cell injury and necrosis mechanism Pathology.ppt

PATHOLOGY AND
MICROBIOLOGY
INTRODUCTION

PATHOLOGY
•Definition: study of disease
•Pathology is the study (logos) of disease (pathos, suffering)
•It involves the investigation of the causes of
disease and the associated changesat the levels
of cells, tissues, and organs, which in turn give
rise to the presenting signs and symptoms of
the patient.
•Pathology provides a logical and scientific foundation for the
practice of medicine.

Important terms
•Etiologyis the origin of a disease, including the underlying causes and
modifying factors
Pathogenesis refers to the steps in the development of disease
It describes how etiologic factors trigger cellular and molecular changes
that give rise to the specific functional and structural abnormalities that
characterize the disease.
Incidence: is a measure of the riskof developing some new condition
within a specified period of time.
Etiology refers to why a disease arises, Pathogenesis describes how a
disease develops.

Pathology
General pathology
cellular and tissue
alterations caused by
pathologic stimuli
in most tissues
Systemic
pathology
examines the
reactions and
abnormalities of
different organs

OVERVIEW OF CELLULAR
RESPONSES TO STRESS AND
NOXIOUS STIMULI
OVERVIEW
INTRODUCTION
CAUSES
MECHANISM
EXAMPLES

OVERVIEW OF CELL INJURY
•Cells –adjust their structure and function to accommodate changing demands
and extracellular stressses.
•-maintain a steady state called homeostasisin which the intracellular milieu is
kept within a fairly narrow range of physiologic parameters.
•As cells encounter physiologicstressesor pathologicstimuli, they can
undergo adaptation, achieving a new steady state and preserving viability
and function.
•The principal adaptive responses are hypertrophy, hyperplasia, atrophy, and
metaplasia.
•If the adaptive capability is exceeded or if the external stress is inherently
harmful, cell injury develops .
•Within certain limits, injury is reversible, and cells return to a stable baseline;
however,
•if the stress is severe,persistent and rapid in onset, it results in irreversible
injury and death of the affected cells.

OVERVIEW OF CELL INJURY
•Cell death is one of the most crucial events in
the evolution of disease in any tissue or organ.
It results from diverse causes, including
ischemia (lack of blood flow), infections,
toxins, and immune reactions.
•Cell death also is a normal and essential
process in embryogenesis, the development
of organs, and the maintenance of homeostasis.

Stages in cellular response

•Example:Myocardiumcells–
•Stimulus/Stress–
•a.persistentincreasedload,asin
hypertension,
•b.withnarrowed(stenotic)valve,
•Adaptations:Myocardialcelladaptsby
•Adaptationprocess:Hypertrophy–increase
insizetogeneraterequiredhighercontractile
force.

•If Stress is severe or arterial occlusion is complete like ,
–the increased demand of oxygen (required higher contractile force ) ,
reduced blood flow from an occluded coronary artery , the muscle
undergo injury.
•If the stress is mild or the arterial occlusion is incomplete or
brief ,
–Myocardium may be reversibly injured .
•Reversibly injured myocytesare not dead and may resemble
morphologically normal myocytesmorphologically. But,
functionally , they are transiently noncontractile.
•If the stress is strong or arterial occlusion is complete and
prolonged , myocardium undergo irreversible injury and cell
death
Note: Stresses and injury affect not only the morphology but
also the functional status of cells and tissues.

The cellular adaptation depicted here is hypertrophy, the type of reversible injury is ischemia, and the
irreversible injury is ischemic coagulative necrosis. In the example of myocardial hypertrophy (lower left),
the left ventricular wall is thicker than 2 cm (normal, 1–1.5 cm). Reversibly injured myocardium shows
functional effects without any gross or light microscopic changes, or reversible changes like cellular swelling
and fatty change (shown here). In the specimen showing necrosis (lower right) the transmural light area in
the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections of
myocardium have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable
myocardium magenta. Failure to stain is due to enzyme loss after cell death.
Not dead

CAUSES OF CELL INJURY
1.OXYGENDEPRIVATION–Differencebetweenhypoxiaandischemia
•Ischemia,whichisalossofbloodsupplyinatissueduetoimpeded
arterialfloworreducedvenousdrainage.
•Hypoxia,oxygendeficiencycanalsoresultfrominadequateoxygenation
oftheblood,asinpneumonia,orfromreductionintheoxygen-
carryingcapacityoftheblood,asinbloodlossanemiaorcarbon
monoxide(CO)poisoning.
•Hypoxia,oroxygendeficiency,interfereswithaerobicoxidative
respiration
•Carbonmonoxide(CO)poisoning-(COformsastablecomplexwith
hemoglobinthatpreventsoxygenbinding.)
2.AGING
•Cellularsenescenceleadstoalterationsinreplicativeandrepairabilities
ofindividualcellsandtissues.

CAUSES OF CELL INJURY
3.CHEMICALAGENTS
•Innocuoussubstancessuchasglucose,salt,orevenwater,ifabsorbedor
administeredinexcess,cansoderangetheosmoticenvironmentthatcell
injuryordeathresults.
•Poisonscauseseveredamageatthecellularlevelbyalteringmembrane
permeability,osmotichomeostasis,ortheintegrityofanenzymeor
cofactor
•Otherpotentiallytoxicagents:airpollutants,insecticides,CO,
asbestos,and“socialstimuli”suchasethanol.
•Manytherapeuticdrugscancausecellortissueinjuryinasusceptible
patientorifusedexcessivelyorinappropriately.
•Evenoxygenatsufficientlyhighpartialpressuresistoxic.
4.INFECTIOUS AGENTS
•range from submicroscopic viruses to meter-long tapeworms; in between
are the rickettsiae, bacteria, fungi, and protozoans.

5.IMMUNOLOGIC REACTIONS
•Althoughtheimmunesystemdefendsthebodyagainst
pathogenicmicrobes,immunereactionscanalsoresultin
cellandtissueinjury.
•Examplesareautoimmunereactionsagainstone’sown
tissuesandallergicreactions(Hypersensitivity)against
environmentalsubstancesingeneticallysusceptible
individuals
6.GENETICFACTORS
•Geneticaberrationscanresultinpathologicchanges
•CongenitalmalformationsassociatedwithDownsyndrome
orassubtleasthesingleaminoacidsubstitutionin
hemoglobinSgivingrisetosicklecellanemia.
•Geneticdefectsmaycausedeficiencyoffunctional
proteins,suchasenzymesininbornerrorsofmetabolism,
oraccumulationofdamagedDNAormisfoldedproteins
•Geneticvariations(polymorphisms)

7. NUTRITIONAL IMBALANCES
•nutritional deficiencies
•Protein–calorie insufficiency
•specific vitamin deficiencies
•Ironically, disorders of nutrition rather than lack of nutrients
are also important causes of morbidity and mortality;
•Moreover, diets rich in animal fat -development of
atherosclerosisas well as in increased vulnerability to
many disorders, including cancer.
8. PHYSICAL AGENTS
•Trauma, extremes of temperature, radiation, electric
shock, and sudden changes in atmospheric pressure all
have wide-ranging effects on cells
CAUSES OF CELL INJURY

MORPHOLOGY OF CELL INJURY
•Cellularfunctionmaybelostlongbeforecelldeathoccurs,andthe
morphologicchangesofcellinjury(ordeath)lagfarbehindboth.
•Myocardialcellsbecomenon-contractileafter1to2minutesofischemia,
althoughtheydonotdieuntil20to30minutesofischemiahaveelapsed.
Thesemyocytesmaynotappeardeadbyelectronmicroscopyfor2to3
hours,orbylightmicroscopyfor6to12hours.

MORPHOLOGY OF CELL INJURY
•Thecellularderangementsofreversibleinjurycanbe
corrected,andiftheinjuriousstimulusabates,the
cellcanreturntonormalcy.
•Persistentorexcessiveinjury,however,causescells
topassthenebulous“pointofnoreturn”into
irreversibleinjuryandcelldeath.
•Twophenomena consistentlycharacterize
irreversibility:
–Inabilitytocorrectmitochondrialdysfunction
–Profounddisturbanceinmembranefunction

MORPHOLOGY OF CELL INJURY
The two main morphologic correlates of reversible cell injury are
cellular swelling and fatty change.
Morphological changes -1. CELLULAR SWELLING:
•The first manifestation of almost all forms of cell injury ,
•a reversible alteration that may be difficult to appreciate with
the light microscope
•When it affects many cells in an organ, it causes some pallor
(as a result of compression of capillaries), increased turgor,
and increase in weight of the organ.
•Microscopic examination may reveal small, clear vacuoles
within the cytoplasm; these represent distended and
pinched-off segments of the endoplasmic reticulum (ER).
•This pattern of nonlethal injury is sometimes called hydropic
change or vacuolar degeneration.

MORPHOLOGY OF CELL INJURY
Thetwomainmorphologiccorrelatesofreversiblecellinjuryare
cellularswellingandfattychange.
Morphologicalchanges-2.FATTYCHANGE:
•Ismanifestedbytheappearanceoflipidvacuolesinthe
cytoplasm.
•Itisprincipallyencounteredincellsparticipatinginfat
metabolism(e.g.,hepatocytes,myocardialcells)andisalso
reversible.
•Injuredcellsmayalsoshowincreasedeosinophilicstaining,
whichbecomesmuchmorepronouncedwithprogressionto
necrosis.

INTRACELLULAR CHANGES –
Reversible Injury
Theintracellularchangesassociatedwithreversibleinjuryinclude
plasmamembranealterationssuchasblebbing,blunting,or
distortionofmicrovilli,andlooseningofintercellular
attachments;
mitochondrialchangessuchasswellingandtheappearanceof
phospholipid-richamorphousdensities
dilationoftheERwithdetachmentofribosomesand
dissociationofpolysomes;and
nuclearalterations,withclumpingofchromatin.The
cytoplasmmaycontainphospholipidmasses,calledmyelin
figures,whicharederivedfromdamagedcellularmembranes.

A: Normal kidney tubules with viable epithelial cells.
B: Early (reversible) ischemic injury showing surface blebs, increased eosinophilia
of cytoplasm, and swelling of occasional cells.
C: Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and
fragmentation of cells and leakage of contents.

MECHANISMS OF CELL INJURY
1.DEPLETION OF ATP:
ATP-the energy store of cells , produced mainly by
–oxidative phosphorylationof adenosine diphosphate
(ADP) during reduction of oxygen in the electron transport
system of mitochondria and
–also by glycolyticpathwayusing glucose in the absence of
oxygen .
•major causes of ATP depletion : reduced supply of oxygen and
nutrients, mitochondrial damage, and the actions of some
toxins (e.g., cyanide).

MECHANISMS OF CELL INJURY
SignificantATPdepletioneffects:
•TheactivityofplasmamembraneATP-dependentsodium
pumpsisreduced,resultinginintracellularaccumulationof
sodiumandeffluxofpotassium.
•Thenetgainofsoluteisaccompaniedbyiso-osmoticgainof
water,causingcellswellinganddilationoftheER.
•Thereisacompensatoryincreaseinanaerobicglycolysisin
anattempttomaintainthecell’senergysources(ATPcontent)
•Asaconsequence,intracellularglycogenstoresarerapidly
depleted,andlacticacidaccumulates,leadingtodecreased
intracellularpHanddecreasedactivityofmanycellular
enzymes.
•FailureofATP-dependentCa2+pumpsleadstoinfluxof
Ca2+,withdamagingeffectsonnumerouscellularcomponents

•Prolonged depletion of ATP causes structural disruption of the protein
synthetic apparatus, (detachment of ribosomes from the rough ER and
dissociation of polysomes into monosomes), with a consequent reduction
in protein synthesis.
ATP Depletion

ATP depletion -Effects
Influx of Calcium:
•Causes: Ischemia and certain toxins cause an
increase in cytoplasmic calcium concentration
•Activates enzymes (phospholipids, proteases ,
endonucleases , ATPase that damage cellular
components and may also trigger apoptosis
by direct caspases and by increasing
mitochondrial permeability.

INFLUX OF
CALCIUM

2. MITOCHONDRIAL DAMAGE AND
DYSFUNCTION
Mitochondria-Mini factories that produce life sustaining
energy
Sensitive to hypoxia, chemical toxins and radiation.
•Mitochondrial damage may result in several biochemical
abnormalities:
•Failure of oxidative phosphorylation leads to progressive
depletion of ATP, culminating in necrosisof the cell
•Abnormal oxidative phosphorylation also leads to the
formation of reactive oxygen species (ROS),which have
many deleterious effects

MITOCHONDRIAL DAMAGE
AND DYSFUNCTION
•Damagetomitochondriaisoftenassociatedwith:
theformationofahigh-conductancechannelinthe
mitochondrialmembrane,calledthemitochondrial
permeabilitytransitionpore.
•Theopeningofthischannelleadstothelossof
mitochondrialmembranepotentialandpH
changes,furthercompromisingoxidative
phosphorylation.
•Releaseofseveralmitochondrialproteinsintothe
cytoplasm,causeinternalcellinjuryandactivatea
pathwayofapoptosis

Mitochondria
dysfunction

ACCUMULATION OF OXYGEN -DERIVED
FREE RADICALS (OXIDATIVE STRESS)
Free radicals –Chemical species with a single unpaired electron in an outer orbital
•Readily react with organic and inorganic chemicals, attack nucleic acids , as well
as a variety of cellular proteins and lipids.
•Reactive oxygen species (ROS) are a type of oxygen derived free radical.
There are different types of ROS, and they are produced by two major pathways:
ROS are produced normally in small amounts in all cells during the reduction-
oxidation (redox) reactions that occur during mitochondrial respiration and energy
generation.
In this redox process,molecular oxygen is sequentially reduced in mitochondria
by the addition of four electrons to generate water.
This reaction is imperfect, however, and small amounts of highly reactive but
/short-lived toxic intermediates are generatedwhen oxygen is only partially
reduced.

ROS produced normally in small
amounts in all cells during the reduction-
oxidation (redox) reactions
ACCUMULATION OF OXYGEN -DERIVED
FREE RADICALS (OXIDATIVE STRESS)
These short lived intermediates include superoxide (O2 • ),
which is converted to hydrogen peroxide (H2O2)spontaneously
and by the action of the enzyme superoxide dismutase.
H2O2 is more stable than O2 • and can cross biologic
membranes.
In the presence of metals, such as Fe2+, H2O2 is converted to the
highly reactive hydroxyl radical •OH by the Fenton reaction.

