanceofgranuloma.
Macrophageinhibitoryfactorhelpstolocalizeactivatedmacrophagesandepitheloidcells.

36. Causes:
Major causes of granulomatious inflammation include:
a) Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis
b) Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis
c) Helminthic: Schistosomiasis
d) Protozoal: Leishmaniasis, Toxoplasmosis
e) Chlamydia: Lymphogranuloma venerum
f) Inorganic material: Berrylliosis
g) Idiopathic: Acidosis, Cohn’s disease, Primary biliary cirrhosis
SYSTEMIC EFFECTS OF INFLAMMATIONS
The systemic effects of inflammation include:
a. Fever
b. Endocrine & metabolic responses
c. Autonomic responses
d. Behavioral responses
e. Leukocytosis
f. Leukopenia
g. Weight loss
a. Fever
Fever is the most important systemic manifestation of inflammation. It is coordinated by the hypothalamus & by cytokines
(IL -1, IL-6, TNF-α) released from macrophages and other cells. Tumor Necrosis Factor -alpha

37. b.Endocrineandmetabolicresponsesinclude:
-Theliversecretsacutephaseproteinssuchas:
C-reactiveproteins
SerumAmyloidA
Complementandcoagulationproteins
-Glucocorticoids(increased)
-Vasopressin(decreased)
c.Autonomicresponsesinclude:
-Redirectionofbloodflowfromthecutaneoustothedeepvascularbed.
-Pulserateandbloodpressure(increased)
-Sweating(decreased)
d.Behavioralresponsesinclude:
-Rigor,chills,anorexia,somnolence,andmalaise.
e.Leucocytosisisalsoacommonfeatureofinflammation,especiallyinbacterialinfections.Itsusualcountis
15,000to20,000cells/mm3.Mostbacterialinfectionsinduceneutrophilia.Someviralinfectionssuchas
infectiousmononucleosis,&mumpscauselymphocytosis.Parasiticinfestations&allergicreactionssuchas
bronchialasthma&hayfeverinduceeosinophilia.
f.Leukopeniaisalsoafeatureoftyphoidfeverandsomeparasiticinfections.
g.WeightlossisthoughttobeduetotheactionofIL-1andTNF-αwhichincreasecatabolisminskeletal
muscle,adiposetissueandtheliverwithresultantnegativenitrogenbalance.

38. HEALING
Topic 4

39. Definitionofhealing
Referstothebody’sreplacementofdestroyedtissuebylivingtissue.
Processesofhealing
Thehealingprocessinvolvestwodistinctprocesses:
a)Regeneration,thereplacementoflosttissuebytissuessimilarintypeand
b)Repair(healingbyscaring),thereplacementoflosttissuebygranulationtissuewhichmaturestoformscar
tissue.
Healingisdeterminedpartlybythetypeofcellsinthedamagedorgan&partlybythedestructionortheintactness
ofthestromalframeworkoftheorgan.Hence,itisimportanttoknowthetypesofcellsinthebody.
Typesofcells
Basedontheirproliferativecapacitytherearethreetypesofcells.
1.Labilecells
Arecellswhichhaveacontinuousturnoverbyprogrammeddivisionofstemcells.Theyarefoundonthesurface
epitheliumoftheGIT,urinarytractortheskin.Thecellsoflymphoidandhaemopoieticsystemsareotherexamples
oflabilecells.Thechancesofregenerationareexcellent.

40. 2. Stable cells
Tissueswithsuchcellshavealowerlevelofreplicationandtherearefewstemcells.However,thecellsofsuch
tissuescanundergorapiddivisioninresponsetoinjury.E.g.mesenchymalcellssuchassmoothmusclecells,
fibroblasts,osteoblastsandendothelialcells.Theliver,endocrineglandsandrenaltubularepitheliumhasalsosuch
typeofcellswhichcanregenerate.Theirchancesofregenerationaregood.
3. Permanent cells
Thesearenon-dividingcells.Iflost,permanentcellscannotbereplaced,becausetheydon’thavethecapacityto
proliferate.E.g.:Adultneurons,striatedmusclecells,andcellsofthelens.
a.Healingbyregeneration
Definition:Regeneration(generare=bringtolife)istherenewalofalosttissueinwhichthelostcellsarereplaced
byidenticalones.
Regenerationinvolvestwoprocesses
1.Proliferationofsurvivingcellstoreplacelosttissue.
2.Migrationofsurvivingcellsintothevacantspace.
Thecapacityofatissueforregenerationdependsonits
1)Proliferativeability.
2)Degreeofdamagetostromalframework.
3)Typeandseverityofthedamage.
Tissuesformedoflabileandstablecellscanregenerateprovidedthatstromalframeworkareintact.

