2011 06 PATHO Cell Injury and Death01

8/6/2019 2011 06 PATHO Cell Injury and Death01

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PATHOLOGY

y study ofsuffering or study ofdisease y study of the structural, biochemical, and

functional consequences of injuriousstimuli on

cells, tissues, and organs

y structural changes: cell tissue organ andsystems

y Serve as bridge between basic sciences andclinical medicine, and is the scientific

foundation for all of medicine.y MAJOR DIVISIONS:

o Anatomic General

y Acc to Doc, memorize understandthe 1

stseven chapters of robbins!

y Concerned with the reactions ofcells andtissuesto abnormal stimuli

andto inheriteddefects

Systemicy Examines the alterations in

specialized organs and tissues thatare responsible for disorders that

involvedthese organs

o Clinical Dealswith laboratoryside of pathology

(hematology, microbiology, etc)

Also used in correlation of anatomicchangeswith physiologicchanges in the

cells

ASPECTS OF DISEASE PROCESSES

What is the cause?

how it happened

what areaffected as seen in the cells or tissues

examinedcorrelate with the individuals sign and

symptoms

1. Etiology or causey Major classes:

o Genetic Born with it (ex. Cleft palate,

polydactyly, etc)

Inherited mutations Disease-associated gene variants polymorphism

o Acquired Primarily environmental Infectious (microbiologic or

biologic)

Nutritional Chemical Physical

2. Pathogenesisy sequence of events in the response ofcells

or tissuesto the cause

3. Morphologic Changesy structural alterations

4. Functional Derangementy functional alterationsy itsclinical significance

ex.

etiology: infectionpathogenesis: injury due to mosquito bite

disruption of skin scratching the area with dirty

nails infection Abscessfunctional derangement

of limb due to abscess

morphologicchanges: abscess

functional derangement: functionallyderanged limb

INTRACELLULAR SYSTEM VULNERABLE TO

INJURY(Target of Injurious Stimuli)

1. Integrity ofcell membrane2. AerobicRespiration3. Synthesis of protein and enzyme4. Cytoskeletal system5. Intact genetic apparatus

PRINCIPLES AND CONCEPTS

Homeostasis

y Present state of cell without any injuriousstimuli

y equilibriumy steadystate

Adaptation

y Introduce stimulus(injurious or non-injurious cell reacts depending on the

lethality of the stimulus(lethal or

sublethal)adaptive state or higher level of

equilibrium

y new but altered steady state achieved topreserve cell viability

y ultimate goal of adaptation:viabilityy reversible functional and structural

responses to more severe physiologic

stresses andsome pathologicstimuli

y Types of adaptation:o Atrophy

decrease in cell sizeo Hypertrophy

increase in cell size entails anincrease in building blocks(protein

synthesis)

Subject: PathologyTopic: Cell Injury and Death ILecturer: Dr. Luis CruzDate of Lecture: 06/09/2011Transcriptionist: Desiree TimtimanPages: 12

SY

2011-2012


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o Hyperplasia increase in the number ofcells as a

result ofcell division also entails an

increase in protein synthesis

o Metaplasia replace adultcell by another type ex. Secretorycolumnar epithelium

injurious stimuliprotective

stratifiedsquamous epithelium

REACTIONS OF CELLS TO STIMULI

y cells can adapt to environment byhypofunctioning or hyperfunctioning

y a persistent sublethat injury can lead tohyperplasia andhypertrophy

y Hypofunctioningo If its not functioning it becomessmallo Relatedto atrophy

y Hyperfunctioningo C

omponents are added for it tohyperfunction

o Relatedto hyperplasia andhypertrophyy Vulnerable systems are relatedto adaptabilityMECHANISMS OF CELL INJURY

y The cellular response to injurious stimulidepends on the type of injury, its duration and

its severity

y The consequences ofcell injurydepend on thetype, state and adaptability of the cell

y Cell injury results from functional andbiochemical abnormalities of several essential

cellular components

HYPERTROPHY

y Result of increased of production of cellularproteins

y Increase in size of an organ or tissue due toincrease in size ofthe cells

y CAUSES:1. Physiologic

a. Hormonal estrogen stimulation of uterus in

pregnancy

average female has a uterus as bigasher clenched fist and an average

Filipino newborn baby is 3 kilos,

hence there is a need for both

hypertrophy and hyperplasia to

accommodate the fetus

b. Compensatory2. Pathologic

Ex. Heart in CHFa. Excessive Hormonal stimulationb. Viral-induced

HYPERPLASIA

y increase in size of an organ due to increasein number ofcells

CAUSES:

