Molecular€Mechanisms€of€Human€Disease …az9194.vo.msecnd.net/pdfs/080704/1.1.pdf · Cellular/Molecular Mechanisms. Etiology Adaptation Repair Loss€of function...

Mechanisms ofMechanisms ofCell Injury & Cell DeathCell Injury & Cell Death

Charleen T. Chu, MD, PhDAssociate Professor of Pathology and Ophthalmology

University of Pittsburgh School of Medicine

Summer Academy 2008Molecular Mechanisms of Human Disease

Lecture Goalsn Basic concepts and ongoing issues in cell

death pathways, including necrosis,apoptosis and cell death associated withautophagy.

n Integration of survival/death mechanisms setinto motion by pathologic cell injury.

n Mechanisms by which adaptive/reparativeresponses represent a double­edged sword.

PathologyPathology

StimulusStimulus > ProcessProcess > ManifestationManifestation

DISEASEDISEASEDiagnosis & PrognosisDiagnosis & Prognosis

(Includes Response to Therapy, Individualized Rx)

Changes in function& morphology

Etiology(initiating cause)

Cellular/MolecularMechanisms

Etiology

AdaptationRepair

Loss ofLoss offunctionfunction

Pathophysiology of Disease

Decompensation

PathogenicMechanismsPhysiologicResponses

RudolfRudolf VirchowVirchow18211821­­19021902

n Organ injury begins with molecular orstructural alterations in cells

n Cell­cell and cell­matrix interactionscontribute to tissue injury responses

n Untested hypothesis is an anathemafor the practice of medicine ...

Paraphrased from www.whonamedit.com

Pathologic

Stimulus

SurvivalSurvival

Cell InjuryCell Injury

Functional integrity

Loss of function

Adaptiveand deathmechanisms

CellDeath

Commitment

SublethalSublethal injuryinjuryn Transient, low level insultn Repair and recovery

n Sustained, gradual, or repetitive insultsn Adaptation & new state of homeostasis

n Minor muscle injury > hypertrophy in athletesn Cellular preconditioning

n Functional trade­offs and new pathologyn Atrophyn Metaplasia

Edema ­ most cell types

HypereosinophiliaCoagulation (aggregation) of proteinsDissolution of ribosomes, loss of RNA

Normal corneal epithelium

Reversible Cell InjuryReversible Cell Injury Irreversible Cell InjuryIrreversible Cell InjuryExtensive loss ofmembrane integrity

Basis of Lab Tests for Heart AttackLDH, creatine kinase­MB, troponin

Fatty change ­ liver, heart

Normal liver

Ischemic cell InjuryIschemic cell Injuryn Impaired oxidative phosphorylationn Adaptive change ­ glycolysis

n Glycogen depletionn Drop in pH > chromatin clumping

n Failure of plasma membrane Na+ pumps >Influx of Na+, Ca++, H2On ER and cell swellingn Calcium overload

n Ribosomes disassemble, unfolded proteinsn Hypereosinophilia (e.g. red dead neuron)

n Oncosis ­ death by swelling (von Recklinghausen, 1910)n Commonly referred to as “necrotic”

Cell Injury & Cell DeathCell Injury & Cell Deathn Imbalance between intensity of injury

and adaptive reserve of the cell leads tocell injury and potentially cell death

Outcome: Context dependent

Linguistics of cell deathLinguistics of cell deathn Necrosis ­

pathologic termreferring to deadcells, independent ofmechanism

n Common usage:passive cell death:Death by bombing ornatural disaster

n Programmed celldeath ­ physiologic,developmental“programs”

n Common usage:active mechanism(s)involving cell death“programs”: Suicide

Classifying cell deathClassifying cell death

StimulusStimulus > ProcessProcess > ManifestationManifestationhttp://david.davies.name/weblog/2004/03/08.html

Classifying cell deathClassifying cell deathn Stimulusn Developmental/Physiologic vs.