41. b.Repair(Healingbyconnectivetissue/scarring)
Definition:-Repairistheorderlyprocessbywhichlosttissueiseventuallyreplacedbyascar.
Awoundinwhichonlytheliningepitheliumisaffectedhealsexclusivelybyregeneration.Incontrast,woundsthat
extendthroughthebasementmembranetotheconnectivetissueleadtotheformationofgranulationtissueand
eventualscarring.
Tissuescontainingterminallydifferentiated(permanent)cellssuchasneuronsandskeletalmusclecellscannotheal
byregeneration.Thelostpermanentcellsarereplacedbyformationofgranulationtissue.
Ingranulation-tissueformation,threephasesmaybeobserved.
1.Phaseofinflammation
Inflammatoryexudatecontainingpolymorphsisseenintheareaoftissueinjury.Inaddition,thereisplatelet
aggregationandfibrindeposition.
2.Phaseofdemolition
Thedeadcellsliberatetheirautolyticenzymes,andotherenzymes(proteolytic)comefromdisintegrating
polymorphs.Thereisanassociatedmacrophageinfiltration.Thesecellsingestparticulatematter,eitherdigestingor
removingit.

42. 3.Ingrowthofgranulationtissue
Ischaracterizedbyproliferationoffibroblastsandaningrowthofnewbloodvesselsintotheareaofinjury,witha
variablenumberofinflammatorycells.(angiogenesis…..new)
Fibroblastsactivelysynthesizeandsecreteextra-cellularmatrixcomponents,includingfibronectin,
proteoglycans,andcollagentypesIandIII.
Thefibronectinandproteoglycansformthe‘scaffolding’forrebuildingofthematrix.Fibronectinbindstofibrinand
actsasachemotacticfactorfortherecruitmentofmorefibroblastsandmacrophages.
Thesynthesisofcollagenbyfibroblastsbeginswithin24hoursoftheinjuryalthoughitsdepositioninthetissueis
notapparentuntil4days.Byday5,collagentypeIIIisthepredominantmatrixproteinbeingproduced;butbyday
7to8,typeIisprominent,anditeventuallybecomesthemajorcollagenofmaturescartissue.
Woundcontraction
Isamechanicalreductioninthesizeofthedefect.Thewoundisreducedapproximatelyby70-80%ofitsoriginal
size.
Contractionresultsinmuchfasterhealing,sinceonlyone-quartertoone-thirdoftheamountofdestroyedtissue
hastobereplaced.Ifcontractionisprevented,healingisslowandalargeuglyscarisformed.

43. Causesofcontraction
Itissaidtobeduetocontractionbymyofibroblasts.Myofibroblastshavethefeaturesintermediatebetweenthose
offibroblastsandsmoothmusclecells.2to3daysaftertheinjurytheymigrateintothewoundandtheiractive
contractiondecreasethesizeofthedefect.SMCscontainthin(actin)and(thick)contractilefilamentsaswellascytoskeletalfilaments.
Molecularcontrolofhealingprocess
Healinginvolvesanorderlysequenceofeventswhichincludesregenerationandmigrationofspecializedcells,
angiogenesis,proliferationoffibroblastsandrelatedcells,matrixproteinsynthesisandfinallycessationofthese
processes.
Theseprocesses,atleastinpart,aremediatedbyaseriesoflowmolecularweightpolypeptidesreferredtoas
growthfactors.
Growthfactorshavethecapacitytostimulatecelldivisionandproliferation.Someofthefactors,knowntoplaya
roleinthehealingprocess.
SourcesofGrowthFactors:
Followinginjury,growthfactorsmaybederivedfromanumberofsourcessuchas:
1.Platelets,activatedafterendothelialdamage,
2.Damagedepithelialcells,
3.Circulatingserumgrowthfactors,
4.Macrophages,or
5.Lymphocytesrecruitedtotheareaofinjury
Thehealingprocessceaseswhenlosttissuehasbeenreplaced.Themechanismsregulatingthisprocessarenot
fullyunderstood.TGF-βactsasagrowthinhibitorforbothepithelialandendothelialcellsandregulatestheir
regeneration.