ACCUMULATION OF OXYGEN -DERIVED
FREE RADICALS (OXIDATIVE STRESS)
ROS are produced in phagocytic leukocytes, mainly neutrophils and
macrophages, as a weapon for destroying ingested microbes and other
substances during inflammation and host defense.
The ROS are generated in the phagosomes and phagolysosomes of
leukocytes by a process that is similar to mitochondrial respiration and is
called the respiratory burst (or oxidative burst).
ROS produced in phagocytic
leukocytes, mainly neutrophils and
macrophages

Inthisprocess,aphagosomemembrane
enzymecatalyzesthegenerationof
superoxide,whichisconvertedto
H2O2.H2O2isinturnconvertedtoa
highlyreactivecompoundhypochlorite
(themajorcomponentofhousehold
bleach)bytheenzymemyeloperoxidase,
whichispresentinleukocytes.
Nitricoxide(NO)isanotherreactive
freeradicalproducedinleukocytesand
othercells.ItcanreactwithO2•toform
ahighlyreactivecompound,
peroxynitrite,whichalsoparticipatesin
cellinjury.
ACCUMULATION OF OXYGEN -DERIVED
FREE RADICALS (OXIDATIVE STRESS)

ACCUMULATION OF OXYGEN -DERIVED
FREE RADICALS (OXIDATIVE STRESS)
THE GENERATION OF FREE RADICALS IS INCREASED UNDER
SEVERAL CIRCUMSTANCES:
•The absorption of radiant energy(e.g., ultraviolet light, x-rays). Ionizing
radiation can hydrolyze water into hydroxyl (•OH) and hydrogen (H•)
free radicals.
•The enzymatic metabolism of exogenous chemicals(e.g., carbon
tetrachloride
•Inflammation, in which free radicals are produced by leukocytes

REACTIVE OXYGEN SPECIES
CAUSE CELL INJURY BY THREE MAIN REACTIONS
a.Lipid peroxidation of membranes:Double bonds in
membrane polyunsaturated lipids are vulnerable to
attack by oxygen-derived free radicals.
•The lipid–radical interactions yield peroxides,
which are themselves unstableand reactive, and an
autocatalyticchainreactionensues.
b. Cross-linking and other changes in proteins:Free
radicals promote sulfhydryl-mediated protein cross-
linking, resulting in enhanced degradation or loss of
enzymatic activity. Free radical reactions may also
directly cause polypeptide fragmentation.

REACTIVE OXYGEN SPECIES
c.DNAdamage:Freeradicalreactionswith
thymineinnuclearandmitochondrialDNA
producesingle-strandbreaks.SuchDNA
damagehasbeenimplicatedincelldeath,
aging,andmalignanttransformationofcells.

EXAMPLES OF CELL INJURY
•ISCHEMIA:
•Diminished blood flow to a tissue -Reduced O2 supply to
tissues
•Glycolysis is inhbited by the accumulation of metabolites that
would normally be removed by blood flow
•Anaerobic energy generation also ceases in ischemic tissues
after potential substrates are exhausted (reduced substrate
delivery) or when glycolysis is inhibited.
•Ischemia injures tissues faster
•If ischemia persists, irreversible injury and necrosis ensue.
•Irreversible injury is associated with severe swelling of
mitochondria, extensive damage to plasma membranes, and
swelling of lysosomes. ROS accumulate in cells, and massive
influx of calcium may occur

EXAMPLES OF CELL INJURY
•HYPOXIA
•reduced supply of oxygen
•The most important biochemical abnormality in hypoxic cells that leads
to cell injury is reduced intracellular generation of ATP
•Loss of ATP leads to the failure of many energy dependent cellular systems,
including ion pumps (leading to cell swelling, and influx of Ca2+
Depletion of glycogen stores and accumulation of lactic acid, thus lowering
the intracellular pH
reduction in protein synthesis

NECROSIS
•CAUSES
•MORPHOLOGY
•PATTERNS OF TISSUE NECROSIS

Necrosis
•-the type of cell death that is associated with loss of
membrane integrity and leakage of cellular contents
•culminating in dissolution of cells, largely resulting
from the degradativeaction of enzymes on lethally
injured cells.
•The leaked cellular contents ( dissolution of cells )
often elicit a local host reaction, called inflammation,
that attempts to eliminate the dead cells and start the
subsequent repairprocess.
•Inflammation leads to recruitment of lysosomes
(enzymes responsible for digestion of the cell)of the
dying cells and leukocytes

CAUSES OF NECROSIS
•Necrosis may occur due to external or internal factors.
•External factors : mechanical trauma (physical damage to the body that
causes cellular breakdown),damage to blood vessels(which may disrupt
blood supply to associated tissue), andischemia.Thermal effects
(extremely high or low temperature) can result in necrosis due to the
disruption of cells.
•Internal factors : trophoneuroticdisorders; injury and paralysis of
nerve cells
•Pathologicalconditions : inadequate secretion ofcytokines.
•Nitric oxide(NO) andreactive oxygen species(ROS) are also
accompanied by intense necrotic death of cells.
•A classic example of a necrotic condition is ischemiathat leads to a
drastic depletion ofoxygen,glucose, and othertrophicfactorsand induces
massive necrotic death of endothelial cells and non-proliferating cells of
surrounding tissues (neurons, cardiomyocytes, renal cells, etc.)

MORPHOLOGY:
•Necrosis is characterized by changes in the cytoplasm and nucleiof the
injured cells:
A. CYTOPLASMIC CHANGES: Inhematoxylin and eosinstains(H&E),
necrotic cells have the following morphologic features:
Necrotic cells show increased eosinophilia (i.e., pink staining from the
eosin dye—theE in the hematoxylin and eosin [H&E] stain), binding of
eosin to denatured cytoplasmic proteins.
Compared with viable cells, the cell may have a more glassy, homogeneous
appearance, mostly because of the loss ofglycogen particles.
Myelin figures (whorl like structures,formed by broken cell membranes)
are more prominentin necrotic cells than during reversible injury.
When enzymes have digested cytoplasmic organelles, the cytoplasm becomes
vacuolated and appears “moth-eaten.”
•By electron microscopy (EM), on the other hand, one can notice
Discontinuous cytoplasmic membranes
Dilated mitochondria
Disruption of lysosomes, and intracytoplasmic myelin figures

B. NUCLEAR CHANGES ( Nuclear Dissolution) : Nuclear changes
assume one of three patterns, all due to breakdown of DNA and
chromatin.
A) The basophilia of the chromatin may fade (karyolysis),
deoxyribonuclease(DNase) activity.
B) A second pattern is pyknosis, characterized by nuclear shrinkage and
increased basophilia; the DNA condenses into a solid shrunken mass.
In the third pattern, karyorrhexis, the pyknotic nucleus undergoes
fragmentation.
In 1 to 2 days, the nucleus in a dead cell may completely disappear.

•FATES OF NECROTIC CELLS:
Necrotic cells may persist for some time ormay be digested by enzymes
and disappear.
Dead cells may be replaced by myelin figures, which are either
phagocytosedby other cells or further degraded into fatty acids.
These fatty acids bind calcium salts, which may result in the dead cells
ultimately becoming calcified.

TYPES OF NECROSIS
Coagulative necrosis
Liquefactive necrosis
Caseous necrosis
Fat necrosis
Fibrinoid necrosis

•Coagulative necrosisis a form of necrosis in which the underlying
tissue architecture is preserved for at least several days.The affected
tissues take on a firm texture.
•Presumably the injury denatures not only structural proteins but also
enzymes,thereby blocking the proteolysis of the dead cells; as a result,
eosinophilic, anucleate cells may persist for days or weeks.
•Leukocytes are recruited to the site of necrosis, and the dead cells are
digested by the action of lysosomal enzymes of the leukocytes.
•The cellular debris is then removed by phagocytosis.
•Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis)
in all of the solid organs except the brain.

•Liquefactivenecrosisisseeninfocalbacterialor,occasionally,fungal
infections,becausemicrobesstimulatetheaccumulationof
inflammatorycellsandtheenzymesofleukocytesdigest(“liquefy”)
thetissue.
•Forobscurereasons,hypoxicdeathofcellswithinthecentralnervous
systemoftenevokesliquefactivenecrosis.
•Whateverthepathogenesis,thedeadcellsarecompletelydigested,
transformingthedeadtissueintoaliquidviscousmass.
•Eventually,thedigestedtissueisremovedbyphagocytes.
•Iftheprocesswasinitiatedbyacuteinflammation,asinabacterial
infection,thematerialisfrequentlycreamyyellowandiscalledpus

•Gangrenous necrosis : It usually refers to the condition of a limb,
generally the lower leg, that has lost its blood supply and has undergone
coagulative necrosis involving multiple tissue layers.
•When bacterial infection is superimposed, coagulative necrosis is
modified by the liquefactive action of the bacteria and the attracted
leukocytes (resulting in so-called wet gangrene).

•Caseous necrosis is encountered most often in foci of
tuberculous infection. Caseous means “cheese-like,”
referring to the friable yellow-white appearance of the area
of necrosis.
•On microscopic examination, the necrotic focus appears as a
collection of fragmented or lysed cells with an amorphous
granular pink appearance in the usual H&E-stained
tissue.
•Unlike with coagulative necrosis, the tissue architecture is
completely obliterated and cellular outlines cannot be
discerned.
•The area of caseous necrosisis often enclosed within a
distinctive inflammatory border;this appearance is
characteristic of a focus of inflammation known as a
granuloma

•Fat necrosis refers to focal areas of fat destruction,
typically resulting fromrelease of activated pancreatic
lipasesinto the substance of the pancreas and the peritoneal
cavity.
•This occurs in the calamitous abdominal emergency known as
acute pancreatitis.
•In this disorder, pancreatic enzymes that have leaked out of
acinar cells and ducts liquefy the membranes of fat cells in
the peritoneum, and lipases split the triglyceride esters
contained within fat cells.
•The released fatty acids combine with calcium to produce
grossly visible chalky white areas (fat saponification),
which enable the surgeon and the pathologist to identify the
lesions

•Fibrinoid necrosis is a special form of necrosis,
visibleby light microscopy, usuallyin immune
reactions in which complexes of antigens and
antibodies are deposited in the walls of arteries.
•The deposited immune complexes, together with
fibrin that has leaked out of vessels, produce a
bright pink and amorphous appearance on H&E
preparations called fibrinoid (fibrin-like) by
pathologists.
•Theleakage of intracellular proteins through the
damaged cell membrane and ultimately into the
circulation provides a mean of detecting tissue-
specific necrosis using blood or serum samples.

APOPTOSIS
•Causes
•Morphology
•Mechanism of apoptosis
•Examples

•Apoptosis is a pathway of cell death in which cells activate
enzymes that degrade the cells’ own nuclear DNA and
nuclear and cytoplasmic proteins.
•Fragments of the apoptotic cells then break off, giving the
appearance that is responsible for the name (apoptosis,
“falling off”).
•The plasma membrane of the apoptotic cell remains intact,
but the membraneis altered in such a waythat the cell and
its fragments become avid targets for phagocytes.
•The dead cell and its fragments are rapidly clearedbefore
cellular contents have leaked out, so apoptotic cell death does
not elicit an inflammatory reaction in the host.

•CAUSES OF APOPTOSIS:
•Apoptosis occurs in many normal situations
and serves to eliminate potentially harmful
cells and cells that have outlived their
usefulness.
•It also occurs as a pathologic event when cells
are damaged beyond repair
•Apoptosis can occur under two situations:
Physiologic
Pathologic

APOPTOSIS IN PHYSIOLOGIC SITUATIONS
•Death by apoptosis is a normal phenomenon that serves to
eliminate cells that are no longer needed and to maintain a
constant number of cells of various types in tissues.
•It is important in the following physiologic situations:
The programmed destruction of cells during embryogenesis:
Normal developmentis associated with the death of some cells
and the appearance of new cells and tissues.
The term programmed cell death was originally coined to denote
this death of specific cell types at defined times during the
development of an organism.
Involution of hormone-dependent tissues upon hormone
deprivation, such as endometrial cell breakdown during the
menstrual cycle, and regression of the lactating breast after
weaning

Elimination of cells that have served their useful
purpose, such as neutrophils in an acute
inflammatory response and lymphocytes at the
end of an immune response.
Cells deprived of necessary survival signals, such
as growth factors -undergo apoptosis .
Elimination of potentially harmful self-reactive
lymphocytes, either before or after they have
completed their maturation, in order to prevent
reactions against the body’s own tissues
Cell death induced by cytotoxic T lymphocytes,a
defense mechanism against viruses and tumors that
serves to kill virus-infected and neoplastic cells

APOPTOSIS IN PATHOLOGIC CONDITIONS
•Apoptosis eliminates cells that are genetically altered or
injured beyond repair and does so without eliciting a
severe host reaction, thereby keeping the extent of tissue
damage to a minimum.
•Death by apoptosis is responsible for loss of cells in a variety of
pathologic states:
•DNA damage:
Radiation, cytotoxic anticancer drugs, extremes of temperature,
and even hypoxia can damage DNA,either directly or through
production of free radicals. In these situations, elimination of the
cell may be a better alternative than risking mutations in the
damaged DNA, which may progress to malignant
transformation.These injurious stimuli cause apoptosis if the insult
is mild, but larger doses of the same stimuli result in necrotic cell
death.

Accumulation of misfolded proteins:Improperly
folded proteins may arise because of mutations in
the genes encoding these proteinsor because of
extrinsic factors, such as damage caused by free
radicals. Excessive accumulation of these proteins
in the ER leads to a condition called ER stress,
which culminates in apoptotic death of cells.
Cell injury in certain infections, particularly viral
infections, in which loss of infected cells is largely
due to apoptotic death that may be induced by the
virus (as in adenovirus and human
immunodeficiency virus infections) or by the host
immune response (as in viral hepatitis).

MORPHOLOGY:
•In H&E-stained tissue sections, the nuclei of apoptotic
cells show various stages of chromatin condensation and
aggregation and, ultimately, karyorrhexis
•at the molecular level this is reflected in fragmentation of
DNA into nucleosome-sized pieces. The cells rapidly
shrink, form cytoplasmic buds,and fragment into apoptotic
bodies composed ofmembrane-bound vesicles of cytosol
and organelles
•Because these fragments are quickly extruded and
phagocytosed without eliciting an inflammatory
response, even substantial apoptosis may be
histologically undetectable.

MECHANISM OF APOPTOSIS:
•Apoptosis results from the activation of
enzymes called caspases (so named because
they are cysteine proteases that cleave proteins
after aspartic residues).
•Two distinct pathways converge on caspase
activation:
the mitochondrial (Intrinsic)pathway
the death receptor (Extrinsic) pathway

•THE MITOCHONDRIAL (INTRINSIC) PATHWAY OF
APOPTOSIS
•Mitochondria contain several proteins that are capable of
inducing apoptosis;
•these proteins include cytochrome c
•The choice between cell survival and death is determined by the
permeability of mitochondria,which is controlled by a family of
more than 20 proteins, the prototype of which is Bcl-2
•When cells are deprived of growth factors and other survival signals,
or are exposed to agents that damage DNA, or accumulate
unacceptable amounts of misfolded proteins, a number of sensors
are activated (BH3 PROTEINS).
•These sensors are members of the Bcl-2 family called “BH3
proteins” (because they contain only the third of multiple conserved
domains of the Bcl-2 family).