Accidental/Unscheduled/Pathologicn Processn Active/regulated vs. Passiven Apoptosis vs. Oncosis (“necrosis”)

(Caspase­dependent vs. ­independent)n Morphologyn Geographic vs. single cell necrosisn Type I ­ apoptotic (condensation)n Type III ­ “necrotic” (swelling)

DiseaseDisease­­related Cell deathrelated Cell deathn Beneficial

n Adapt cell number toneed and nutritionalstatus

n Eliminate cancer cellsn Eliminate auto­

reactive lymphocytesn Eliminate viral

infected cells

n Detrimentaln Loss of non­

regenerative cellsn Ischemia, trauman viral infection

n Neurodegenerativediseases

n Bystander effects(inflammation,autoimmunity)

Diseases often reflect too little or toomuch cell death...

NecrosisNecrosis

Typically yellow

Can be soft, firm orform a viscous liquid

Spleen with infarct Image courtesy of Larry Nichols

Glioblastoma with necrosis

CoagulativeCoagulative necrosisnecrosisn Bioenergetic failure,

physical damagen Confluent

eosinophilic cells withloss of hematoxylin(nucleic acid) staining

n Leads toinflammatoryclearance andfibrous scarring

Top: Embolic pituitary infarct; Bottom: Glioblastoma

SuppurativeSuppurative necrosisnecrosisnInfection

nNuclear andcytoplasmic debrisnLeucocytedegranulationnA form of liquefactivenecrosis

nLeads to fibrousscarring +/­ chronicinflammation

Loss of calcium homeostasisLoss of calcium homeostasisn Sources:

n failure of membrane Ca2+, Mg2+ ATPasesn release from mitochondria and ERn Increase from <0.1 µM to 1.3 mM (10,000 fold)

n Activation of:n ATPasesn Phospholipasesn Proteases (M­calpains)n Endonucleasesn Kinases

Loss of membrane integrityLoss of membrane integrityn Physical/chemical agents ­ not always lethal!

n Bacterial toxins, viral proteins,complement

n Calcium activated phospholipases >detergent effect > dystrophic mineralization

n Cytoskeletal detachment > stretch and rupture

n ATP depletion, decreased mitochondriallipid synthesis

n Lysosomal leakage ­ RNase, DNase,cathepsins, phosphatase, glucosidase

Contagious cell death?Contagious cell death?n Leakage of nuclear and cytosolic proteins

n HMGB1, S100 family proteinsn Purine metabolites (ATP, AMP, adenosine, uric acid)n Heat shock proteins

n Endogenous “danger” signaln RAGE (receptor for advanced glycation end

products), Toll­like receptorsn Recruit inflammatory cells > BYSTANDER cell deathn Elicit cytokines

n Epithelial, fibroblast and vascular proliferationn Secondary reparative pathologies

Reparative PathologyReparative Pathologyn Pseudotumors

n Florid reactions can simulate tumorsn “Pyogenic granuloma” ­ exophytic mass

n Fragile neo­vessels prone to rebleedingn Subdural hematoma, subacute cerebral stroke

n Extensive scarring or fibrous adhesionsn Interfere with tissue function

n heart, lung, joints, anterior chamber of eye, cornea

n Dystrophic mineralizationn Calcified plaques and loss of vessel wall compliance

Recurrent bleeding associated withRecurrent bleeding associated withreparativereparative neovascularizationneovascularization

Fresh hemorrhage in an organizing subdural membrane

Asbestosis of the lung, Images courtesy of Dr. Tim Oury

Normal lung

Pulmonary fibrosisPulmonary fibrosis

Pathologic CalcificationsPathologic Calcificationsn Dystrophic calcification ­ normal blood calcium

n Occurs with agingn Regions of necrotic tissue damagen Interferes with elasticity of tissues, transparency of

ocular tissuen Metastatic calcification ­ high blood calcium

n Excess in: PTH (neoplasia), Vitamin D, bone resorption

Microcalcifications in radiographicassessment of retinoblastoma, high grade

ductal breast carcinoma in situ, severeatherosclerosis, etc.