44. WoundHealing
Thetwoprocessesofhealing,canoccurduringhealingofadiseasedorganorduringhealingofawound.Awound
canbeaccidentalorsurgical.
Healingofawounddemonstratesbothepithelialregeneration(healingoftheepidermis)andrepairbyscarring
(healingofthedermis).
Therearetwopatternsofwoundhealingdependingontheamountoftissuedamage:
1.Healingbyfirstintention(Primaryunion)
2.Healingbysecondintention
Thesetwopatternsareessentiallythesameprocessvaryingonlyinamount.
1.Healingbyfirstintention(primaryunion)
Theleastcomplicatedexampleofwoundhealingisthehealingofacleansurgicalincision.Fillingwithclotted
blood,containingfibrin(proteasethrombinactivatesfibrinogentoformfibrin)andbloodcells;dehydrationofthesurfaceclotformsthe
well-knownscabthatcoversthewoundandsealsitfromtheenvironmentalmostatonce.
Within24hours,neutrophilsappearatthemarginsoftheincision,movingtowardthefibrinclot.
Theepidermisatitscutedgesthickensasaresultofmitoticactivityofbasalcellsand,within24to48hours,spurs
ofepithelialcellsfromtheedgesbothmigrateandgrowalongthecutmarginsofthedermisandbeneaththe
surfacescabtofuseinthemidline,thusproducingacontinuousbutthinepitheliallayer.
Byday3,theneutrophilshavebeenlargelyreplacedbymacrophages.Granulationtissueprogressivelyinvadesthe
incisionalspace.Collagenfibersarenowpresentinthemarginsoftheincision,butatfirstthesearevertically
orientedanddonotbridgetheincision.Epithelialcellproliferationcontinues,thickeningtheepidermalcovering
layer.Byday5,theincisionalspaceisfilledwithgranulationtissue.

45. 2.Healingbysecondintention(secondaryunion)
Whenthereismoreextensivelossofcellsandtissue,suchasoccursininfarction,inflammatoryulceration,abscess
formation,andsurfacewoundsthatcreatelargedefects,thereparativeprocessismorecomplicated.
Thecommondenominatorinallthesesituationsisalargetissuedefectthatmustbefilled.Regenerationof
parenchymalcellscannotcompletelyreconstitutetheoriginalarchitecture.Abundantgranulationtissuegrowsinfrom
themargintocompletetherepair.Thisformofhealingisreferredtoas“secondaryunion”or“healingbysecond
intention.”
Secondaryhealingdiffersfromprimaryhealinginseveralrespects:
1.Largetissuedefectsinitiallyhavemorefibrinandmorenecroticdebrisandexudatethatmustberemoved.
Consequently,theinflammatoryreactionismoreintense.
2.Muchlargeramountsofgranulationtissueareformed.Whenalargedefectoccursindeepertissues,suchasina
viscus,granulationtissuebearsthefullresponsibilityforitsclosure,becausedrainagetothesurfacecannotoccur.
3.Woundcontraction,whichoccursinlargesurfacewounds.
4.Healingbysecondintentiontakesmuchlongerthanwhenitoccursbyfirstintention.

46. Factorsthatinfluencewoundhealing
Anumberoffactorscanaltertherateandefficiencyofhealing.Thesecanbeclassifiedintothosewhichact
locally,andthosewhichhavesystemiceffects.
LocalFactors
i)Type,size,andlocationofthewound
Aclean,asepticwoundproducedbythesurgeon’sscalpelhealsfasterthanawoundproducedbyblunttrauma.
Smallbluntwoundshealfasterthanlargerones.Injuriesinrichlyvascularizedareas(e.g.,theface)healfaster
thanthoseinpoorlyvascularizedones(e.g.,thefoot).Inareaswheretheskinadherestobonysurfaces,asin
injuriesoverthetibia,woundcontractionandadequateappositionoftheedgesaredifficult.Hence,suchwounds
healslowly.
ii)Vascularsupply
Woundswithimpairedbloodsupplyhealslowly.Forexample,thehealingoflegwoundsinpatientswithvaricose
veinsisprolonged
iii)Infection
Woundsprovideaportalofentryformicroorganisms.Infectiondelaysorpreventshealing,promotestheformation
ofexcessivegranulationtissue(proudflesh),andmayresultinlarge,deformingscars.
iv)Movement
Earlymotion,particularlybeforetensilestrengthhasbeenestablished,subjectsawoundtopersistenttrauma,thus
preventingorretardinghealing.
v)Ionizingradiation
Priorirradiationleavesvascularlesionsthatinterferewithbloodsupplyandresultinslowwoundhealing.Acutely,
irradiationofawoundblockscellproliferation,inhibitscontraction,andretardstheformationofgranulationtissue.