1. Physiologica. Hormonal

y estrogen stimulation of uterus; occurswithhypertrophy

y glandural proliferation of breastduringpregnancy

b. Compensatory2. Pathologic

a. Excessive Hormonal stimulationy ex. Endometrial hyperplasia

b. Viral inducedy growth factors produced by virus

Normal cell in homeostasis has to adapt because of increase

demand or stresses. If itdoes not adaptdue to some injurious

stimulus, it will result into cell injury. Cell injury can lead to

subcellular alterations which cant be seen under the light

microscope or reversible cell injury called light microscopic

pattern of injurythat is observable under the light microscope.

If cell is unable to adapt due to severe, progressive and

irreversible injury the cell may die or undergo apoptosis

(programmedcell death) or necrosis.

Hypertrophiedheart (lt), normal heart (middle), heartwithcell

injury (upper rt), heartwith necrosis (lower rt)

Morphologicchange:hypertrophiedheart

Functional derangement:decreased in blood volume ejected by

the heart and as a physiologic response leadsto HPN

Signals that result into cardiac hypertrophy:


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o mechanical triggers (stretch) best explained byStarlings law

y stretching the muscle has acorresponding amount of

contraction

y overstretching can cause dilationo trophic triggers (activation of a-adrenergic

receptors)

hormonal growth factors

y Signal transduction pathwayscan be turned onbythe stimuli and leadto:

o induction of genes that stimulate proteinsynthesis such as growth factors and

structural proteins

End result of Hyperplasia and Hypertrophy:

y Synthesis of more proteins and myofilamentsper cell which achieves improved performance

and thus, a balance between demand and the

cell functional capacity

y since its a reversible adaptive mechanism,removing the stresses will cause the heart to

revert backto its normal functioning cell

y In summary, stable tissue abnormalstimulus(inc in functional[work]/metabolicdemand, inc endocrine stimulus or persistent

tissue injuryadaptive response(hypertrophy or

hyperplasia or both)stable tissuereturn back

to normal cell or persistent alteredstate

y At a certain point, however, the adaptiveresponse can bring about a dysfunctional state

in the condition

This is a schematicdiagram ofhypertrophy andhyperplasia.

AGENESIS

y failure of formation of embryoniccell massAPLASIAy failure ofdifferentiation to organ specifictissue

(ex. Kidney)

y Failure ofcell productiony Fetal life

o results in agenesisy later life

o cause of permanent loss of precursor cellsin proliferative tissue such as bone marrow

y Aplastic Anemiao aplasia in the bone marrowo R

emember that BM contains the precursorcells forRBC, WBC, and platelets

DYSGENESIS

y failure to undergo structural organization oftissues into organs

HYPOPLASIA

y decrease in cell production that is less extremethan that found in aplasia; failure to growto fullsize;

y ex. Klinefelter andTurner Syndromeo dysgonadal syndromeo partial lack of growth and maturation of

gonadal structures


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He didnt go into so muchdetails in this diagram but its self

explanatory. Ill letyour brains figure it out!Haha!