Retinoblastoma with punctate Ca2+

““Single cell necrosis”Single cell necrosis”n Individual dying

cells observed inmany tissuesn Eosinophilian Pyknosisn Karyorrhexis

n No destructiveinflammatoryresponse,preservation oftissue structure

n Now recognized asapoptosis

Rat liver, Image courtesy of George Michalopoulos

ApoptosisApoptosisn Liver ischemia ­ John Kerr 1960’s

n “Shrinkage necrosis” of individual cellsn Nuclear and cytoplasmic condensationn Fragmentation into membrane bound apoptotic

bodiesn Contents remain enclosed by membranes and no

inflammatory response is elicitedn Final disposition ­ heterophagy

n Kerr, Wyllie and Currie 1972n Similar morphology in hormonal adrenocortical

and breast CA death, and review of publisheddevelopmental electron micrographs

n “Falling off” of petals or leaves

HepatocyteHepatocyte apoptosisapoptosis

TNFα/Actinomycin D treated mouse hepatocytes, Image courtesy of Xiao­Ming Yin

phase contrast

round up

shrinking

fragmentation

Budding, boiling

Spread out

Molecular basis of apoptosisMolecular basis of apoptosisn Cancer (1988)n bcl­2n Proto­oncogene in t(14:18)

translocationnmediates cell survival rather than

proliferationn Developmental studies in C.

elegans (1990s) ­ ced genes

Tonsil, Ki­67 proliferation Ag

Reactive follicleReactive follicle

Secondary follicle in lacrimal gland, H&E

Bcl­2

Small memory B and T cells

Large germinal center cells

Bcl­2

Follicular BFollicular B­­cell lymphomacell lymphoma

Translocation (14:18)n Bcl­2 gene on chromosome 18n Immunoglobulin promoter on chromosome 14q

Follicular B cell lymphoma, H&E

Apoptotic MechanismsApoptotic Mechanisms(Lecture 2, Dr.(Lecture 2, Dr. ZinkelZinkel))

n Intrinsic pathway ­ “suicidal ideation”nMitochondria

n Extrinsic pathwaysn Death receptors ­ “witch doctor”n Cytotoxic T lymphocytes ­ “euthanasia”

Image courtesy of Donna Beer Stolz

nInhibitors of apoptosisnClearance of dead cells

Caspases ­ “execution”

Inhibitors of apoptosisInhibitors of apoptosisn Viral infected cells will try

to kill themselvesn Viral inhibitors of

apoptosis (IAP)

n Growing number ofendogenous inhibitorsn Combined deletion of

SMN­1 and NAIP (neuronalapoptosis inhibitoryprotein) in Werdnig­Hoffman disease (SMA­1)

n Death of motor neurons >>severe muscle atrophy Image courtesy of David Lacomis

Clearance of dead cellsClearance of dead cellsn Necrosis >> release of cell contents >>

active inflammation and 2° tissue injury

n Orderly clearance of apoptotic cellsn Cells undergoing apoptosis secrete factors

that attract, but do not activate, phagocytes.n Phosphatidylserine externalization as an

“eat me” signal

Alternative “Alternative “DeathstylesDeathstyles”?”?

Perinatal ischemiaApoptotic neurons abundant

Adult ischemiaRed dead neurons Viable neuron

Alzheimer DiseaseNeurofibrillary tangle (*)Granulovacuolar degeneration (arrow)

*

Neuronal cell death over a lifespanNeuronal cell death over a lifespan

n Developmental wave of neuronal celldeath by apoptosis

n Perinatal ischemia ­ pontosubicularnecrosis ­ prominent apoptoticmorphology

n Adult ischemia and neurodegenerativediseases ­ less clearn Biochemical markers of apoptotic

pathways more frequently observed thanmorphologic apoptosis

(Lecture 3, Dr. Roth)(Lecture 3, Dr. Roth)

Age effects in model systemsAge effects in model systemsn The rat 6­OHDA neurotoxin modeln Predominant morphology is apoptotic at

14, 21 and 29 days of agen 42­day old rats also exhibit a prominent

non­apoptotic form of cell death Brain Research (2002)958: 185

Cell type dependenceCell type dependencen K+ and serum withdrawaln Cerebellar granule cells ­ apoptosisn Purkinje neurons ­ autophagic J Neurosci (2004) 24: 4498

Adult postAdult post­­mitotic cellsmitotic cellsn Arrested apoptosis or diversion to

alternative pathways?n Energetics

n Switch to passive necrosis?n Expression of endogenous inhibitors

n Sympathetic neurons must developcompetence to undergo apoptosis ­ XIAP

n Fundamentally different pathways ofregulated death?