47. SystemicFactors
i)Circulatorystatus
Cardiovascularstatus,bydeterminingthebloodsupplytotheinjuredarea,isimportantforwoundhealing.Poor
healingattributedtooldageisoftendue,largely,toimpairedcirculation.
ii)Infection
Systemicinfectionsdelaywoundhealing.
iii)Metabolicstatus
Poorlycontrolleddiabetesmellitusisassociatedwithdelayedwoundhealing.Theriskofinfectionincleanwound
approachesfivefoldtheriskinnon-diabetics.Indiabeticpatients,therecanbeimpairedcirculationsecondaryto
arteriosclerosisandimpairedsensationduetodiabeticneuropathy.Theimpairedsensationrendersthelower
extremityblindtoeverydayhazards.Hence,indiabeticpatients,woundshealtheveryslowly.
iv)Nutritionaldeficiencies
a)Proteindeficiency
Inproteindepletionthereisanimpairmentofgranulationtissueandcollagenformation,resultinginagreatdelayin
woundhealing.
b)Vitamindeficiency
VitaminCisrequiredforcollagensynthesisandsecretion.Itisrequiredinhydroxylationofprolineandlysineinthe
processofcollagensynthesis.VitaminCdeficiency(scurvy)resultsingrosslydeficientwoundhealing,withalack
ofvascularproliferationandcollagendeposition.
c)Traceelementdeficiency
Zinc(aco-factorofseveralenzymes)deficiencywillretardhealingbypreventingcellproliferation.Zincis
necessaryinseveralDNAandRNApolymerasesandtransferases;hence,adeficiencystatewillinhibitmitosis.
Proliferationoffibroblasts(fibroplasia)is,therefore,retarded.

48. v)Hormones
Corticosteroidsimpairwoundhealing,aneffectattributedtoaninhibitionofcollagensynthesis.Italsoinhibits
fibroplasiaandneovascularization.
Thyroidhormones,androgens,estrogensandgrowthhormonealsoinfluencewoundhealing.Thiseffect,
however,maybemoreduetotheirregulationofgeneralmetabolicstatusratherthantoaspecificmodificationof
thehealingprocess.
vi)Anti-inflammatorydrugs
Anti-inflammatorymedicationsdonotinterferewithwoundhealingwhenadministeredattheusualdailydosages.
Asprinandindomethalinbothinhibitprostaglandinsynthesisandthusdelayhealing.
ComplicationsofWoundHealing
Abnormalitiesinanyofthethreebasichealingprocesses–contraction,repair,andregeneration–resultinthe
complicationsofwoundhealing.
1.Infection
Awoundmayprovidetheportalofentryformanyorganisms.Infectionmaydelayhealing,andifseverestopit
completely.
2.DeficientScarFormation
Inadequateformationofgranulationtissueoraninabilitytoformasuitableextracellularmatrixleadstodeficient
scarformationanditscomplications.Thecomplicationsofdeficientscarformationare:
a.Wounddehiscence(burstingofthewound)&incisionalhernias
b.Ulceration;duetopoorintrinsicbloodsupply.

49. 3. Excessive Scar Formation
An excessive deposition of extracellular matrix at the wound site results in a hypertrophic scar or a keloid. The
rate of collagen synthesis, the ratio of type III to type I collagen, and the number of reducible cross-links remain
high, a situation that indicates a “maturation arrest”, or block, in the healing process.
Keloid Formation
An excessive formation of collagenous tissue results in the appearance of a raised area of scar tissue called keloid.
Hypertrophic Scar
Is structurally similar to keloid. However, hypertrophic scar never gets worse after 6 months unlike keloid, which
gets worse even after a year and some may even progress for 5 to 10 years. Following excision keloid recurres,
whereas a hypertrophic scar does not.
4.Excessivecontraction
Adecreaseinthesizeofawounddependsonthepresenceofmyofibroblasts,developmentofcell-cellcontacts
andsustainedcellcontraction.Anexaggerationoftheseprocessesistermedcontracture(cicatrisation)and
resultsinseveredeformityofthewoundandsurroundingtissues.
5.Miscellaneous
Implantation(orepidermoidcyst:Epithelialcellswhichflowintothehealingwoundmaylatersometimespersist,
andproliferatetoformanepidermoidcyst.