ATROPHY

y Decrease in the size of an organ or tissueresulting from decrease in the mass of pre-

existing cells

y Decrease in the mass of cell is the result ofdecrease in organelles;unnecessary organelles

can be loss for itto be viable

y Results from decreased protein synthesis andincreased protein degradation because of

reduced metabolic activity

y Ubiquitin-proteasome pathwayo main pathway in the degradation of

proteins

o disuse and nutrient deficiency activatesubiquitin ligases

o Ubiquitin ligases Attaches ubiquitin to cellular proteins

and target these proteins for

degradation in proteasomes

o responsible for accelerated proteolysisy Accompanied by increased AUTOPHAGY and

HETEROPHAGY

o Autophagy- eating up your cellso Heterophagy- eaten up by another cell

y Marked by presence of AUTOPHAGICGRANULES

y Autophagic granuleso Intracytoplasmic vacuolescontaining debris

from degraded organelles

y Cancer cachexia is an example of atrophyy CAUSES:

Physiologic:

o Tissues/structures present in embryo or inchildhood(e.g. thymus) may undergo

atrophy as growth and development

progress

o Thymusdisappears bythe age of 2 y/o.Pathologic:

1. Decreasedworkload or disusedo Immobilized fractured bone in cast arm

results in disused of muscleswithin the

castwhich leadsto atrophy

2. Loss of innervations/dennervation atrophyo Damage to the nerves leadsto atrophy

of the muscle fibers supplied by those

nerves

o Due transaction of nerve or infectionlike polio

3. Ischemiao Diminished blood supply or oxygen

deprivation

4. Inadequate nutrition (ex. Marasmus)5. Loss of endocrine stimulation

o Deprivation ofhormonal stimulationo Ex. Loss of estrogen stimulation after

menopause results in physiologic

atrophy ofthe endometrium, vagina epi

and breast

6. Senile atrophyo Agingo Decrease bld supply due to

atherosclerosis

o Reduced activity leads to reduction insize ofthe skeletal muscle

7. Pressure or Physical stresso tissue compression for any length of

time can cause atrophy

o ex. Benign tumor can cause atrophy in thesurrounding uninvolvedtissues

o ex. bedulcersy Kinds of atrophy:

o General Atrophy Starvation atrophy Senile atrophy

o Local Atrophy Disuse Atrophy P

ressureAtrophy

Endocrine Atrophy Denervation Atrophy

Patientwithcancer cachexia


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The figure above shows both atrophy andhypertrophy ofsk.

Muscle. Note the distinctive features of sk. Muscle:

eccentrically multinucleated cell. The hypertrophied muscle is

possiblycompensating for the atrophied muscle.

This is an example of an atrophied brain. Compare the sulci of

the normal brain(lt) and atrophied brain (rt)The sulci iswider

due to the thinned gyri ofthe atrophied brain.

atrophiedtestes(rt)due to loss ofhormonal stimulation. (lack of

use dawsabi ni fi! Lol!)

Schematicdiagram of autophagy leading to atrophy

METAPLASIA

y A reversiblechange in which one mature/adultcell type (epithelial or mesenchymal) is replaced

by another mature cell type

y A protective mechanism rather than apremalignantchange

y According to older schools, dysplasia is acontinuousspectrum of metaplasia

y CAUSES:o Persistent Irritationo Infectiono Malnutrition

y Examples:o Bronchial (pseudostratified, ciliated

columnar) to stratified squamous

epithelium

E.g., respiratorytract ofsmokers St. sq is more protective than columnar

but this will cause to the loss of

secretory function that traps foreign

material leading to compensatory

mechanism:coughing

o Endocervical (columnar) to squamousepithelium

E.g., chroniccervicitiso Esophageal (squamous) to gastric or

intestinal epithelium

E.g., Barrett esophagus Mucous barrier is more protective than

st. squamous ep.


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Arrow is pointing atthe Squamous metaplasia

Transition area in the cervix from endocervical epi to st. sq.Transformation zone (OBGYN terminology)/ squamocolumnar

zone/squamocolumnar junction/transition zone

*calculus- stone

*chronictrauma leading to cartilage osseousdue to calcification

* vit a deficiency loss oftranslucencydue to kerato-conjunctivitis or keratinization ofcornea


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Same as the principles mentioned above. If the cell is able to adapt it will survive and leads to adaptive changes: hypertrophy,

hyperplasia, metaplasia and atrophy. And ifthe cell isunable to adapt itwill notsurvive and leadto cell death