•They in turn activate two pro-apoptotic members
of the family called Bax and Bak, which dimerize,
insert into the mitochondrial membrane, and form
channels through which cytochrome c and other
mitochondrial proteins escape into the cytosol.
•These sensors BH3 PROTEINS also inhibit the
anti-apoptotic molecules Bcl-2 and Bcl-xL,
enhancing the leakage of mitochondrial proteins.
•Cytochrome c, together with some cofactors,
activates caspase-9.
•The net result is the activation of the caspase
cascade, ultimately leading to nuclear
fragmentation.

THE DEATH RECEPTOR (EXTRINSIC)
PATHWAY OF APOPTOSIS
•Many cells express surface molecules, called
death receptors, that trigger apoptosis.
•Most of these are members of the tumor
necrosis factor (TNF) receptor family, which
contain in their cytoplasmicregions a conserved
“death domain”so named because it mediates
interaction with other proteins involved in cell
death.
•The prototypic death receptors are the type I TNF
receptor and Fas(CD95).
•Fasligand(FasL) is a membrane protein
expressed mainly on activated T lymphocytes.

•When these T cells recognize Fas-expressing
targets, Fas molecules are cross-linked by
FasLand bind adaptor proteins via the death
domain.
•These in turn recruit and activate caspase-8.
•In many cell types caspase-8 may cleave and
activate a pro-apoptotic member of the Bcl-
2 family called Bid, thus feeding into the
mitochondrial pathway.

•The combined activation of both pathways delivers
a lethal blow to the cell.
•The death receptor pathway is involved in
elimination of self-reactive lymphocytes and in
killing of target cells by some cytotoxic T
lymphocytes.

ACTIVATION AND FUNCTION OF CASPASES
•The mitochondrial and death receptor pathways lead
to theactivation of the initiator caspases, caspase-
9 and -8, respectively.
•Active forms of these enzymes are produced, and
these cleave and thereby activate another series of
caspases that are called the executioner caspases.
•These activated caspases cleave numerous targets,
culminating in activation of nucleases that
degrade DNA and nucleoproteins.
•Caspases also degrade components of the nuclear
matrix and cytoskeleton, leading to fragmentation of
cells.

CLEARANCE OF APOPTOTIC CELLS
•Apoptotic cells entice phagocytes by producing
“eat-me” signals. In normal cells phosphatidyl
serine is present on the inner leafletof the plasma
membrane, but in apoptotic cells this phospholipid
“flips” to the outer leaflet, where it is recognized
by tissue macrophages and leads to phagocytosis
•Cells that are dying by apoptosis also secrete
soluble factors that recruit phagocytes.
•This facilitates prompt clearance of the dead cells
before they undergo secondary membrane damage
and release their cellular contents (which can induce
inflammation).

CLEARANCE OF APOPTOTIC CELLS
•Some apoptotic bodies express adhesive
glycoproteins that are recognized by
phagocytes, and macrophages themselves
may produce proteins that bind to apoptotic
cells (but not to live cells) and target the dead
cells for engulfment.

EXAMPLES OF APOPTOSIS:
Growth Factor Deprivation: Hormone-sensitive cells deprived of the relevant
hormone, lymphocytes that are not stimulated by antigens and cytokines, and
neurons deprived of nerve growth factor, die by apoptosis. In all these situations,
apoptosis is triggered by the mitochondrial pathway.
•DNA Damage: Exposure of cells to radiation or chemotherapeutic agents induces
DNA damage, which if severe may trigger apoptotic death. When DNA is damaged,
the p53 protein accumulates in cells. It first arrests the cell cycle (at the G1 phase) to
allow the DNA to be repaired before it is replicated. However, if the damage is too
great to be repaired successfully, p53 triggers apoptosis, mainly by stimulating
sensors that ultimately activate Baxand Bak, and by increasing the synthesis of pro-
apoptotic members of the Bcl-2 family.
•Accumulation of MisfoldedProteins: ER Stress -During normal protein
synthesis, chaperones in the ER control the proper folding of newly synthesized
proteins, and misfoldedpolypeptides are ubiquitinatedand targeted for proteolysis.
If, however, unfolded or misfoldedproteins accumulate in the ER because of
inherited mutations , induce a protective cellular response that is called the unfolded
protein response. This response activates signaling pathways that increase the
production of chaperones and retard protein translation, thus reducing the levels of
misfoldedproteins in the cell. In circumstances in which the accumulation of
misfoldedproteins overwhelms these adaptations, the result is ER stress, which
leads to the activation of caspasesand ultimately apoptosis.

Growth factor
and DNA
damage leading
to apoptosis

Accumulation of Misfolded Proteins: ER
Stress

Apoptosis versus Necrosis comparison chart
Apoptosis Necrosis
Introduction
Apoptosis, or programmed
cell death, is a form of cell
death that is generally
triggered by normal,
healthy processes in the
body.
Necrosis is the premature
death of cells and living
tissue. Though necrosis is
being researched as a
possible form of
programmed cell death, it
is considered an
"unprogrammed" cell
death process at this time.
Natural Yes
Caused by factors external
to the cell or tissue, such
as infection, toxins, or
trauma.
Effects
Usually beneficial. Only
abnormal when cellular
processes that keep the
body in balance cause too
many cell deaths or too
Always detrimental

INTRACELLULAR
ACCUMULATIONS
•Pathways
•Types

•Under some circumstances cells may
accumulate abnormal amounts of various
substances,which may be harmless or
associated with varying degrees of injury.
•The substance may be located in the
cytoplasm, within organelles (typically
lysosomes), or in the nucleus, and it may be
synthesized by the affected cellsor may be
produced elsewhere

•There are four mainpathways of abnormal
intracellular accumulations:
1. Abnormal Metabolism:
Inadequate removal of a normal substance
secondary to defects in mechanisms of packaging
and transport, as in fatty change in the liver
2.Accumulation of an abnormal endogenous
substance as a result of genetic or acquired defects
in its folding, packaging, transport, or secretion,
as with certain mutated forms of α1-antitrypsin
3. Failure to degrade a metabolite due to
inherited enzyme deficiencies. The resulting
disorders are called storage diseases.

•4. Deposition and accumulation of an
abnormal exogenous substance
•when the cell has neither the enzymatic
machinery to degrade the substance nor the
ability to transport it to other sites.
•Accumulation of carbon or silica particles is an
example of this type of alteration.

•Fatty Change (Steatosis): {abnormal metabolism}
•Fatty change refers to any abnormal accumulation of
triglycerides within parenchymal cells.
•It is most often seen in the liver, since this is the major
organ involved in fat metabolism,but it may also occur in
heart, skeletal muscle, kidney, and other organs.
•Steatosismay be caused by toxins, protein malnutrition,
diabetes mellitus, obesity, or anoxia.
•Alcohol abuse and diabetes associated with obesity are the
most common causes of fatty change in the liver (fatty
liver) in industrialized nations.

•Cholesterol and Cholesteryl Esters:
{Exogenous material}
•Cellularcholesterolmetabolismistightly
regulatedtoensurenormalcellmembrane
synthesiswithoutsignificantintracellular
accumulation.
•However,phagocyticcellsmaybecome
overloadedwithlipid(triglycerides,
cholesterol,andcholesterylesters)inseveral
differentpathologicprocesses.

•Proteins: {Exogenous and genetic defect}
Morphologically visible protein
accumulations are much less common than
lipid accumulations; they may occur when
excesses are presented to the cells or if the
cells synthesize excessive amounts.
•Inthekidney,forexample,traceamountsof
albuminfilteredthroughtheglomerulusare
normallyreabsorbedbypinocytosisinthe
proximalconvolutedtubules.

•However, in disorders with heavy protein leakage
across the glomerular filter (e.g., nephrotic
syndrome), there is a much larger reabsorption of
the protein, and vesicles containing this protein
accumulate, giving the histologic appearance of
pink, hyaline cytoplasmic droplets.
•The process is reversible: If the proteinuriaabates,
the protein droplets are metabolized and disappear.
•Another example is the marked accumulation of
newly synthesized immunoglobulins that may occur
in the RER of some plasma cells, forming rounded,
eosinophilic Russell bodies.

•Glycogen: {Lack of enzymes}
•Excessive intracellular deposits of glycogen are
associated with abnormalities in the metabolism
of either glucose or glycogen.
•In poorly controlled diabetes mellitus, the prime
example of abnormal glucose metabolism, glycogen
accumulates in renal tubular epithelium, cardiac
myocytes, and β cells of the islets of Langerhans.
•Glycogen also accumulates within cells in a group
of closely related genetic disorders collectively
referred to as glycogen storage diseases

•Pigments: {exogenous} Pigments are colored
substancesthat are either exogenous,coming from
outside the body, such as carbon, or endogenous,
synthesized within the body itself, such as lipofuscin,
melanin, and certain derivatives of hemoglobin.
The most common exogenous pigment is carbon(an
example is coal dust), a ubiquitous air pollutant of
urban life. When inhaled, it is phagocytosedby
alveolar macrophages and transported through
lymphatic channels to the regional tracheobronchial
lymph nodes.
Aggregates of the pigment blacken the draining
lymph nodes and pulmonary parenchyma
(anthracosis)

•Melanin is an endogenous, brown-black
pigment that is synthesized by
melanocyteslocated in the epidermis and
acts as a screen against harmful
ultraviolet radiation.
•Although melanocytes are the only
source of melanin, adjacent basal
keratinocytes in the skincan
accumulate the pigment (e.g., in
freckles), as can dermal macrophages.

PATHOLOGIC
CALCIFICATION
•DYSTROPHIC CALCIFICATION
•METASTATIC CALCIFICATION

•Pathologic calcification is a common process in a wide
variety of disease states; it implies the abnormal
deposition of calcium salts, together with smaller
amounts of iron, magnesium, and other minerals.
•When the deposition occurs in dead or dying tissues, it
is called dystrophic calcification; it occurs in the
absence of derangements in calcium metabolism (i.e.,
with normal serum levels of calcium).
•In contrast, the deposition of calcium salts in normal
tissuesis known as metastatic calcificationand is
almost always secondary to some derangement in
calcium metabolism (hypercalcemia).

DYSTROPHIC CALCIFICATION:
•Dystrophic calcification is encountered in areas of necrosis
of any type.
•atheromas( degeneration of the walls of arteries caused by
accumulated fatty deposits and scar tissue) of advanced
atherosclerosis, associated with intimal injury in the
aorta and large arteries and characterized by
accumulation of lipids. it may also be a cause of organ
dysfunction.
•For example, calcification can develop in aging or damaged
heart valves, resulting in severely compromised valve
motion.
•Dystrophic calcification of the aortic valves is an
important cause of aortic stenosis in elderly persons.

pathogenesis of dystrophic
calcification
•This involves initiation (or nucleation) and
propagation,both of which may be either
intracellular or extracellular;
•the ultimate end product is the formation of
crystallinecalcium phosphate.
•Initiation in extracellular sites occurs in
membrane bound vesiclesabout 200 nm in
diameter; in normal cartilage and bonethey are
known as matrix vesicles, and in pathologic
calcification they derive from degenerating cells.

•It is thought that calcium is initially concentrated in these
vesicles by its affinity for membrane phospholipids,
while phosphates accumulate as a result of the action of
membrane-bound phosphatases.
•Initiation of intracellular calcificationoccurs in the
mitochondria of dead or dying cellsthat have lost their
ability to regulate intracellular calcium.
•After initiation in either location, propagation of crystal
formationoccurs. This is dependent on the concentration
of Ca2+ and PO4−,the presence of mineral inhibitors,
and the degree of collagenization, which enhances the
rate of crystal growth.

DYSTROPHIC CALCIFICATION

METASTATIC CALCIFICATION
•It can occur in normal tissues whenever there is
hypercalcemia. The major causes of hypercalcemiaare
increased secretion of parathyroid hormone, due to either
primary parathyroid tumors or production of parathyroid
hormone–related protein by other malignant tumors
destruction of bone due to the effects of accelerated
turnover (e.g., Paget disease), immobilization, or tumors
(increased bone catabolism associated with multiple
myeloma, leukemia, or diffuse skeletal metastases)
vitamin D–related disorders including vitamin D
intoxication and sarcoidosis
renal failure, in which phosphate retention leads to
secondary hyperparathyroidism.

MORPHOLOGY
•Regardless of the site, calcium salts are seen on gross examination
as fine white granules or clumps, often felt as gritty deposits.
•Dystrophic calcification is common in areas of caseous necrosisin
tuberculosis. Sometimes a tuberculous lymph node is essentially
converted to radiopaque stone.
•On histologic examination, calcification appears as intracellular
and/or extracellular basophilic deposits.
•Metastatic calcification can occur widely throughout the body but
principally affects the interstitial tissues of the vasculature,
kidneys, lungs, and gastric mucosa.
•The calcium deposits morphologically resemble those described in
dystrophic calcification.
•Extensive calcifications in the lungs may produce respiratory
deficits, and massive deposits in the kidney (nephrocalcinosis) can
lead to renal damage.