50. FractureHealing
Healingofbonefracturesbearmanyresemblancestothoseseeninskinwoundhealing.Unlikehealingofaskin
wound,however,thedefectcausedbyafractureisrepairednotbyafibrous“scar”tissue,butbyspecializedbone
formingtissuesothat,underfavorablecircumstances,theboneisrestorednearlytonormal.
Structureofbone
Boneiscomposedofcalcifiedosteoidtissue,whichconsistsofcollagenfibersembeddedinamucoproteinmatrix
(osteomucin).Dependingonthearrangementofthecollagenfibers,therearetwohistologicaltypesofbone:
1.Woven,immatureornon-lamellarbone
Thisshowsirregularityinthearrangementofthecollagenbundlesandinthedistributionoftheosteocytes.The
osseomucinislessabundantanditalsocontainslesscalcium.
2.Lamellaroradultbone
Inthistypeofbone,thecollagenbundlesarearrangedinparallelsheets.
StagesinFractureHealing(BoneRegeneration)
Stage1:Haematomaformation.Immediatelyfollowingtheinjury,thereisavariableamountofbleedingfromtorn
vessels;iftheperiosteumistorn,thisbloodmayextendintothesurroundingmuscles.Ifitissubsequentlyorganized
andossified,myositisossificansresults.
Stage2:Inflammation.Thetissuedamageexcitesaninflammatoryresponse,theexudateaddingmorefibrintothe
clotalreadypresent.Theinflammatorychangesdifferinnowayfromthoseseeninotherinflamedtissues.Thereis
anincreasedbloodflowandaPMNleucocyticinfiltration.Thehaematomaattainsafusiformshape.
Stage3:Demolition.Macrophagesinvadetheclotandremovethefibrin,redcells,theinflammatoryexudate,and
debris.Anyfragmentsofbone,whichhavebecomedetachedfromtheirbloodsupply,undergonecrosis,andare
attackedbymacrophagesandosteoclasts.

51. Stage4:Formationofgranulationtissue.Followingthisphaseofdemolition,thereisaningrowthofcapillary
loopsandmesenchymalcellsderivedfromtheperiosteumandtheendosteumofthecancellousbone.Thesecells
haveosteogenicpotentialandtogetherwiththenewlyformedbloodvesselscontributetothegranulation–tissue
formation.
Stage5:Wovenboneandcartilageformation.Themesenchymal“osteoblasts”nextdifferentiatetoformeither
wovenboneorcartilage.Theterm“callus”,derivedfromtheLatinandmeaninghard,isoftenusedtodescribethe
materialunitingthefractureendsregardlessofitsconsistency.Whenthisisgranulationtissue,the“callus”issoft,
butasboneorcartilageformationoccurs,itbecomeshard.
Stage6:Formationoflamellarbone.Thedeadcalcifiedcartilageorwovenboneisnextinvadedbycapillaries
headedbyosteoclasts.Astheinitialscaffolding(“provisionalcallus”)isremoved,osteoblastslaydownosteoid,
whichcalcifiestoformbone.Itscollagenbundlesarenowarrangedinorderlylamellarfashion,forthemostpart
concentricallyaroundthebloodvessels,andinthiswaytheHaversiansystemsareformed.Adjacenttothe
periosteumandendosteumthelamellaeareparalleltothesurfaceasinthenormalbone.Thisphaseofformationof
definitivelamellarbonemergeswiththelaststage.
Stage7:Remodelling.Thefinalremodelingprocessinvolvingthecontinuedosteoclasticremovalandosteoblastic
layingdownofboneresultsintheformationofabone,whichdiffersremarkablylittlefromtheoriginaltissue.The
externalcallusisslowlyremoved,theintermediatecallusbecomesconvertedintocompactbonecontaining
Haversiansystems,whiletheinternalcallusishollowedoutintoamarrowcavityinwhichonlyafewspiculesof
cancellousboneremain.

52. Assignment (50 Marks)
Explaintheetiology,pathogenesis,morphologic,&someclinicalfeaturesoftyphoidfever,tuberculosis,syphilis,
malaria,leishmaniasis,schistosomiasis,Viralinfectionsandfungi(Candidiasis).