DYSPLASIA

y Derangeddevelopmenty Proliferation and atypical cytologic alterationsy change in size, shape and organization NOT an

adaptive mechanism but a change for the

WORSE

Cell Adaptation Key Facts:

y Adaptable within physiological limits; beyondphysiologic limits maycause cell death

y Heat shock proteins can respond to injury byproducing cell stress proteins, which protect

from damage andhelp in recovery

y Increased demands met by hypertrophy andhyperplasia

y Reduceddemand met by atrophyy Apoptosis- cell loss from tissues can be

achieved by programmedcell death

y Tissues can adapt to demand by a change indifferentiation known as metaplasia

Reaction of cells to injury on a biochemicallevel

y Functional (biochemical)changes occur beforegross morphologicchanges appear

y Changes occur as follows:Ultrastructurallightmicroscopic changes gross morphological

change

y Again, the light microscopicchangesthatcan beappreciated are fatty change and cellular

swelling

Reactions of cell injury

y Reversible injury(degeneration)o Cell functions impaired but cell can

recover

o Removing the stimuli will return the cellbackto its original state

y Irreversible injuryo Cessation of all cell functions with

cellular death

o Apoptosis Programmedcell death

o Necrosis Sum of degradative and

inflammatory reactions occurringafter tissue death


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Note the influx of calcium, sodium and radicals that brings about cellular changes. Thiswill be further discussed in the succeeding

lectures.

REVERSIBLE INJURY : Morphologic changes

y Light microscopicchangeso Cell swelling (a/k/a hydropicchange)o Fatty change Cell is replaced by a blankspace which

is actually fat thatwas removed by the

alcohol (this is during the process of

tissue slide preparation) with the

nucleus atthe periphery

y Ultrastructural changeso Cannot be seen but impliedo Alterations ofcell membraneo Swelling of and small amorphous deposits

in mitochondria

o Swelling of RER and detachment ofribosomes

o Seen ascytoplasmic blebsIRREVERSIBLE INJURY: Morphologic changes

y Light microscopicchangeso Increased cytoplasmic eosinophilia (loss of

RNA, which is more basophilic)

o Cytoplasmic vacuolizationo Nuclear chromatin clumping

Veryhardto distinguishedy Ultrastructural changes

o Breaks in cellular and organellarmembranes

o Larger amorphousdensities in mitochondriao Nuclear changes:

Pyknosisy Nuclear shrinkage and increased

basophilia

Karyorrhexis

y Fragmentation of the pyknoticnucleus

Karyolysisy Fading of basophilia ofchromatiny Dissolution

Lung with pneumonia showing morphologic changes in the

alveoli. Most cells in the picture are eosinophilic and lacking

nucleus or having fragmented nucleus.

CAUSES OF INJURY:

y Hypoxiay Chemicals anddrugsy Physical Agentsy MicrobiologicAgentsy Immunologic reactionsy Genetic Defectsy Nutritional Imbalancesy Aging


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MECHANISMS OF CELL INJURY

y Loss ofcalcium homeostasiso related to ATP depletion, because

maintaining intracellular Calcium

necessitatesATP

y Defects in membrane permeabilityo Due to defective Na-K channel which is also

ATPdependent

o Sodium is retained inside the cell due tolack ofNa-K ATPase pump. Thiswill leadtoswelling due to increase water content of

the cell (water followssodium).

o Vulnerable in injuriousstimuliy ATPdepletion

o Loss of aerobic respiration (TCA andETC)y Oxygen and oxygen-derived free radicalsy Membrane damage and loss of calcium

homeostasis are mostcrucial

LOSS OF CALCIUM HOMEOSTASIS

y Some models of cell death suggest that amassive influx ofcalcium causes cell death

y Too muchcytoplasmiccalcium:o Denatures proteinso Poisons mitochondria (oxidative

phosphorylation and aerobic respiration)

o Inhibitscellular enzymes (protein synthesis)

Schematicdiagram of mechanism ofcell injury.