CELLULAR ADAPTATIONS OF
GOWTH AND
DIFFERRENTIATION
•Hypertrophy
•Hyperplasia
•Atrophy
•Metaplasia

Cellular Adaptations
•Cellular Adaptations
–Reversible changes in number, size , metabolic
activity and functions ofcells
–Due to
•Physiologic –normal response to stimuli
•Pathologic-modified cellular response

HYPERTROPHY
•Hypertrophyisanincreaseinthesizeofcellsresultinginincrease
inthesizeoftheorgan.
•Inpurehypertrophytherearenonewcells,justbiggercells
containingincreasedamountsofstructuralproteinsand
organelles
•Hypertrophyoccurswhencellshavealimitedcapacitytodivide
•Hypertrophycanbephysiologicorpathologicandiscausedeither
byincreasedfunctionaldemandorbygrowthfactororhormonal
stimulation
•Themassivephysiologicenlargementoftheuterusduring
pregnancyoccursasaconsequenceofestrogenstimulatedsmooth
musclehypertrophyandsmoothmusclehyperplasia

Hypertrophy
•Pathologic–increased functional demand
•An example of pathologic cellular
hypertrophy is the cardiac enlargement that
occurs with hypertension or aortic valve
disease

PHYSIOLOGIC HYPERTROPHY: UTERUS ENLARGEMENT DURING PREGNANCY

Normal Myocytes
Myocytes showing hypertrophy
Pathologic hypertrophy: Cardiac Enlargement
The mechanisms driving cardiac hypertrophy involve at least two types of signals:
mechanical triggers,such as stretch
trophic triggers, which typically are soluble mediators that stimulate cell growth,
such as growth factors and adrenergic hormones.
These stimuli turn on signal transduction pathways that lead to the induction of a
number of genes, which in turn stimulate synthesis of many cellular proteins,
including growth factors and structural proteins.
•If stress is not removed, several “degenerative” changes occur in the myocardial
fibers, of which the most important are fragmentation and loss of myofibrillar
contractile elements
•net result of these changes is ventricular dilation and ultimately cardiac failure, a
sequence of events that illustrates how an adaptation to stress can progress to
functionally significant cell injury if the stress is not relieved

HYPERPLASIA:
•characterized by an increase in cell number because of proliferation of
differentiated cells and replacement by tissue stem cells.
•Hyperplasia is an adaptive response in cells capable of replication
•Hypertrophy and hyperplasia also can occur together, and obviously both
result in an enlarged hypertrophic organ.
Hyperplasia
Physiologic
Hormonal
Compensatory
Pathologic
Hormonal
Growth factor

Hyperplasia –Types
•HORMONAL HYPERPLASIA (Physiologic):Proliferationofthe
glandularepitheliumofthefemalebreastatpubertyandduringpregnancy
•COMPENSATORY HYPERPLASIA (Physiologic):Residualtissue
growsafterremovalorlossofpartofanorgan.
•Forexample,whenpartofaliverisresected,mitoticactivityinthe
remainingcellsbeginsasearlyas12hourslater,eventuallyrestoringthe
livertoitsnormalweight.
•HORMONAL HYPERPLASIA (Pathologic):Disturbedbalance
(imbalance)betweenestrogenandprogesteronecausesendometrial
hyperplasia,whichisacommoncauseofabnormalmenstrualbleeding.
•GROWTH FACTORINDUCEDHYPERPLASIA:eg.Responseof
connectivetissuecellsinwoundhealing,inwhichproliferatingfibroblasts
andbloodvesselsaidinrepair.
•Inthisprocess,growthfactorsareproducedbywhitebloodcells(leukocytes)responding
totheinjuryandbycellsintheextracellularmatrix.

Hyperplasia
•Thehyperplasicprocessremainscontrolled;
ifthesignalsthatinitiateitabate,the
hyperplasiadisappears.
•Incancer,thegrowthcontrolmechanisms
becomedysregulatedorineffective.
•Pathologichyperplasiaconstitutesafertilesoil
inwhichcancersmayeventuallyarise.
•Forexample,patientswithhyperplasiaofthe
endometriumareatincreasedriskof
developingendometrialcancer

ATROPHY
•Shrinkage in the size of the cell by the loss of cell
substance is known as atrophy.
•When a sufficient number of cells are involved, the
entire tissue or organ diminishes in size, becoming
atrophic. Although atrophic cells may have
diminished function, they are not dead.
•CAUSES OF ATROPHY:
Physiologic: loss of innervation, diminished blood
supply, inadequate nutrition, loss of endocrine
stimulation, and aging (senile atrophy)
Pathologic: the loss of hormone stimulation in
menopause , decreased workload, pain

Atrophy
•The mechanisms of atrophy -a combination of
decreased protein synthesis, decreased metabolic
activity and increased protein degradation in cells.
•Protein synthesis decreases because of reduced
metabolic activity.
•The degradation of cellular proteins occurs mainly by
the ubiquitin-proteasome pathway.
•Nutrient deficiency and disuse may activate ubiquitin
ligases, which attach multiple copies of the small
peptide ubiquitin to cellular proteins and target them
for degradation in proteasomes.

Atrophy
•Inmanysituations,atrophyisalso
accompaniedbyincreasedautophagy,with
resultingincreasesinthenumberof
autophagicvacuoles.
•Autophagy(“self-eating”)istheprocessin
whichthestarvedcelleatsitsowncomponents
inanattempttosurvive.

ATROPHY OF BRAIN

METAPLASIA
•Metaplasiaisareversiblechangeinwhichone
adultcelltype(epithelialormesenchymal)is
replacedbyanotheradultcelltype.
•Inthistypeofcellularadaptation,acelltype
sensitivetoaparticularstressisreplacedby
anothercelltypebetterabletowithstandthe
adverseenvironment

Metaplasia
•Inhabitualcigarettesmokers:Thenormalciliated
columnarepithelialcellsofthetracheaandbronchi
arefocallyorwidelyreplacedbystratifiedsquamous
epithelialcells.
•Theruggedstratifiedsquamousepitheliummaybe
abletosurvivethenoxiouschemicalsincigarette
smokethatthemorefragilespecializedepithelium
wouldnottolerate.
•Althoughthemetaplasticsquamousepitheliumhas
survivaladvantages,importantprotective
mechanismsarelost,suchasmucussecretionand
ciliaryclearanceofparticulatematter.

Metaplasia
•Moreover,theinfluencesthatinducemetaplastic
change,ifpersistent,maypredisposetomalignant
transformationoftheepithelium.
•Itisthoughtthatcigarettesmokinginitiallycauses
squamousmetaplasia,andcancersariselaterin
someofthesealteredfoci.
•SincevitaminAisessentialfornormalepithelial
differentiation,itsdeficiencymayalsoinduce
squamousmetaplasiaintherespiratoryepithelium.

METAPLASIA

INFLAMMATION
•Causes
•Acute Inflammation
•Chronic inflammation

Inflammation
Definition:
•Inflammation is a local response (reaction) of living vasculaized tissues
to endogenous and 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.

•CAUSES OF INFLAMMATION:
•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…

CLASSIFICATION
Inflammation
Acute
Inflammation
Chronic
Inflammation

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.
•The Vascular response has the following steps:
Immediate (momentary) vasoconstrictionin seconds due to neurogenic or
chemical stimuli. Vasodilatation of arterioles and venules resulting in increased
blood flow.
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.

•Cellular response
•The cellular response has the following stages:
•A. Migration, rolling, pavementing, & adhesion of leukocytes
•B. Transmigration of leukocytes
•C. Chemotaxis
•D. Phagocytosis
•Migration, rolling, pavementing, and adhesion of leukocytes
Marginationis a peripheral positioning of white cells along the endothelial
cells.
Subsequently, rows of leukocytes tumble slowly along the endothelium in
a process known as rolling
In time, the endothelium can be virtually lined by white cells. This
appearance is called pavementing
Thereafter, the binding of leukocytes with endothelial cells is facilitated by
cell adhesion molecules such as selectins, immunoglobulins, integrins, etc
which result in adhesion of leukocytes with the endothelium.

•Transmigration of leukocytes:
Leukocytes escape from venulesand small veins but only occasionally from
capillaries. The movement of leukocytes by extending pseudopodiathrough
the vascular wall occurs by a process called diapedesis.
The most important mechanism of leukocyte emigration is via widening of
interendothelialjunctions after endothelial cells contractions.The basement
membrane is disrupted and resealed thereafter immediately.
•Chemotaxis:
A unidirectional attraction of leukocytes from vascular channels towards the site
of inflammation within the tissue space guided by chemical gradients (including
bacteria and cellular debris) is called chemotaxis.
The most important chemotacticfactors for neutrophilsare components of the
complement system (C5a), bacterial and mitochondrial products of
arachidonicacid metabolism such as leukotrieneB4 and cytokines (IL-8).
All granulocytes, monocytesand to lesser extent lymphocytes respond to
chemotacticstimuli.
How do leukocytes "see" or "smell" the chemotacticagent? This is because
receptors on cell membrane of the leukocytes react with the
chemoattractantsresulting in the activation of phospholipaseC that
ultimately leads to release of cytocoliccalcium ions and these ions trigger
cell movement towards the stimulus.

•Phagocytosis:
•Phagocytosisis the process of engulfment and internalization by
specialized cells of particulate material, which includes invading
microorganisms, damaged cells, and tissue debris.
•These phagocyticcells include polymorphonuclearleukocytes (particularly
neutrophiles), monocytesand tissue macrophages.
•Phagocytosisinvolves three distinct but interrelated steps:
Recognition and attachment of the particle to be ingested by the
leukocytes: Phagocytosisis enhanced if the material to be phagocytosedis
coated with certain plasma proteins called opsonins. These opsonins
promote the adhesion between the particulate material and the phagocyte’s
cell membrane.
Engulfment: During engulfment, extension of the cytoplasm (pseudopods)
flow around the object to be engulfed, eventually resulting in complete
enclosure of the particle within the phagosomecreated by the cytoplasmic
membrane of the phagocyticcell. As a result of fusion between the
phagosomeand lysosome, a phagolysosomeis formedand the engulfed
particle is exposed to the degradative lysosomalenzymes.
Killing or degradation: The ultimate step in phagocytosisof bacteria is
killing and degradation.

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 meditors of inflammation can be derived from plasma or cells.
Plasma-derived mediators:
Complement activation
increases vascular permeability (C3a,C5a)
activates chemotaxis (C5a)
opsoninization (C3b,C3bi)
Factor XII (Hegman factor) activation
Its activation results in recruitment of four systems: the kinin, the clotting, the
fibrinolytic and the compliment systems.
Cell-derived chemical mediatos:
•Cell-derived chemical mediators include: Histamine, Serotonine, lysozomal
enzymes, Cytokines

MORPHOLOGY OF ACUTE INFLAMMATION
•Characteristically, the acute inflammatory response involves production of
exudates: An exudateis an edema fluid with high protein concentration, which
frequently contains inflammatory cells.
•A transudateis simply a non-inflammatory edemacaused by cardiac, renal,
undernutritional, & other disorders.
•There are different morphologic types of acute inflammation:
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.
Fibrinousinflammation
•More severe injuries result in greater vascular permeability that ultimately leads to
exudation of larger molecules such as fibrinogens through the vascular barrier.
•Fibrinousexudateis 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.

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 suppurative inflammation:
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).

Catarrhal inflammation
•This is a mild and 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.

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 lymphaics 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 intracranialpressure.
Inappropriate response: The inflammatory seen in hypersensitivity
reactions is inappropriate (i.e. exaggerated).

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 shallt ( you shold ) 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 Septicemiaor 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 etc characteristically cause chronic inflammation.
•These organisms are of low toxicity and evoke delayed hypersensitivity reactions.
2. Prolonged exposure
•to nondegradable 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:
• Persistent suppuration as a result of uncollapsed abscess cavities, foreign body
materials (dirt, cloth, wool, etc), sequesterum in osteomylitis, or a sinus/fistula
from chronic abscesses.
4. Autoimmuniy. Autoimmune diseases such as rheumatoid arthritis and systemic
lupus erythematosis are chronic inflammations from the outset.

MORPHOLOGY:
•Cells Of Chronic Inflammation:
•Monocytesand Macrophagesare 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
(Kupffercells), spleen, lymph nodes (sinus histiocytes), lungs (alviolar
macrophages), bone marrow, brain (microglia), skin (Langerhan’scells), etc….
These cells constitute the mononuclear-phagocyticsystem.
•Macrophages are scavenger cells of the body
•Other cells in chronic inflammation:
T-Lymphocytes are primarily involved in cellular immunity with lymphokine
production, and they are the key regulator and effectorcells of the immune system.
B-lymphocytes and Plasma cells produce antibody directed either against
persistent antigen in the inflammatory site or against altered tissue components.
Mast cells and eosinophilsappear predominantly in response to parasitic
infestations & allergic reactions.

Chronic
Inflammation
Non Specific Specific

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.

SPECIFIC INFLAMMATION (GRANULOMATOUS
INFLAMMATION):
•Definition: Granulomatous inflammation is characterized by the presence
of granuloma.
•A granulomais a microscopic aggregate of epithelioid cells.
•Epithelioid cell is an activated macrophage, with a modified epithelial cell-
like appearance (hence the name epithelioid).
•The epithelioid cells can fuse with each other & form multinucleated giant
cells.
•There are two types of giant cells:
Foreign body-type giant cells which have irregularly scattered nuclei in
presence of indigestible materials.
Langhans giant cells in which the nuclei are arranged peripherally in a
horse –shoe pattern which is seen typically in tuberculosis, sarcoidosis
etc… Giant cells are formed by fusion of macrophages perhaps by a
concerted attempt of two or more cells to engulf a single particle.

•SYSTEMIC EFFECTS OF INFLAMMATIONS
•The systemic effects of inflammation include:
Fever
Endocrine & metabolic responses
Autonomic responses
Behavioral responses
Leukocytosis
Leukopenia
Weight loss

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.
Endocrine and metabolic responses include:
The liver secrets acute phase proteins such as:
C-reactive proteins
Serum Amyloid A
Complement and coagulation proteins
Glucocorticoids (increased)
Vasopressin (decreased)
Autonomic responses include:
Redirection of blood flow from the cutaneous to the deep vascular bed.
Pulse rate and blood pressure (increased)
Sweating (decreased)

Endocrine and metabolic responses include:
The liver secrets acute phase proteins such as:
C-reactive proteins
Serum Amyloid A
Complement and coagulation proteins
Glucocorticoids (increased)
Vasopressin (decreased)
Autonomic responses include:
Redirection of blood flow from the cutaneous to the deep vascular bed.
Pulse rate and blood pressure (increased)
Sweating (decreased)

REPAIR AND
HEALING PROCESS
•Introduction
•Repair process
•Molecular control of healing process
•Factors influencing wound healing
•Abnormalities in wound healing

Definition of healing
•The word healing, used in a pathological context,
refers to the body’s replacement of destroyed tissue
by living tissue.
Processes of healing
•The healing process involves two distinct processes:
Regeneration-Replacement of lost tissue by
tissues similar in type
Repair(healing by scaring), the replacement of lost
tissue by granulation tissuewhich matures to form
scar tissue. Healing by fibrosis is inevitable when the
surrounding specialized cells do not possess the
capacity to proliferate.
Healing

Healing

•Whether healing takes place by regeneration or by repair
(scarring) is determined partly by the type of cellsin the
damaged organ & partly by the destruction or the
intactness of the stromal frame work of the organ.
Types of cells
•Based on their proliferative capacity there are three
types of cells.
Labile cells
•These are cells which have a continuous turn over by
programmed division of stem cells.
•They are found in the surface epithelium of the gastro
intestinal tract, urinary tract or the skin.
•Examples of labile cells: The cells of lymphoid and
haemopoietic systems .The chances of regeneration are
excellent.

Stable cells
•Tissues which have such type of cells have
normally a much lower level of replication and
there are few stem cells.
•However, the cells of such tissues can undergo
rapid division in response to injury.
•For example, mesenchymal cells such as smooth
muscle cells, fibroblasts, osteoblasts and
endothelial cells are stable cells which can
proliferate.
•Liver, endocrine glands and renal tubular
epithelium has also such type of cells which can
regenerate. Their chances of regeneration are good.