53. HEMODYNAMIC DISORDERS
Topic 5

54. Thehealthandwell-beingofcells&tissuesdependnotonlyonanintactcirculationtodelivernutrientsbutalsoon
normalfluidhemostasis.
Thecommonderangementsofbodyfluidare:
1.Edema
2.Dehydration
3.Over-hydration
TheGreekwordoidemameansswelling.Edemaisabnormalandexcessiveaccumulationof“freefluid”in
theinterstitialtissuespacesandserouscavities.
Thepresenceofabnormalcollectionoffluidwithinthecellissometimescalledintracellularedemabutshould
moreappropriatelybecalledhydropicdegeneration.
Theedemamaybeof2maintypes:
1.Localizedwhenlimitedtoanorganorlimbe.g.lymphaticedema,inflammatoryedema,allergicedema.
2.Generalized(anasarcaordropsy)whenitissystemicindistribution,particularlynoticeableinthesubcutaneous
tissuese.g.renaledema,cardiacedema,nutritionaledema.

55. PATHOGENESIS OFEDEMA
Edemaiscausedbymechanismsthatinterferewithnormalfluidbalanceofplasma,interstitialfluidandlymphflow.
Thefollowingmechanismsmaybeoperatingsinglyorincombinationtoproduceedema:
1.Decreasedplasmaoncoticpressure(Thispressuretendstocauseosmosisoffluidinwardthroughthecapillary
membranefromtheinterstitium).
2.Increasedcapillaryhydrostaticpressure
3.Lymphaticobstruction
4.Tissuefactors(increasedoncoticpressureofinterstitialfluid,anddecreasedtissuetension)
5.Increasedcapillarypermeability
6.Sodiumandwaterretention.
DEHYDRATION
Isastateofdeprivationofpurewaterleadingtosodiumretentionandhenceastateofhypernatraemia.
Clinically,thepatientspresentwithintensethirst,mentalconfusion,fever,andoliguria(lowoutputofurine).
ETIOLOGY.Purewaterdeficiencyislesscommonthansaltdepletionbutcanoccurinthefollowingconditions:
1.Gastro-Intestinalexcretion:
i)Severevomiting
ii)Diarrhea
iii)Cholera

56. 2.Renalexcretion:
i)Acuterenalfailureindiureticphase
ii)Extensiveuseofdiuretics
iii)Endocrinediseasese.g.diabetesinsipidus,Addison’sdisease
3.Lossofbloodandplasma:
i)Severeinjuries,severeburns
ii)Duringchildbirth
4.Lossthroughskin:
i)Excessiveperspiration
ii)Hyperthermia
5.Accumulationinthirdspace:
i)Suddendevelopmentofascites(anaccumulationoffluidintheperitonealcavity)
ii)Acuteintestinalobstructionwithaccumulationoffluidinthebowel.
OVERHYDRATION
Isincreasedextracellularfluidvolumeduetopurewaterexcessorwaterintoxication.Clinically,thepatientswouldpresent
withdisorderedcerebralfunctione.g.nausea,vomiting,headache,confusionandinseverecasesconvulsions,coma,and
evendeath.
ETIOLOGY.Overhydrationisgenerallyaninducedconditionandisencounteredinthefollowingsituations:
1.Excessiveunmonitoredintravascularinfusion:
i)Normalsaline(0.9%NaCl)
ii)Ringerlactate
2.Renalretentionofsodiumandwater:
i)Congestiveheartfailure
ii)Acuteglomerulonephritis

57. HYPERAEMIAANDCONGESTION
Thesetermsmeanlocalizedincreaseinthevolumeofbloodwithindilatedvesselsofanorganortissue.
Increasedvolumefromarterialandarteriolardilatationisreferredtoashyperaemiaoractivehyperaemia.
Impairedvenousdrainageiscalledvenouscongestionorpassivehyperaemia.
Iftheconditiondevelopsrapidlyitiscalledacute,whilemoreprolongedandgradualresponseisknownaschronic.
ActiveHyperaemia
Thedilatationofarteries,arteriolesandcapillariesiseffectedeitherthroughsympatheticneurogenicmechanismor
viathereleaseofvasoactivesubstances.Theaffectedtissueororganispinkorredinappearance(erythema).
Activehyperaemiacanbeseeninthefollowingconditions:
1.Inflammatione.g.congestedvesselsinthewallsofalveoliinpneumonia
2.Blushingi.e.flushingoftheskinoffaceinresponsetoemotions
3.Menopausalflush
4.Muscularexercise
5.Highgradefever
6.Goitre
7.Arteriovenousmalformations
Clinically,hyperaemiaischaracterizedbyrednessandraisedtemperatureintheaffectedpart.