INTEGRITY OF CELLMEMBRANES

y Injured membranes are leakyy Enzymes and other proteins that escape

throughthe leaky membranes make their way

to the bloodstream, where they can be

measured in the serum

Some enzymes that leak out are dangerous to the

cell and cause lysis or metabolic derangement

increase cytosolic calcium can increase your ATPase,

Phospholipase, Protease and endonuclease causing thedecreased in ATP, decreased in phospholipids(component of

cell membrane), disruptions of membrane and cytoskeletal

proteins anddamage the nuclear chromatin, respectively

HYPOXICCELL INJURY

y Hypoxiao any state of reduction of O2 supplied to

cells and tissues and results in decreased

ATP production.

y Hypoxia can result from:o cardiorespiratory failureo loss of bloodsupplyo reduced transport ofO2 in blood (anemia

or COtoxicosis)

anemia because of lessO2 carrier COtoxicosis:COhas a greater affinityto

Hgb than Oxygen, replacing it and

decreasing the oxygen tension leading

to a decrease in release of oxygen in the

tissue.

o blockage ofcell enzymes (e.g. cyanide) affectsthe CYP450 blocks the last electron acceptor in

ETC no ATP production

o Ischemia is decreased blood supply orperfusion of tissues usually due to

constriction or obstruction of blood vessels.

Spastic phenomenony Vasospasm or vasoconstriction for a

long time leadsto hypoxic episodes,

however, when bld vessels dilates,

too much blood passes through

leading to ischemia reperfussion

injury (increase in bld supply

hyperoxygenation inc free

radicals)


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y Ischemia tends to injure tissue faster becausesubstrates for glycolysis are notdelivered,

y anaerobic generation of ATP stops faster,glycolytic function is inhibited by metabolite

accumulation.

Schematicdiagram ofhypoxia and its effects on the cellular components ofthe cell.

ISCHEMIA -- REPERFUSION INJURY Reoxygenation by increased generation of free

radicals

y Compromisedcellular antioxidantdefenses Promotion of the mitochondrial permeability

transition precludes mitochondrial

energization andATP recovery

y Inflammation resulting from cytokines andincreased adhesion molecules from

parenchymal and endothelial cells. Leukocyte

influxes addsto damage.

y Activation ofcomplement pathway

y Mitochondrial oxidative phosphorylation isdisrupted first DecreasedATP

o Decreased Na/K ATPase gain ofintracellular Na cell swelling

o Decreased ATP-dependent Ca pumps increasedcytoplasmicCa concentration

o Altered metabolism depletion of glycogeno Lactic acid accumulation decreased pHo Detachment of ribosomes from RER

decreased protein synthesis

y End result iscytoskeletal disruption with loss ofmicrovilli, bleb formation, etc


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y Mitochondrial swelling with formation oflarge amorphousdensities in matrix

y Lysosomal membrane damage leakage ofproteolytic enzymes into cytoplasm

y Mechanisms include:o Irreversible mitochondrial dysfunction

markedlydecreasedATP

o Severe impairment of cellular andorganellar membranes

FREE RADICAL

y Free radicalshave an unpaired electron in theirouter orbit

y Free radicalscause chain reactionsy Generated by:

o Absorption of radiant energyo Oxidation of endogenousconstituentso Oxidation of exogenouscompounds

Oxygen and oxygen derived free radicalscausing cell injury

EXAMPLES OF FREE RADICALS

y Chemical (e.g., CCl4, acetaminophen)y Inflammation /Microbial killingy Irradiation (e.g., UV raysskin cancer)y Oxygen (e.g., exposure to very high oxygen

tension on ventilator)

y Physiological age-relatedchangesMECHANISMS OF FREE RADICAL INJURY

y Lipid peroxidation damage to cellular andorganellar membranes

y Protein cross-linking and fragmentation due tooxidative modification of amino acids and

proteins

y DNA damage due to reactions of free radicalswiththymine


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Free radicals and its pathologic effects.

End oftranscription

Whew! I didnt thought Ill be making a twelve-

pagedtranx for an hour lecture!!Hahaha!

Anyways, good luck andstudyhard batch 2014!

Heresto a greatyear for all ofus!

In all these thingswe have complete victory

throughhim who lovedus. Romans 8:37-39

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2011 06 PATHO Cell Injury and Death01