3. Permanent cells
•These are non-dividing cells.
•If lost, permanent cells cannot be replaced,
because they don’t not have the capacity to
proliferate.
•For example: adult neurons, striated muscle
cells, and cells of the lens.

REPAIR (HEALING BY CONNECTIVE TISSUE)
•Definition:-Repair is the orderly process by which lost
tissue is eventually replaced by a scar.
•A wound in which only the lining epithelium is affected
heals exclusively by regeneration.
•In contrast, wounds that extend through the basement
membrane to the connective tissue,for example, the
dermis in the skin or the sub-mucosa in the
gastrointestinal tract, lead to the formation of granulation
tissue and eventual scarring.
•Tissues containing terminally differentiated (permanent)
cellssuch as neurons and skeletal muscle cells cannot
heal by regeneration.
•Rather the lost permanent cells are replaced by
formation of granulation tissue.

In granulation-tissue (Scar) formation, three phasesmay be
observed.
1. Phase of inflammation
At this phase,inflammatory exudatecontaining
polymorphs is seenin the area of tissue injury.
In addition, there is platelet aggregation and fibrin
deposition.
2. Phase of demolition
The dead cells liberate their autolytic enzymes, and other
enzymes (proteolytic) come from disintegrating
polymorphs.
There is an associated macrophage infiltration.These cells
ingest particulate matter, either digesting or removing it.
REPAIR (HEALING BY CONNECTIVE TISSUE)

REPAIR (HEALING BY CONNECTIVE TISSUE)
3. Ingrowth of granulation tissue
This is characterized by proliferation of
fibroblasts and an ingrowth of new blood
vessels into the area of injury, with a variable
number of inflammatory cells
Fibroblasts actively synthesize and secrete
extra-cellular matrix components, including
fibronectin, proteoglycans, and collagen types
I and III.

REPAIR (HEALING BY CONNECTIVE TISSUE)
•The fibronectin and proteoglycans form the
‘scaffolding’ for rebuilding of the matrix.
•Fibronectin binds to fibrin and acts as a
chemotactic factor for the recruitment of more
fibroblasts and macrophages.
•The synthesis of collagen by fibroblasts begins
within 24 hours of the injuryalthough its
deposition in the tissue is not apparent until 4 days.

REPAIR (HEALING BY CONNECTIVE TISSUE)
•By day 5, collagen type III is the predominant
matrix protein being produced; but by day 7 to
8, collagen type I is prominent, and it
eventuallybecomes the major collagen of
mature scar tissue.
•Despite an increased collagenase activity in
the wound (responsible for removal of built
collagen), collagen accumulates at a steady
rate, usually reaching a maximum 2 to 3
months after the injury.

REPAIR (HEALING BY
CONNECTIVE TISSUE)
•The tensile strength of the healed wound
continues to increase many months after the
collagen content has reached a maximum.
•As the collagen content of the wound
increases, many of the newly formed vessels
disappear.
•This vascular involution which takes place in
a few weeks, dramatically transforms a richly
vascularized tissue in to a pale, avascular
scar tissue.

WOUND CONTRACTION
•Woundcontractionisamechanicalreductioninthesizeofthe
defect.Thewoundisreducedapproximatelyby70-80%ofits
originalsize.
•Contractionresultsinmuchfasterhealing,sinceonlyone-
quartertoone-thirdoftheamountofdestroyedtissuehasto
bereplaced.
•Ifcontractionisprevented,healingisslowandalargeugly
scarisformed.
Causesofcontraction
•Itissaidtobeduetocontractionbymyofibroblasts.
•Myofibroblastshavethefeaturesintermediatebetweenthoseof
fibroblastsandsmoothmusclecells.
•Twotothreedaysaftertheinjury,myofibroblastsmigrateinto
thewoundandtheiractivecontractiondecreasethesizeofthe
defect.

MOLECULAR CONTROL OF HEALING PROCESS:
mediated bya series of low molecular weight polypeptides
referred to as growth factors.
Sources of Growth Factors:
Following injury, growth factors may be derived from
1. Platelets, activated after endothelial damage,
2. Damaged epithelial cells,
3. Circulating serum growth factors,
4. Macrophages, or
5. Lymphocytes recruited to the area of injury
The healing process ceases when lost tissue has been replaced

FACTORS THAT INFLUENCE WOUND HEALING
•A number of factors can alter the rate and efficiency of
healing. These can be classified into those which act
locally, and those which have systemic effects.
LOCAL FACTORS
1.Type, size, and location of the wound
•A clean, aseptic wound produced by the surgeon’s scalpel
heals faster than a wound produced by blunt trauma,
which exhibits abundant necrosis and irregular edges.
•Small blunt wounds heal faster than larger ones.
•Injuries in richly vascularized areas (e.g., the face) heal
faster than those in poorly vascularized ones (e.g., the
foot).

FACTORS THAT INFLUENCE WOUND
HEALING
•In areas where the skin adheres to bony
surfaces, as in injuries over the tibia, wound
contraction and adequate apposition of the
edges are difficult.Hence, such wounds heal
slowly.
2.VASCULAR SUPPLY
•Wounds with impaired blood supply heal
slowly. For example, the healing of leg wounds in
patients with varicose veins is prolonged.

•Ischemia due to pressure produces bed
sores and then prevents their healing.
•Ischemia due to arterial obstruction,often in
the lower extremities of diabetics, also
prevents healing.
3.INFECTION
•Wounds provide a portal of entry for
microorganisms.Infection delays or
prevents healing, promotes the formation of
excessive granulation tissue (proud flesh),
and may result in large, deforming scars.

4. MOVEMENT
•Early motion, particularly before tensile strength has
been established,subjects a wound to persistent trauma,
thus preventing or retarding healing.
5. IONIZING RADIATION
•Prior irradiation leaves vascular lesions that interfere
with blood supply and result in slow wound healing.
•Acutely, irradiation of a wound blocks cell proliferation,
inhibits contraction, and retards the formation of
granulation tissue.

SYSTEMIC FACTORS
1. CIRCULATORY STATUS
•determines the blood supply to the injured area
•Poor healing attributed toold age is often due, largely,
to impaired circulation.
2. INFECTION
•Systemic infections delay wound healing.
3. METABOLIC STATUS
•Poorly controlled diabetes mellitus
•In diabetic patients, there can be impaired circulation
secondary to arteriosclerosis and impaired sensation
due to diabetic neuropathy.

SYSTEMIC FACTORS
4. NUTRITIONAL DEFICIENCIES
PROTEIN DEFICIENCY
•In protein depletion there is an impairment of
granulation tissue and collagen formation, resulting in
a great delay in wound healing.
VITAMIN DEFICIENCY
•Vitamin Cis required in hydroxylation of proline and
lysine in the process of collagen synthesisand
secretion.
•Vitamin C deficiency (scurvy) results in grossly
deficient wound healing, with a lack of vascular
proliferation and collagen deposition.

TRACE ELEMENT DEFICIENCY
•Zinc (a co-factor of several enzymes) deficiency
will retard healing by preventing cell
proliferation.
•Zinc is necessary in several DNA and RNA
polymerases and transferases; hence, a deficiency
state will inhibit mitosis.
•Proliferation of fibroblasts (fibroplasia) is,
therefore, retarded.

SYSTEMIC FACTORS
HORMONES
•Corticosteroids impair wound healing, an effect
attributed to an inhibition of collagen synthesis.
•However, these hormones have many other effects,
including anti-inflammatory actions and a
general depression of protein synthesis.
•It also inhibits fibroplasia and neovascularization.
•Both epithelialization and contraction are impaired.
It is, therefore, difficult to attribute their inhibition
of wound healing to any one specific mechanism.

•ABNORMALITIES in any of the three basic healing
processes –contraction, repair, and regeneration –result
in the complications of WOUND HEALING.
INFECTION
•A wound may provide the portal of entry for many
organisms.Infection may delay healing,and if severe
stop it completely.
DEFICIENT SCAR FORMATION
•Inadequate formation of granulation tissue or an
inability to form a suitable extracellular matrix leads
to deficient scar formation and its complications.
•The complications of deficient scar formation are:
–a. Wound dehiscence & incisionalhernias
–b. Ulceration

Complications of WOUND HEALING.
a. Wound Dehiscence and Incisional Hernias:
•Dehiscence (bursting of a wound) is of most concern
after abdominal surgery.
•If insufficient extracellular matrix is deposited or there
is inadequate cross-linking of the matrix, weak scars
result.
•Inappropriate suture material and poor surgical
techiniques are important factors. Also age , diabetes
and obesity and trauma to wound after surgery.
•Wound infection, increased mechanical stress on the
wound from vomiting, coughing, or ileusis a factor in
most cases of abdominal dehiscence.

•ULCERATION:
•Wounds ulcerate because of an inadequate
intrinsic blood supply or insufficient
vascularization during healing.
•For example, leg wounds in persons with varicose
veins or severe atherosclerosis typically ulcerate.
•Non healing wounds also develop in areas devoid of
sensation because of persistent trauma.

EXCESSIVE( Hypertrophic) 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 scartissue called
keloid.
•It is an exuberant scar that
tends to progress and recur
after excision.The cause of
this is unknown.
Genetic predisposition, repeated trauma, and irritation caused
by foreign body, hair, keratin, etc., may play a part.
It is especially frequent after burns. It is common in areas of the
neck & in the ear lobes

HYPERTROPHIC SCAR
•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.

EXCESSIVE CONTRACTION
•A decrease in the size of a wounddepends on the
presence of myofibroblasts, development of cell-
cell contacts and sustained cell contraction.
•An exaggeration of these processes is termed
contracture (cicatrisation) and results in severe
deformity of the wound and surrounding tissues.
•Contracture (cicatrisation) is also said to arise as a
result of late reduction in the size of the wound.
•Interestingly, the regions that normally show
minimal wound contraction (such as the palms,
the soles, and the anterior aspect of the thorax)
are the ones prone to contractures.

•Contracturesareparticularlyconspicuousinthehealing
ofseriousburns.
•Contracturesoftheskinandunderlyingconnective
tissuecanbesevereenoughtocompromisethe
movementofjoints.
•Cicatrisationisalsoimportantinhollowviscerasuchas
urethra,esophagus,andintestine.
•Itleadstoprogressivestenosiswithstricture
formation.
•Inthealimentarytract,acontracture(stricture)can
resultinanobstructiontothepassageoffoodinthe
esophagusorablockintheflowofintestinalcontents.

FRACTURE HEALING
•The basic processes involved in the healing of bone
fractures bear many resemblances to those seen in
skin wound healing.
•Unlike healing of a skin wound, however,
the defect caused by a fracture is repaired
not by a fibrous “scar” tissue, but by
specialized bone forming tissueso that,
under favorable circumstances, the bone is
restored nearly to normal

STRUCTURE OF BONE
•Bone is composed of calcified osteoid tissue,
which consists of collagen fibers embedded in a
mucoprotein matrix (osteomucin).
•Depending on the arrangement of the collagen
fibers, there are two histological types of bone:
1. Woven, immature or non-lamellar bone
•This shows irregularity in the arrangement of the
collagen bundles and in the distribution of the
osteocytes. The osteomucin is less abundant and it
also contains less calcium.

2. Lamellar or adult bone
•In this type of bone, the collagen bundles are
arranged in parallel sheets.

STAGES IN FRACTURE HEALING (BONE
REGENERATION)
PHASE 1: Reactive Phase
STAGE 1: HAEMATOMA FORMATION
Immediately following the injury,there is a presence of
blood cells within the tissues adjacent to the injury site.
Soon after fracture,the blood vessels constrict, stopping
any further bleeding.
Within a few hours after fracture,the extravascular blood
cells form a blood clot, known as a hematoma.
All the cells within the blood clot degenerate and die.
Some of the cells outside the blood clot, but adjacent to
the injury site , also degenerate and die.

STAGE 2: INFLAMMATION
•The tissue damage excites an inflammatory
response, the exudate adding more fibrin to the clot
already present.
•There is an increased blood flow and a PMNL
infiltration. The haematoma attains a fusiform
shape.
STAGE 3: DEMOLITION
•Macrophages invade the clot and remove the fibrin,
red cells, the inflammatory exudate, and debris.
•Any fragments of bone, which have become detached
from their blood supply, undergo necrosis, and are
attacked by macrophages and osteoclasts.

STAGES IN FRACTURE HEALING
STAGE 4: FORMATION OF GRANULATION TISSUE
•Following this phase of demolition, Within this same area,
capillary loops and mesenchymal cells ((fibroblasts)
derived from the periosteum and the endosteum of the
cancellous bone ) survive and replicate.
•These cells have osteogenic potential and together with the
newly formed blood vessels contribute to the granulation –
tissue formation.

STAGES IN FRACTURE HEALING (BONE
REGENERATION)
•STAGE 5: WOVEN BONE AND CARTILAGE
FORMATION.
•Days after fracture, the cells of the periosteum
replicate and transform.
•The periosteal cells proximal to the fracture gap
develop into chondroblasts which form hyaline
cartilage.
•The periosteal cells distal to the fracture gap
develop into osteoblasts .

•The mesenchymal “osteoblasts” next
differentiate to form either woven bone or
cartilage.
•The fibroblasts within the granulation tissue
develop into chondroblasts which also form
hyaline cartilage.
•These two new tissues grow in size until they
unite with their counter parts from other parts
of the fracture.

•These processes culminate in a new mass of
heterogeneous tissue which is known as the
fracture callus.
•The term “callus”, ( Latin -meaning hard), is
often used to describe the material uniting the
fracture ends regardless of its consistency.
•When this is in granulation tissue formation, the
“callus” is soft, but as bone or cartilage
formation occurs, it becomes hard.
•Eventually, the fracture gap is bridged by the
hyaline cartilage and woven bone , restoring
some of its original strength

STAGES IN FRACTURE HEALING (BONE
REGENERATION)
STAGE 6: FORMATION OF LAMELLAR BONE
•The next phase is the replacement of the hyaline cartilage
and woven bone with lamellar bone.
•The replacement process is known as endochondral
ossificationwith respect to the hyaline cartilage and bony
substitution with respect to the woven bone.
•Substitution of the woven bone with lamellar bone precedes
the substitution of the hyaline cartilage with lamellar bone.
•The lamellar bone begins forming soon after the collagen
matrix of either tissue becomes mineralized.

•At this point, the mineralized matrix is
penetrated by channels, each containing a
microvessel and numerous osteoblasts.
•The osteoblasts form new lamellar bone upon
the recently exposed surface of the mineralized
matrix. This new lamellar bone is in the form of
trabecular bone.
•Eventually, all of the woven bone and cartilage
of the original fracture callus is replaced by
trabecular bone, restoring most of the bone's
original strength.