58. PassiveHyperaemia(VenousCongestion)
Thedilatationofveinsandcapillariesduetoimpairedvenousdrainageresultsinpassivehyperaemiaorvenous
congestion,commonlyreferredtoascongestion.
Congestionmaybeacuteorchronic,thelatterbeingmorecommonandcalledchronicvenouscongestion(CVC).
Theaffectedtissueororganisbluishincolourduetoaccumulationofvenousblood(cyanosis).Obstructiontothe
venousoutflowmaybelocalorsystemic.
Accordingly,venouscongestionisof2types:
Localvenouscongestion:Resultsfromobstructiontothevenousoutflowfromanorganorpartofthebodye.g.
portalvenousobstructioninlivercirrhosis,tightbandage,plasters,tumours,pregnancy,herniaetc,orintraluminal
occlusionbythrombosis.
Systemic(General)venouscongestion:Istheengorgementofsystemicveinse.g.inleft-sidedandright-sided
heartfailureanddiseasesofthelungswhichinterferewithpulmonarybloodflowlikepulmonaryfibrosis,
emphysemaetc.

59. HEMORRHAGE
Is the escape of blood from a blood vessel. The bleeding may occur externally, or internally into the serous cavities.
Extravasation of blood into the tissues with resultant swelling is known as hematoma.
Large extravasations of blood into the skin and mucous membranes are called ecchymoses.
Purpurasare small areas of hemorrhages (up to 1 cm) into the skin and mucous membrane.
Petechiaeare minute pinhead-sized hemorrhages.
Microscopic escape of erythrocytes into loose tissues may occur following marked congestion and is known as
diapedesis.
ETIOLOGY. The blood loss may be large and sudden (acute), or small repeated bleeds may occur over a period of
time (chronic). The various causes of hemorrhage are as under:
1.Trauma to the vessel wall
2. Spontaneous hemorrhage e.g. septicemia, bleeding diathesis (such as purpura), acute
leukemias, pernicious anemia, scurvy.
3. Inflammatory lesions of the vessel wall e.g. bleeding from chronic peptic ulcer, typhoid ulcers.
4. Neoplastic invasion e.g. hemorrhage following vascular invasion in carcinoma of the tongue.
5. Vascular diseases e.g. atherosclerosis.
6. Elevated pressure within the vessels e.g. cerebral and retinal hemorrhage in systemic hypertension.

60. EFFECTSOFBLOODLOSS
Dependupon;1)Theamountofbloodloss
2)Thespeedofbloodloss
3)Thesiteofhemorrhage
Lossupto20%ofbloodvolumesuddenlyorslowlygenerallyhaslittleclinicaleffects.
Asuddenlossof33%ofbloodvolumemaycausedeath,whilelossofupto50%ofbloodvolumeoveraperiodof24hours
maynotbenecessarilyfatal.
Chronicbloodlossgenerallyproducesirondeficiencyanemia,whereasacutehemorrhagemayleadtoseriousimmediate
consequencessuchashypovolaemicshock.
SHOCK
Isalife-threateningclinicalsyndromeofcardiovascularcollapsecharacterizedby:anacutereductionofeffectivecirculating
bloodvolume(hypotension);andaninadequateperfusionofcellsandtissues(hypoperfusion).Mayleadtoimpairedcellular
metabolismanddeath.
Bydefinition“true(orsecondary)shock”isacirculatoryimbalancebetweenoxygensupplyandoxygenrequirementsatthe
cellularlevel,andisalsocalledascirculatoryshock.
“initial(orprimary)shock”isusedfortransientandusuallyabenignvasovagalattackresultingfromsuddenreductionof
venousreturntotheheartcausedbyneurogenicvasodilatationandconsequentperipheralpoolingofbloode.g.immediately
followingtrauma,severepainoremotionaloverreactionsuchasduetofear,sorroworsurprise.
Anothertypeofshockwhichisnotduetocirculatoryderangementisanaphylacticshockfromtype1immunologicreaction.
Trueshockistheformwhichoccursduetohemodynamicderangementswithhypoperfusionofthecells;thisisthetype
whichiscommonlyreferredtoas‘shock’ifnotspecified.