Programmed Cell DeathProgrammed Cell Death

No universalconcensus

RNAi Atggenes

CaspaseinhibitorsBcl­2

3a ­ generaldisintegration3b ­ dilated ER &mitochondria

Abundantautophagicvacuoles

Condensation ofchromatin andcytoplasm

Cytoplasmic“Regulatednecrosis”“Paraptosis*”“Necroptosis†”

AutophagicNuclear/Apoptotic

Type 3Type 2Type 1

Reviewed by Clarke 1990; †Junying Yuan lab; *Dale Bredesen lab

AutophagyAutophagy

Autophagosome

AmphisomeLysosome

Autophagy: PhysiologicStarvation, Turnover of organelles,long­lived proteins, aggregatesAutophagic cell death?Hormonally driven tissue regressionOxidative injuries

J. Neurosci (2004) 24: 4498

J. Neuropathol Exp Neurol (2006) 65: 423

EM of dying cellsEM of dying cellsCell with

organelle swellingApoptotic cells –

committed &beyond rescue

Autophagicmorphology –failed

adaptation vs.suicide? Injured, but

rescuable?

Beyond rescue

Image courtesy of Donna Beer Stolz

Type 1 Type 2 Type 3

Potential role(s) ofPotential role(s) of autophagyautophagy in cell deathin cell deathn Pro­survival  ­ death from failed compensation.

n Atrophic response to limiting resources.n Sequester damaged mitochondria?

n Pro­deathn Gatekeeper role upstream of apoptosis

n Mechanism of controlling death­related debris?

n Alternative executionary system?

n Context dependent, “autophagic stress”n Excessive or imbalanced induction/clearancen Most stress responses lead to repair or cell suicide

nCorrelation   Causation

SummarySummary­­Part 1Part 1n Pathologic cell death can serve both

beneficial and detrimental rolesn Necrosis describes cell corpses ­

typically with loss of membrane integrityn Apoptosisn Regulated set of events activated by

developmental and pathologic signalsn Controlled removal of superfluous,

neoplastic, infected or otherwise damagedcells for the benefit of the tissue ororganism as a whole

n AND...

APOPTOSIS

Unscheduled cell deathUnscheduled cell death

PASSIVE“Necrosis”

OTHER DEATHPATHWAYS?

ADAPTATIONBalance of adaptive/reparative &Balance of adaptive/reparative &injurious mechanismsinjurious mechanisms

APOPTOSIS

Unscheduled cell deathUnscheduled cell death

PASSIVE“Necrosis”

OTHER DEATHPATHWAYS?

ADAPTATIONBalance of adaptive/reparative &Balance of adaptive/reparative &injurious mechanismsinjurious mechanisms

Cellular Repair and Cell DeathCellular Repair and Cell Death

Pathologic

Stress

Reparativeresponses

Survival

Unfolded proteinresponse

ER stress

Cell cycle arrest,p53, PARP

DNA damage SuicideSuicide

DNA DamageDNA DamageROS, Radiation,ROS, Radiation, GenotoxinsGenotoxins

p53p53

Cell Cycle Arrest ApoptosisDNA repair

Proliferating Mutated CellNeoplastic Transformation

FailureFailure Failure

ER stressER stressn ER functionsn Protein synthesis, post­translational

modification, foldingn Calcium homeostasis and lipid

homeostasisn Accumulation of misfolded proteinsn Genetic defects in protein 1° structuren Protein overexpressionn Many drugs/toxicants disrupt ER functions

n Unfolded protein response

Unfolded protein responseUnfolded protein response

n Suppress initiation of protein synthesisn Induce chaperone proteinsn Enhanced ER associated degradationn Induce apoptosis if damage is

overwhelmingn ?Caspase 12 (but just a pseudogene in humans)n Casp 8 cleavage of ER protein > redistribution of

Ca2+ > induction of intrinsic pathway?