STAGES IN FRACTURE HEALING (BONE
REGENERATION)
STAGE 7: REMODELLING
•The remodeling process substitutes the trabecular
bone with compact bone. The trabecular bone is first
resorbed by osteoclasts, creating a shallow resorption
pit known as a "Howship's lacuna".
•Then osteoblasts deposit compact bone within the
resorption pit.
•Eventually, the fracture callus is remodelled into a new
shape which closely duplicates the bone's original
shape and strength.
•The remodeling phase takes 3 to 5 years depending on
factors such as age or general condition.

NEOPLASIA

DEFINITION:
Neoplasia means new growthand technically, it is
defined as abnormal mass of, the growth of which
exceeds and persists in the same excessive manner
after cessation of the stimulus, evoking the
transformation.
NOMENCLATURE: Neoplasms are named based
upon two factors
On the histologic types : mesenchymal and epithelial
On behavioral patterns : benign and malignant
neoplasms

•The suffix -oma denotes a benign neoplasm.
•BENIGN MESENCHYMAL NEOPLASMS
•Originating from muscle, bone, fat, blood vessel, nerve,
fibrous tissue and cartilages are named as
Rhabdomyoma, osteoma, lipoma, hemangioma,
neuroma, fibroma and chondroma respectively.
•BENIGN EPITHELIAL NEOPLASMS are classified
on the basis of cell of origin
•For example : adenomais the term for benign epithelial
neoplasm that form glandular pattern. (eg: thyroid,
breast).
•Outward projection of benign epithelial tumor is called
as papilloma. (warts caused by human papilloma virus.)

•MALIGNANT NEOPLASMS
•arising from MESENCHYMA l tissues are called
sarcomas(Greek sar =fleshy). Thus, it is a fleshy tumour.
•These neoplasms are named as fibrosarcoma, liposarcoma,
osteosarcoma, hemangiosarcoma etc.
•MALIGNANT NEOPLASMS OF EPITHELIAL cell
origin derived from any of the three germ layers are called
carcinomas.
Ectodermalorigin: skin , epidermis squamous cell
carcinoma, basal cell carcinoma
Mesodermalorigin: renal tubules (renal cell carcinoma)
Endodermalorigin: linings of the gastrointestinal tract
(colonic carcinoma)

CHARACTERISTICS OF BENIGN
AND MALIGNANT NEOPLASMS
•1. Differentiation & anaplasia
•2. Rate of growth
•3. Local invasion
•4. Metastasis

1. DIFFERENTIATION AND ANAPLASIA
•Differentiation refers to the extent to which
parenchymal cells resemble comparable normal
cells both morphologically and functionally.
•Thus, well-differentiated tumors cells resemble mature
normal cellsof tissue of origin.
•Poorly differentiated or undifferentiated tumors have
primitive appearing, unspecialized cells.
•In general,benign neoplasms are well differentiated.
Malignant neoplasms in contrast, range from well
differentiated, moderately differentiated to poorly
differentiate types.
•Malignant neoplasm composed of undifferentiated
cells are said to be anaplastic,

•Morphology of anaplastic cell :
•literally anaplasia means to form backward.-
dedifferentiation ,loss of structural and functional
differentiation of normal cells.
•Includes large Pleomorphic; hyperchromatic
nucleus with highnuclear cytoplasmic ratio 1:1
(normally 1:4 to 1:6).
•The cell usually reveals large nucleoli with high and
often abnormal mitoses.
•Tumour giant cells and frequent loss of polarity of
epithelial arrangementsare encountered.
•The more rapidly growing and the more anaplastic a
tumor, the less likely it is to have specialized
functional activity.

RATE OF GROWTH
•Most benign tumours grow slowly whereas; most
malignant tumours grow rapidly sometimes, at erratic
pace.
•Some benign tumours for example uterine leiomyoma
increase in size during pregnancy due to probably
steroidal effects (estrogen) and regress in menopause.
•In general, the growth rate of neoplasms correlate
with their level of differentiation and thus, most
malignant neoplasms grow more rapidly than do
benign neoplasms.

LOCAL INVASION
•Nearly all benign neoplasms grow as cohesive expansile masses that remains
localized to their site of origin and do not have the capacity to invade or
metastasize to distant sites, as do malignant neoplasms.
•Rims of fibrous capsules encapsulate most benign neoplasms.
•Thus, such encapsulations tend to contain the benign neoplasms as a discrete,
rapidly palpable and easily movable mass that can easily surgically
enucleated.

•The growth of malignant neoplasms is accompanied by progressive infiltration,
invasion and destruction of the surrounding tissue.
•Generally, they are poorly demarcated from the surrounding normal tissue
•Next to the development of metastasis, invasiveness is the most reliable feature
that differentiates malignant from benign neoplasms.
•Even though, malignant neoplasms can invade all tissues in the body, connective
tissues are the favoured invasive path for most malignant neoplasms, due to the
elaboration of some enzymes such as type IV collagnases & plasmin, which is
specific to collagen of basement membrane.
•Several matrix-degrading enzymes including glycosidase may be associated with
tumour invasion.
•Arteries are much more resistant to invasion than are veins and lymphatic
channels due to its increased elastic fibers contents and its thickened wall.

•SEQUENTIAL STEPS IN MECHANISMS OF TUMOR INVASION &
METASTASIS:
Carcinoma in-situ
Malignant cell surface receptors bind to basement membrane components
(eg.laminin).
Malignant cell disrupt and invade basement membrane by releasing
collagenase type IV and other protease.
Invasion of the extracellular matrix
Detachment
Embolization
Survival in the circulation
Arrest
Extravasation
Evasion of host defense
Progressive growth
Metastasis

METASTASIS
•It is defined as a transfer of malignant cells from one site to another not directly
connected with it (as it is described in the above steps).
•Metastasis is the most reliable sign of malignancy. The invasiveness of cancers
permits them to penetrate in to the blood vessel, lymphatic and body cavities
providing the opportunity for spread.
•Most malignant neoplasm metastasies except few such as gliomas in the central
nervous system, basal cell carcinoma (Rodent ulcer) in the skin and
dermatofibrosarcoma in soft tissues.
•Organs least favoured for metastatic spread include striated muscles and
spleen.
•Since the pattern of metastasis is unpredictable, no judgment can be made about
the possibility of metastasis from pathologic examination of the primary
tumour.
•Approximately 30% of newly diagnosed patients with solid tumours (excluding
skin cancers other than melanoma) present with metastasis in the studied
populations.

•PATHWAYS OF SPREAD:
•Dissemination of malignant neoplasm may occur through one of the following
pathways.
SEEDING OF BODY CAVITIES AND SURFACES (TRANSCOELOMIC
SPREAD)
•This seeding may occur wherever a malignant neoplasm penetrates into a
natural “open field”.
•Most often involved is the peritoneal cavity, but any other cavities such as
pleural, pericardial, sub-arachnoid and joint spaces-may be affected.
•Particular examples are krukenberg tumour that is a classical example of mucin
producing signet ring adenocarcinomas arising from gastrointestinal tract,
pancreas, breast, and gall bladder may spread to one or both ovaries and the
peritoneal cavities.
•The other example is pseudomyxoma peritoni which are mucus secreting
adrocarcinoma arising either from ovary or appendix.
•These carcinomas fill the peritoneal cavity with a gelatinous soft, translucent
neoplastic mass.
•It can also be associated with primaries in the gallbladder and pancreas.

•LYMPHATIC SPREAD
•Lymphatic route is the most common pathway for the initial dissemination of
carcinomas
•The pattern of lymph node involvement follows the natural routes of
drainage.
•Lymph nodes involvement in cancers is in direct proportion to the number of
tumour cell reaching the nodes.
•Metastasis to lymph nodes first lodge in the marginal sinus and then extends
throughout the node.
•The cut surface of this enlarged lymph node usually resembles that of the
primary tumour in colour and consistency.
•The best examples of lymphatic spread of malignant neoplasm can be
exemplified by breast carcinoma.

HEMATOGENOUS SPREAD
•Lung & liver are common sites of metastasis because they receive the
systemic and venous out flow respectively.
•Other major sites of hematogenous spread include brain and bones.
•In the circulation, tumour cells form emboli by aggregation and by adhering
to circulating, leukocytes particularly platelets.
•The site where tumour cell emboli lodge and produce secondary growth is
influenced by:
Vascular (and lymphatic) drainage from the site of the primary tumour
Interaction of tumour cells with organ specific receptors
The microenvironment of the organ or site, example a tissue rich in protease
inhibitors might be resistant to penetration by tumour cells.

•CANCER EPIDEMIOLOGY
•Geographic factors (geographic pathology):
Specific differences in incidence rates of cancers are seen worldwide.For
example,
Stomach carcinoma -Japan
Lung cancer -USA
Skin cancer -New zeland & Australia
Liver cancer -Ethiopia
•Environmental factors (occupational hazards) include:
Asbestos-----Lung cancer, mesothelioma,esophagus and, stomach
carcinomas;
Vinyl chloride----Angiosarcoma of liver
Benzene ---Leukemias
Cigarette smoking-----Brochogenic carcinomas
Venereal infection --Cervical carcinoma

PREMALIGNANT DISORDERS
•Heredity premalignant disorders
•Inherited predisposition to cancer is categorized in to three groups:
•i. Inherited cancer syndromes (Autosomal dominant) with strong familial
history include
•-Familial retinoblastomas usually bilateral, and a second cancer risk
particularly , osteogenic sarcoma.
•Oncosupressor gene is the basis for this carcinogenesis
•Familial adenomatous polyps of the colon. virtually all cases are fatal to
develop carcinoma of the colon by the age of 50.
•ii. Familial cancers:
•Evidence of familial clustering of cancer are documented
•E.g. Breast, ovarian, colonic, and brain cancers
•iii. Autosmal recessive syndromes of defective DNA repair Characterized
by chromosomal or DNA instability syndrome such as xeroderma
pigmentosium.

RETINOBLASTOMA
XERODERMA
PIGMENTOSIUM .

ACQUIRED PRENEOPLASTIC DISORDERS
•Regenerative, hyperplasic and dysplastic proliferations are fertile soil
for the origin of malignant neoplasms.
Endometrial hyperplasia -endometrial carcinoma
Cervical dysplasia -cervical cancer
Bronchial dysplasia -bronchogenic carcinoma
Regenerative nodules -liver cancer
•Certain non-neoplastic disorders may predispose to cancers.
Chronic atrophic gastritis -gastric cancer
Solar keratosis of skin -skin cancer
Chronic ulcerative colitis -colonic cancer
Leukoplakia of the oral cavity, vulva and penis -squamous cell carcinoma
•Certain types of benign neoplasms
•Large cumulative experiences indicate that most benign neoplasms do not
become malignant. However, some benign neoplasms can constitute
premalignant conditions.
•For example: Villous colonic adenoma -Colonic cancer

MOLECULAR BASIS OF CANCER (CARCINOGENESIS)
•BASIC PRINCIPLES OF CARCINOGENESIS:
The fundamental principles in carcinogenesis include
1) Non-lethal genetic damage lies at the heart of carcinogenesis. Such genetic
damage (mutation) may be acquired by the action of environmental agents such
as chemicals, radiation or viruses or it may be inherited in the germ line.
•2) The three classes of normal regulatory genes are:
The growth promoting proto-oncogenes
•Activation of proto-oncogenes activation gives rise to oncogenes (cancer
causing genes).
•Proto -oncogenes are activated by
-Point mutation
-Chromosomal rearrangements ranslocation Inversion
-Gene amplification
Cancer suppressor genes (anti oncogenes)
Its physiologic role is to regulate cell growth however, the inactivation of cancer
suppressor genes is the key event in cancer genesis
Examples of tumour suppressor genes include-Rb, P53, APC and NF-1&2 genes

Genes that regulate apoptosis
•Genes that prevent or induce programmed cell death are also important
variables in the cancer equation.
•These genes include bcl-2 that inhibits apoptosis whereas, others such as
bax. Bad, and bcl-x5 favour programmed cell death.
•Genes that regulate apoptosis may be dominant as are protooncogenes or
may behave as cancer suppressor genes (recessive in nature)
Genes that regulate DNA repair
•Inability to DNA repair can predispose to mutations in the genome and
hence, to neoplastic transformations

•Types of carcinogenesis:
•A large number of agents cause genetic damages and induce neoplastic
transformation of cells.
•They fall into the following three categories:
a) Chemical carcinogenesis
b) Radiation carcinogenesis
c) Viral carcinogenesis

•CHEMICAL CARCINOGENESIS
•An enormous variety of chemicals may induce tumours and this was
exemplified by Sir Percival Pott’s observation in the last century that
astutely related the increased incidence of scrotal skin cancer in chimney
sweeps to chronic exposure to soot.

•Steps involved in chemical carcinogenesis
•appropriate dose of a chemical carcinogenic agents to a cell results in the
formation of initiation –promotion sequence
•Initiation causes permanent DNA damage (mutation) which, is rapid and
irreversible.
•However, initiation alone is not sufficient for tumour formation and thus,
promoters can induce tumours in initiated cells, but they are non-
tumourogenic by themselves.
•Furthermore, tumours do not result when a promoting agent applied before,
the initiating agent.
•In contrast to the effects of initiators, the cellular changes resulting from the
application of promoters do not affect DNA directly and are reversible.
•Promoters render cells susceptible to additional mutations by causing cellular
proliferation. Examples of promoters include phorbol ester, hormones,
phenols and drugs.

•Chemical carcinogenic agents fall into two categories
Directly acting compound
•These are ultimate carcinogens and have one property in common:
•They are highly reactive electrophiles (have electron deficient atoms) that
can react with nucleophilic (electron-rich) sites in the cell.
•This reaction is non-enzymatic and result in the formation of covalent
adducts (addition products) between the chemical carcinogen and a
nucleotide in DNA.
•Electrophilic reactions may attack several electron-rich sites in the target
cells including DNA, RNA, and proteins.
•Only a few alkylating and acylating agents are directly acting carcinogens

Indirect acting compounds (or pro-carcinogens)
•Requires metabolic conversion in vivo to produce ultimate carcinogens
capable of transforming cells.
•Most known carcinogens are metabolized by cytochrome p-450 dependent
monooxygenase.
•Examples of this group include polycyclic and heterocyclic aromatic
hydocarbones, and aromatic amines etc….
•These chemical carcinogens lead to mutations in cells by affecting the
functions of oncogenes, onco-suppressor genes and genes that regulate
apoptosis.