61. ClassificationandEtiology
Etiologicclassificationofshocksyndromedividesitinto3majortypesandafewothervariants.
1.Hypovolemicshock.Thisformofshockresultsfrominadequatecirculatorybloodvolumebyvariousetiologic
factorsthatmaybeeitherfromthelossofredcellmassandplasmafromhemorrhage,orfromthelossofplasma
volumealone.
2.Cardiogenicshock.Acutecirculatoryfailurewithsuddenfallincardiacoutputfromacutediseasesoftheheart
withoutincardiogenicshock.
3.Septic(Toxemic)shock.Severebacterialinfectionsorsepticemiainducesepticshock.Itmaybetheresultof
Gramnegativesepticemia(endotoxicshock)whichismorecommon,orGram-positivesepticemia(exotoxicshock).
4.Othertypes.Theseincludefollowingtypes:
i)Traumaticshock.Shockresultingfromtraumaisinitiallyduetohypovolemia,butevenafterhemorrhagehasbeen
controlled,thesepatientscontinuetosufferlossofplasmavolumeintotheinterstitiumofinjuredtissueandhenceis
consideredseparatelyinsomedescriptions.
ii)Neurogenicshock.Neurogenicshockresultsfromcausesofinterruptionofsympatheticvasomotorsupply.
iii)Hypoadrenalshock.Hypoadrenalshockoccursfromunknownadrenalinsufficiencyinwhichthepatientfailsto
respondnormallytothestressoftrauma,surgeryorillness.

62. Classification and Etiology of Shock
1. HYPOVOLEMIC SHOCK
i) Acute hemorrhage
ii) Dehydration from vomitings, diarrhoea
iii) Burns
iv) Excessive use of diuretics
v) Acute pancreatitis
2. CARDIOGENIC SHOCK
i) Deficient emptying e.g.
a) Myocardial infarction
b) Cardiomyopathies
c) Rupture of the heart, ventricle or papillary muscle
c) Cardiac arrhythmias
ii) Deficient filling e.g.
a)Cardiac tamponadefrom hemopericardium
iii) Obstruction to the outflow e.g.
a) Pulmonary embolism
b) Ball valve thrombus
c) Tension pneumothorax
d) Dissecting aortic aneurysm

63. 3. SEPTIC SHOCK
i) Gram-negative septicaemia (endotoxic shock) e.g. Infection with E. coli OH:157, Proteus, Klebsiella,
Pseudomonas and bacteroides
ii) Gram-positive septicaemia (exotoxic shock) e.g. Infection with streptococci, pneumococci
4. OTHER TYPES
i) Traumatic shock
a) Severe injuries
b) Surgery with marked blood loss
c) Obstetrical trauma
ii) Neurogenic shock
a) High cervical spinal cord injury
b) Accidental high spinal anaesthesia
c) Severe head injury
iii) Hypoadrenal shock
a) Administration of high doses of glucocorticoids
b) Secondary adrenal insufficiency (e.g. in tuberculosis, metastatic disease, bilateral adrenal haemorrhage,
idiopathic adrenal atrophy)

64. Pathogenesis
Allformsofshockinvolvefollowing3derangements:
Thesederangementsinitiallysetincompensatorymechanismsbuteventuallyaviciouscycleofcellinjuryand
severecellulardysfunctionleadtobreakdownoforganfunction.
1.Reducedeffectivecirculatingbloodvolume.Itmayresultbyeitherofthefollowingmechanisms:
i)byactuallossofbloodvolumeasoccursinhypovolaemicshock;or
ii)bydecreasedcardiacoutputwithoutactuallossofblood(normovolaemia)asoccursincardiogenicshockand
septicshock.
2.Impairedtissueoxygenation.Followingreductionintheeffectivecirculatingbloodvolumefromeitherofthe
abovetwomechanismsandfromanyoftheetiologicagents,thereisdecreasedvenousreturntotheheartresulting
indecreasedcardiacoutput.Thisconsequentlycausesreducedsupplyofoxygentotheorgansandtissuesand
hencetissueanoxia,whichsetsincellularinjury.
3.Releaseofinflammatorymediators.Inresponsetocellularinjury,innateimmunityofthebodygetsactivatedas
abodydefensemechanismandreleaseinflammatorymediatorsbuteventuallytheseagentsthemselvesbecome
thecauseofcellinjury.Endotoxinsinbacterialwallinsepticshockstimulatemassivereleaseofpro-inflammatory
mediators(cytokines)butasimilarprocessofreleaseoftheseagentstakesplaceinlatestagesofshockfromother
causes.Severalpro-inflammatoryinflammatorymediatorsarereleasedfrommonocytes-macrophages,other
leucocytesandotherbodycells,themostimportantbeingthetumournecrosisfactor-(TNF)-αandinterleukin-1(IL-
1)cytokines.