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