Radiation carcinogenesis
•Radiant energy whether in form of ultraviolet (UV) sun light or ionizing
electromagnetic (X rays and gamma (δ ) rays) and particulates (α,β, protons
and neutrons) radiation can transform and induce neoplasm in both humans
and experimental animals.
•Two types of radiation injuries are recognized:
Ultraviolet rays (UV light)
•UV rays are examples of non-ionizing radiation that cause vibration and
rotation of atoms in biologic molecules
•UV rays induce an increased incidence of squamous cell carcinoma, basal
cell carcinoma and possibly malignant melanoma of skin.
•Risk factors for developing UV rays related disorders depend on
-Type of UV rays –UV type B
-Intensity of exposure
-Quality of light absorbing “protective mantle” of melanin in the skin

•UV rays’ effects on cell nucleus are:
-The carcinogenesis of UV type B rays is attributable to its formation of
pyrimidine dimmers in DNA
-However, UV rays can also cause inhibition of cell division, inactivation
of enzymes,
Induction of mutation and sufficient dose kill cells.

IONIZING RADIATION
•Ionizing radiations are of short wave lengh and high frequency which can ionize
biologic target molecules and eject electrons
•Electromagnetic and particulate radiations in forms of theureptic, occupational or
atomic bomb incidents can be carcinogenic
•Occupational hazards include:
•Many of the poineers in the development of roentegen rays develop skin cancers.
•Miners for radioactive elements---lung cancer
•Therapeutic irradiations have been documented to be carcinogenic. Thyroid cancer
may result from childhood & infancy irradiation (9%), and by the same taken
radiation therapy for spondylitis may lead to a possible acute leukemia year later.
•In atomic bonds dropped in Hiroshima and Nagasaki initially principal cancers
were acute and chronic mylogenous leukemias after a latent of about 7 years solid
tumours such as breast, colon, thyroid and lung cancers) increased in incidence.
•Most frequent are the leukemia except CLL, which almost never follow radiation
injury. Cancer of the thyroid follows closely but only in the young. In intermediate
category are cancers of the breast, lungs, and salivary glands
•In contrast, skin, bone and gastrointestinal tract are relatively resistant to radiation
induced neoplasia.

Viral and bacterial carcinogenesis
•Large groups of DNA and RNA viruses have proved to be oncogenic and there
is an association between infections by the bacterium Helicobacter Pylori and
gastric lymphoma.
•DNA oncogenic viruses
•This group includes:
Human Papilloma Virus (HPV)
Epstein Barr Virus (EBV)
Hepatitis B Virus (HBV)
•General feature of the oncogenic DNA virus
•Transforming DNA virus form stable associations with the host cell genome.
•The integrated virus is unable to complete its replicative cycle because the viral
genes essential for completion of replication are interrupted during integration
of viral DNA (E1/E2)
•Those viral genes that are transcribed early (early genes) in the viral life cycle
are expressed in the transformed cells.

•Hepatitis B-virus (HBV)
•Strong epidemiologic association prevails between HBV and hepato cellular
carcinoma.
•HBV genome, however, does not encode any oncoproteins, and there is no
consistent pattern of integration in the vicinity of any known proto
oncogenes.
•The effects of HBV is indirect and possibly multi factorial.
•By causing chronic liver cell injury and accompanying regenerative
hyperplasia, HBV encodes a regulatory element called HBx protein, which
disrupts normal growth control of infected liver cells by transcriptional
activation of several growth promoting genes such as insulin like growth
factor II
•HBV binds to P53 and appears to interfere with its growth suppressing
activities.
•Although not a DNA virus hepatitis virus is also strongly linked to the
pathogenesis of hepato cellular carcinoma as evidenced by epidemiologic
studies.

RNA ONCOGENIC VIRUSES
•Although the study of animal retroviruses has provided spectacular insights
to molecular basis of cancer , only one retrovirus is firmly implicated in the
causation of cancer and it is Human T cells leukemia/ lymphoma virus type
1 (HTLV-1) .
•Similar to HIV virus. HTLV-1 has tropism for CD4+T cells > Human
infection requires transmission of infected T cells through sexual
intercourse, blood products, or breast feedings.
•Leukemia develops after a 20 or 30 years of latency in about 1% of
patients. HTLV-1 is also associated tropical spastic Para paresis

AUTOPSY

•Greek word autopsia: "to see
with one's own eyes."
•A post mortem examination
preformed to determine the
cause of death.

•Anautopsy—also known as apost-mortem
examination,necropsy(particularly as to non-human bodies),autopsia
cadaverum, orobduction
•It is a highly specialized surgical procedure that consists of a
thoroughexaminationof acorpseto determine the cause and manner
ofdeathand to evaluate anydiseaseorinjurythat may be present.
•Autopsies are performed to determine the cause of death, for legal purposes,
and for education and research.
•It is usually performed by a specialized medical doctor called apathologist,
who have received specialty training in the diagnosis of diseases by the
examination of body fluids and tissues.
•An autopsy may be restricted to a specific organ or region of the body.

THERE ARE FOUR MAIN TYPES OF AUTOPSIES:
•Medico-Legal Autopsy or Forensicorcoroner's autopsiesseek to find
the cause and manner of death and to identify the decedent.They are
generally performed, as prescribed by applicable law, in cases of violent,
suspicious or sudden deaths, deaths without medical assistance or during
surgical procedures.
•ClinicalorPathological autopsiesare performed to diagnose a particular
disease or for research purposes. They aim to determine, clarify, or confirm
medicaldiagnosesthat remained unknown or unclear prior to the patient's
death.
•Anatomicaloracademic autopsiesare performed by students of anatomy
for study purpose only.
•Virtualormedical imaging autopsiesare performed utilizing imaging
technology only, primarily magnetic resonance imaging (MRI) and
computed tomography (CT)

•A forensic autopsy is used to determine the cause and manner of death.
•Forensic scienceinvolves the application of the sciences to answer questions
of interest to the legal system.
•InUnited Stateslaw, deaths are classified under one of five manners:
Natural
Accident
Homicide
Suicide
Unknown

NATURAL DEATH
•Caused by a known disease: cancer, heart disease, stroke, genetic disorders,
etc.
•Often just simply “old age”
ACCIDENTAL DEATH
•Caused by mistake or freak occurrence.
•Death not planned, but can be explained by circumstances.
HOMICIDAL DEATH
•Killing another person.
•Close to you?
Infanticide, Fratricide, Sororicide, Parricide, Patricide, Matricide,
Mariticide, Uxoricide
•Lots of people…
Genocide –Killing a national, ethnic, racial or religious group
•Homicide is the most investigated death, therefore the most autopsied.

SUICIDAL DEATH
•Killing of self.
•Often the easiest to identify the cause.
•Can be elaborated further in the report…
Toxic, firearm, blunt force trauma, asphyxiation, etc.
UNKNOWN DEATH
•Deaths in absentia
At sea
Badly decayed bodies

•Medical examiners also attempt to determine the time of death, the exact
cause of death, and what, if anything, preceded the death, such as a struggle.
•A forensic autopsy may include obtaining biological specimens from the
deceased for toxicological testing, including stomach contents.
•Toxicology tests may reveal the presence of one or more chemical "poisons"
(all chemicals, insufficient quantities, can be classified as a poison) and their
quantity.
•Because post-mortem deterioration of the body, together with the
gravitational pooling of bodily fluids, will necessarily alter the bodily
environment, toxicology tests may overestimate, rather than underestimate,
the quantity of the suspected chemical.
•Most states require the state medical examiner to complete an autopsy report,
and many mandate that the autopsy be videotaped.
•Following an in-depth examination of all theevidence, a medical examiner
orcoronerwill assign one of the five manners of death listed above, and
detail the evidence on the mechanism of the death.

PROCESS OF AUTOPSY
•The body is received at a medical examiner's office or hospital in abody
bagor evidence sheet.
•A new body bag is used for each body to ensure that onlyevidencefrom that
body is contained within the bag.
•Evidence sheets are an alternative way to transport the body. An evidence
sheet is asterilesheet that the body is covered in when it is moved. If it is
believed there may be any significantresidueon the hands, for
instancegunpowder, a separate paper sack is put around each hand and taped
shut around the wrist.
•There are two parts to the physical examination of the body: the external and
internal examination.Toxicology,biochemical testsand/orgenetic
testingoften supplement these and frequently assist thepathologistin
assigning the cause or causes of death.

EXTERNAL EXAMINATION
•At many institutions the person responsible for handling, cleaning, and moving
the body is often called adiener, theGermanword forservant.
•In the UK this role is performed by an Anatomical Pathology Technologist
who will also assist the pathologist in eviscerating the body and reconstruction
after the autopsy.
•After the body is received, it is firstphotographed.
•The examiner then notes the kind of clothesand their position on the body
before they are removed.
•Next, any evidence such as residue, flakes of paint or other materialis
collected from the external surfacesof the body.
•Ultravioletlight may also be used to search body surfaces for any evidence not
easily visible to the naked eye.
•Samples ofhair,nailsand the like are taken, and the body may also
beradiographically imaged.
•Once the external evidence is collected, the body is removed from the bag,
undressed, and anywoundspresent are examined.
•The body is then cleaned, weighed, and measured in preparation for the
internal examination.

•Thescaleused to weigh the body is often designed to accommodate
thecartthat the body is transported on; its weight is then deducted from the
total weight shown to give the weight of the body.
•If not already within an autopsy room at the city/county morgue, the body is
transportedto one and placed on a table.
•A general description of the body as regardsethnicity,sex, age,hair
colorand length,eye colorand other distinguishing features (birthmarks,
oldscartissue,moles,tattoos, etc.) is then made.
•A handheldvoice recorderor a standard examination form is normally used
to record this information.
•In some countries e.g. France, Germany, and Canada, an autopsy may
comprise an external examination only.
•This concept is sometimes termed a "view and grant".
•The principles behind this being that the medical records, history of the
deceased and circumstances of death have all indicated as to the cause and
manner of death without the need for an internal examination.

INTERNAL EXAMINATION
•If not already in place, a plastic or rubber brick called a "body block" is
placed under the back of the body, causing the arms and neck to fall
backward while stretching and pushing thechestupward to make it easier to
cut open.
•This gives the prosector, a pathologist or assistant, maximum exposure to
thetrunk. After this is done, the internal examination begins.
•The internal examination consists of inspecting theinternal organsof the
body for evidence oftraumaor other indications of the cause of death. For
the internal examination there are a number of different approaches
available:
a large and deep Y-shapedincisioncan be made starting at the top of each
shoulder and running down the front of the chest, meeting at the lower point
of thesternum. This is the approach most often used.
a T-shaped incision made from the tips of both shoulder, in a horizontal line
across the region of the collar bones to meet at the sternum (breastbone) in
the middle.
a single vertical cut is made from the middle of the neck (in the region of
the 'adam's apple' on a male body)

•In all of the above cases the cut then extends all the way down to thepubic
bone(making a deviation to the left side of the navel).
•Bleedingfrom the cuts is minimal, or non-existent, because the pull
ofgravityis producing the onlyblood pressureat this point, related directly to
the complete lack of cardiac functionality.
•However, in certain cases there is anecdotal evidence that bleeding can be
quite profuse, especially in cases ofdrowning.
•At this point, shears are used to open the chest cavity. It is also possible to
utilise a simple scalpel blade.
•The prosector uses the tool to sawthrough the ribson the lateral sides of the
chest cavity to allow thesternumand attached ribs to be lifted as one chest
plate; this is done so that the heart and lungs can be seenin situand that the
heart, in particular thepericardial sacis not damaged or disturbed from
opening.
•Ascalpelis used to remove any soft tissue that is still attached to the
posterior side of the chest plate. Now thelungsand the heart are exposed. The
chest plate is set aside and will be eventually replaced at the end of the
autopsy.

•At this stage theorgansare exposed.
•Usually, the organs are removed in a systematic fashion.
•One method is described here: Thepericardial sacis opened to view the
heart.
•Bloodfor chemical analysis may be removed from theinferior vena cavaor
the pulmonary veins.
•Before removing the heart, thepulmonary arteryis opened in order to
search for a blood clot.
•The heart can then be removed by cutting the inferior vena cava, the
pulmonary veins, theaortaand pulmonary artery, and thesuperior vena cava.
•This method leaves the aortic arch intact, which will make things easier for
the embalmer. The left lung is then easily accessible and can be removed by
cutting thebronchus, artery, and vein at thehilum. The right lung can then be
similarly removed. The abdominal organs can be removed one by one after
first examining their relationships and vessels.

•To examine thebrain, an incision is made from behind one ear, over the
crown of the head, to a point behind the other ear.
•When the autopsy is completed, theincisioncan be neatly sewn up and is
not noticed when the head is resting on a pillow in an open casketfuneral.
•Thescalpis pulled away from theskullin two flaps with the front flap going
over the face and the rear flap over the back of the neck. The skull is then cut
with what is called aStryker saw, named for its manufacturer, to create a
"cap" that can be pulled off, exposing the brain.
•The brain is then observed in situ. Then the brain's connection to the cranial
nerves andspinal cordare severed, and the brain is lifted out of the skull for
further examination.
•If the brain needs to be preserved before being inspected, it is contained in a
large container offormalin(15 percent solution offormaldehydegas in
bufferedwater) for at least two but preferably four weeks.
•This not only preserves the brain, but also makes it firmer allowing easier
handling without corrupting the tissue.

RECONSTITUTION OF THE BODY
•An important component of the autopsy is the reconstitution of the body such
that it can be viewed, if desired, by relatives of the deceased following the
procedure.
•After the examination, the body has an open and emptychest cavitywith
chest flaps open on both sides, the top of the skull is missing, and the skull
flaps are pulled over the face and neck. It is unusual to examine the face,
arms, hands or legs internally.
•In the UK, following theHuman Tissue Act 2004all organs and tissue must
be returned to the body unless permission is given by the family to retain any
tissue for further investigation.
•Normally the internal body cavity is lined with cotton wool or an appropriate
material, the organs are then placed into a plastic bag to prevent leakage and
returned to the body cavity.
•The chest flaps are then closed and sewn back together and the skull cap is
sewed back in place.
•Then the body may be wrapped in ashroudand it is common for relatives to
not be able to tell the procedure has been done when the body is viewed in
afuneral parlorafterembalming.

RIGOR MORTIS
•Defined as ‘Stiffness of Death’.
–Flexibility of the body.
•Shows up 2 hours after death
•Peaks 12 hours after death.
•Takes 12-24 hours for entire rigor mortis effect to take place.
•At approximately 0 hours after death, the body is at its stiffest.
•The eyelids are affected first, the the jaw, face, trunk, arms, legs.
•Ends after 24-36 hours.

LIVOR MORTIS
•Meaning…‘Color of Death’.
–Coloration of the skin.
•Death = the heart stops = blood stops cycling.
•Red blood cells, plasma gather on the bottom part of the body,
closest to the floor.
•A line forms after 8 hours if the body hasn’t been moved. If moved,
a new line forms.
•The thicker the line, the longer the body held that position.

ALGOR MORTIS
•Defined as ‘Coolness of Death’.
–Temperature of body.
•In a controlled environment, stating at 98.6 degrees, the body will
drop one degree per hour.
•This happens because at death, the respiratory system stops
working, the body stops functioning, it is no longer moving.
•When taking the temperature of a corpse, you can’t take it in the
mouth because the muscles will be relaxed and the tongue wont
stay on top of the thermometer.
•Thinner people cool faster then fat people.

PALLOR MORTIS
•Defined as ‘Paleness of Death’.
–Tone of the body.
•Happens 15-20 minutes after death.
•Happens due to lack of capillary circulation in the body.
•Can not be used to determine time of death except if body is found
still with color.

BIOPSY

•A biopsy is when a small sample of tissue is removed from
a part of the body.
•The sample of tissue is then examined under the
microscope to look for abnormal cells.
•Commonly performed by asurgeon,interventional
radiologist, or aninterventional cardiologistinvolving
samplingofcellsortissuesfor examination.
•The tissue is generally examined under amicroscopeby
apathologist, and can also be analyzed chemically
•Biopsies are most commonly performed for insight into
possible cancerous and inflammatory conditions.

TYPES OF BIOPSY PROCEDURES
•BONE MARROW BIOPSY:
•Your doctor may recommend a bone marrow biopsy if an abnormality
is detected in your blood or if your doctor suspects cancer has
originated in or traveled to your bone marrow.
•Bone marrow is the spongy material inside some of your larger bones
where blood cells are produced. Analyzing a sample of bone marrow
may reveal what's causing your blood problem.
•Bone marrow biopsy is commonly used to diagnose a variety of blood
problems —both noncancerous and cancerous —including blood
cancers, such as leukemia, lymphoma and multiple myeloma. A bone
marrow biopsy may also detect cancers that started elsewhere and
traveled to the bone marrow.
•During a bone marrow biopsy, your doctor draws a sample of bone
marrow out of the back of your hipbone using a long needle. In some
cases, your doctor may biopsy marrow from other bones in your body.
You receive a local anesthetic before a bone marrow biopsy in order to
minimize discomfort during the procedure

•ENDOSCOPIC BIOPSY :
•During endoscopy, your doctor uses
a thin, flexible tube (endoscope) with
a light on the end to see structures
inside your body. Special tools are
passed through the tube to take a
small sample of tissue to be
analyzed.
•Tubes used in an endoscopic biopsy
can be inserted through your mouth,
rectum, urinary tract or a small
incision in your skin. Examples of
endoscopic biopsy procedures

•NEEDLE BIOPSY
•During a needle biopsy, your doctor uses a special needle to extract cells
from a suspicious area.
•A needle biopsy is often used on tumors that your doctor can feel through
your skin, such as suspicious breast lumps and enlarged lymph nodes.
When combined with an imaging procedure, such as X-ray, needle biopsy
can be used to collect cells from a suspicious area that can't be felt through
the skin.

•Needle biopsy procedures include:
•Fine-needle aspiration.During fine-needle aspiration, a
long, thin needle is inserted into the suspicious area. A
syringe is used to draw out fluid and cells for analysis.
•Core needle biopsy.A larger needle with a cutting tip is
used during core needle biopsy to draw a column of tissue
out of a suspicious area.
•Vacuum-assisted biopsy.During vacuum-assisted biopsy,
a suction device increases the amount of fluid and cells that
is extracted through the needle. This can reduce the number
of times the needle must be inserted to collect an adequate
sample.
•Image-guided biopsy.Image-guided biopsy combines an
imaging procedure —such as X-ray, computerized
tomography (CT), magnetic resonance imaging (MRI) or
ultrasound —with a needle biopsy. Image-guided biopsy
allows your doctor to access suspicious areas that can't be
felt through the skin, such as abnormalities on the liver,
lung or prostate. Using real-time images, your doctor can
make sure the needle reaches the correct spot.

•A skin (cutaneous) biopsy removes cells from the surface
of your body. A skin biopsy is used most often to diagnose
skin conditions, including cancers, such as melanoma.
What type of skin biopsy you undergo will depend on the
type of cancer suspected and the extent of the suspicious
cells. Skin biopsy procedures include:
•Shave biopsy.During a shave biopsy, the doctor uses a tool
similar to a razor to scrape the surface of your skin.
•Punch biopsy.During a punch biopsy, the doctor uses a
circular tool to remove a small section of your skin's deeper
layers.
•Incisional biopsy.During an incisional biopsy, the doctor
uses a scalpel to remove a small area of skin. Whether you
receive stitches to close the biopsy site depends on the
amount of skin removed.
•Excisional biopsy.During an excisional biopsy, the doctor
removes an entire lump or an entire area of abnormal skin.
You'll likely receive stitches to close the biopsy site.

punch
shave
excisional

•SURGICAL BIOPSY
•If the cells in question can't be accessed with other biopsy procedures or if
other biopsy results have been inconclusive, your doctor may recommend
a surgical biopsy.
•During a surgical biopsy, a surgeon makes an incision in your skin to
access the suspicious area of cells. Examples of surgical biopsy
procedures include surgery to remove a breast lump for a possible breast
cancer diagnosis and surgery to remove a lymph node for a possible
lymphoma diagnosis.
•Surgical biopsy procedures can be used to remove part of an abnormal
area of cells (incisional biopsy). Or surgical biopsy may be used to
remove an entire area of abnormal cells (excisional biopsy).
•You may receive local anesthetics to numb the area of the biopsy. Some
surgical biopsy procedures require general anesthetics to make you
unconscious during the procedure. You may also be required to stay in the
hospital for observation after the procedure

•CONDITIONS IDENTIFIED BY BIOPSY:
•When a nodule is detected, imaging tests may be performed to help
determine if it isbenignor malignant. If imaging studies cannot clearly
define the abnormality, a biopsy may be necessary.
•Usually, a biopsy is performed to examine tissue for disease. Biopsies are
frequently used to diagnose cancer, but they can help identify other
conditions such as infections and autoimmune disorders. They may also
be done to match organ tissue before a transplant.
•Abdominal biopsy is used to diagnose whether a lump in the abdomen is
cancerous or benign. The lumps can be located in the fat, deep within the
abdomen. A sample of the lump is removed percutaneously under image
guidance (ultrasound or CT), or surgically using alaparoscopeor by
open surgery.
•Bone biopsy is used to diagnose cancer or infection in the bones. This
type of biopsy can be performed through the skin (percutaneous) with a
needle or surgically.
•Bone marrow biopsy is used to diagnose cancer in the blood, such as
leukemia. A small sample of the bone and bone marrow are removed
using a needle. Sometimes, only the bone marrow is removed for
examination.

•Breast biopsy is used to determine if a lump in the breast is cancerous or
benign. It can be performed a number of ways:
Stereotactic(mammographically-guided)
Ultrasound-guided
MRI-guided
•Lung or chest nodule biopsy is performed when an abnormality of the lung is
visible on an x-ray or CT scan. Lung biopsies can be performed through
bronchoscopy by insertion of an instrument called a bronchoscope through
the patient's mouth to reach the area to be biopsied, through the skin by
inserting a needle percutaneously, or by surgically removing the lump.
•Lymph node biopsy is performed whenever there are enlarged or
abnormallymph nodes. They can be performed with a needle or surgically.
•Nerve biopsy is used to examine damage to small nerves, degeneration and
destruction of the nerve and inflammatory nerve conditions. Nerve biopsies
are typically performed surgically.
•Skin biopsy examines a growth or an area on the skin, such as a mole, that
has changed its appearance. Skin biopsies can be performed by shaving a
small sample of the skin, removing a sample with a scalpel or by way of an
instrument used to punch through a portion of the skin.

•Biopsy analysis and results
•After your doctor obtains a tissue sample, it's sent to a laboratory for analysis.
The sample may be chemically treated or frozen and sliced into very thin
sections. The sections are placed on glass slides, stained to enhance contrast
and studied under a microscope.
•The results help your doctor determine whether the cells are cancerous. If the
cells are cancerous, the biopsy results can tell your doctor where the cancer
originated —the type of cancer.
•A biopsy also helps your doctor determine how aggressive your cancer is —
the cancer's grade. The grade is sometimes expressed as a number on a scale
of 1 to 4 and is determined by how cancer cells look under the microscope.
Grade 1, or low-grade, cancers are generally the least aggressive and grade 4,
or high-grade, cancers are generally the most aggressive. This information
may help guide treatment options. Other special tests on the cancer cells also
can help to guide treatment choices.
•In certain cases, such as during surgery, a pathologist examines the sample of
cells immediately and results are available to your surgeon within minutes.
But in most cases, the results of your biopsy are available in a few days.
Some samples may need more time to be analyzed. Ask your doctor how long
to expect to wait for your biopsy results.

CELLULAR ADAPTATIONS OF
GOWTH AND
DIFFERRENTIATION
•Hypertrophy
•Hyperplasia
•Atrophy
•Metaplasia

HYPERTROPHY
•Hypertrophy is an increase in the size of cells
resulting in increase in the size of the organ.
•In pure hypertrophy, there are no new cells, just
bigger cells containingincreased amounts of
structural proteins and organelles
•Hypertrophy occurs when cells have a limited
capacity to divide
•Hypertrophy can be physiologic or pathologic
•Cause : 1. increased functional demand , 2.
growth factor or hormonal stimulation

Physiologic cellular Hypertrophy
•The massive physiologic enlargement of the
uterus during pregnancy occurs as a consequence of
estrogenstimulated smooth muscle hypertrophy
and smooth muscle hyperplasia
Pathologic cellular Hypertrophy
•An example of pathologic cellular hypertrophy is
the cardiac enlargement that occurs with
hypertension or aortic valve disease

PHYSIOLOGIC HYPERTROPHY: UTERUS ENLARGEMENT DURING
PREGNANCY

Normal Myocytes
Myocytes showing hypertrophy
Pathologic hypertrophy: Cardiac Enlargement
The mechanisms driving cardiac hypertrophy
involve at least two types of signals:
mechanical triggers,such as stretch
trophic triggers, which typically are soluble
mediators that stimulate cell growth, such as
growth factors and adrenergic hormones.

•These (mechanical and tropical ) stimuli turn
on signal transduction pathwaysthat lead to
the induction of number of genes, which in
turn stimulate synthesis of many cellular
proteins, including growth factors and
structural proteins.

•If stress (Hypertension / cardiac valve
disease )is not removed,several
“degenerative” changes occur in the
myocardial fibers, of which the most
important are fragmentation and loss of
myofibrillar contractile elements
•Net result of these changes is ventricular
dilation and ultimately cardiac failure, a
sequence of events that illustrates how an
adaptation to stress can progress to
functionally significant cell injury if the
stress is not relieved

HYPERPLASIA:
•characterized by an increase in cell number because of
proliferation of differentiated cells and replacement by tissue
stem cells.
•Hyperplasia is anadaptive response in cells capable of
replication
•Hypertrophy and hyperplasia also can occur together, and
obviously both result in an enlarged hypertrophic organ.
Hyperplasia
Physiologic
Hormonal
Compensatory
Pathologic
Hormonal
Growth factor

•The hyperplastic process remains controlled;
if the signals that initiate it abate, the
hyperplasia disappears.
•In cancer, the growth control mechanisms
become dysregulated or ineffective
•Pathologic hyperplasia constitutes a fertile soil
in which cancers may eventually arise.
•For example, patients with hyperplasia of
the endometrium are at increased risk of
developingendometrial cancer

•HORMONAL HYPERPLASIA
(Physiologic): Proliferation of the glandular
epithelium of the female breast at puberty
and during pregnancy
•COMPENSATORY HYPERPLASIA
(Physiologic): Residual tissue grows after
removal or loss of part of an organ.
•For example, when part of a liver is resected,
mitotic activity in the remaining cells begins
as early as 12 hours later, eventually
restoring the liver to its normal weight.

•HORMONAL HYPERPLASIA (Pathologic) :
Disturbed balance between estrogen and
progesterone causes endometrial hyperplasia,
which is a common cause of abnormal menstrual
bleeding.
•GROWTH FACTOR INDUCED
HYPERPLASIA: eg. Response of connective
tissue cells in wound healing, in which
proliferating fibroblasts and blood vessels aid in
repair.In this process, growth factors are produced
by white blood cells (leukocytes) responding to
the injury and by cells in the extracellular matrix.

•ATROPHY:
•Shrinkage in the size of the cell by the loss of cell substance
•When a sufficient number of cells are involved, the entire
tissue or organ diminishes in size, becoming atrophic.
Althoughatrophic cells may have diminished function,
they are not dead.
•CAUSES OF ATROPHY:
Physiologic: loss of innervation, diminished blood supply,
inadequate nutrition, loss of endocrine stimulation, and
aging (senile atrophy),
Pathologic: the loss of hormone stimulation in menopause
•The mechanisms of atrophy consist of a combination of
decreased protein synthesis and increased protein
degradation in cells.

•Protein synthesis decreases because of reduced
metabolic activity.
•The degradation of cellular proteins occurs mainly by
the ubiquitin-proteasomepathway.
•Nutrient deficiency and disuse may activate
ubiquitinligases,which attach multiple copies of the
small peptide ubiquitinto cellular proteins and
target them for degradationin proteasomes.
•In many situations, atrophy is also accompanied by
increased autophagy, with resulting increases in the
number of autophagicvacuoles.
•Autophagy(“self-eating”) is the process in which
the starved cell eats its own components in an
attempt to survive.

ATROPHY OF BRAIN

METAPLASIA:
•Metaplasia is a reversible change in which one adult cell
type (epithelial or mesenchymal) is replaced by another
adult cell type.
•In this type of cellular adaptation, a cell type sensitive to a
particular stress is replaced by another cell type better able
to withstand the adverse environment
•In habitual cigarette smokers: The normal ciliated
columnar epithelial cells of the trachea and bronchi are
focally or widely replaced by stratified squamous
epithelial cells.
•The rugged stratified squamous epithelium may be able
to survive the noxious chemicals in cigarette smoke that
the more fragile specialized epithelium would not
tolerate.

•Although the metaplasticsquamousepithelium has
survival advantages, important protective
mechanisms are lost, such as mucus secretion and
ciliaryclearance of particulate matter.
•Moreover, the influences that induce metaplastic
change, if persistent, may predispose to malignant
transformation of the epithelium.
•It is thought that cigarette smoking initially causes
squamousmetaplasia, and cancers arise later in
some of these altered foci.
•Since vitamin Ais essential for normal epithelial
differentiation, its deficiencymay also induce
squamousmetaplasiain the respiratory
epithelium.
•