Emerging directionsEmerging directions

n It is clear that adaptive responses inmulticellular organisms can lead to celldeath

n Emerging data indicate that agents witha proven role in cell death may alsoregulate cellular adaptation,differentiation and function.

Reactive Oxygen/Nitrogen SpeciesReactive Oxygen/Nitrogen Species•Free radical ­ one unpaired electron

n Superoxide •O2­, Hydroxyl radical •OH

n Nitric oxide •NO

•Other oxidantsn Hydrogen peroxide H2O2, Singlet oxygenn Peroxynitrite ONOO­

n Oxygen is a biradical

•Energy barrier can be bridged by metalcatalysis, heat

Reactive Oxygen SpeciesReactive Oxygen Speciesn Evolution of thought

n Initially thought to not be biologically relevant

n With the discovery of antioxidant enzymes...n ROS as unfortunate by­product of respirationn Mediator of cell deathn Implicated in aging and most diseases!

n Growing recognition of ROS and •NO assignaling mediatorsn Learning and memory, vasodilatationn Pro­survival adaptations

PreconditioningPreconditioningn Transient  sublethal  insult >> resistance

to subsequent “lethal” insultsn Ischemic and hyperoxic preconditioning ­

heart, lung, kidney, liver, brainShared mechanisms with adaptive responses ton Chronic hypoxian Changes in temperature

n Transcriptional induction of antioxidants,detoxifying enzymes, heat shock proteins(chaperones), and kinases

Emerging roles forEmerging roles for caspasescaspasesn Caspases may have non­death related

functionsn Caspase 3 activation is essential for

anoxic pre­conditioning in vitron Localized “apoptotic” signaling and

neurite remodeling?

Too much of a “good” thingToo much of a “good” thing

n Growth factors promote proliferation,differentiation, and survival

n The same growth factor, receptor, orkinase can sometimes promote cellsurvival and sometimes cell death

n Too much, too little? Cell type, context?

Dual role of a growth factor receptorDual role of a growth factor receptorFas

FasL

HGFExcess HGF

C­Met

Mol Cell (2002) 9: 411

Dual role of a “death receptor”Dual role of a “death receptor”

TNFR

TNF­α

TRADDFADD

TRAF

cIAPNF­KB

TRAFcIAP

FADDDefects inNF­kBactivationor proteinsynthesis

ERK can mediate death or survivalERK can mediate death or survival

Nuclear Cytoplasmic/Mitochondrial

Grb2Shc

Grb2 Sos Raf

MEK

ERKY

T

GTPRasGDP

S

Y

Y

Y

Transcription

ROSROS

ERKY

T

Tx FS

Extracellular signal Regulated protein Kinase Eur J Biochem, 271: 2060­2066

Mitochondria:Mitochondria:Integration of survivalIntegration of survival­­death signalsdeath signals

Apoptosis inducing factorEndonuclease G

Cytochrome CSMAC/DIABLOHtrA2/Omi

ROSCa2+, Fe2+

Bcl­2Bax

+/­ Permeability transition

PKA

PKC

MAPK

PI­3K

Metabolic stimuli

Survival Death

Growth Factors ROS

CELLULAR CONTEXTSUBCELLULAR LOCATION

CytCyt CC

Caspases

Dichotomous ModelDichotomous ModelIntegrating the BALANCE ofIntegrating the BALANCE ofmultidimensional continuumsmultidimensional continuums

SummarySummary ­­ Part 2Part 2n Multiplicity of adaptive responses and

death pathways activatedn What factors determine if cells commit

to death and the death pathway used?n Severity or type of insultn Pre­existing cellular context

n Aging, genetic or nutritional backgroundn Pre­conditioning and adaptive reserve of the

cell typen Shifting emphasis from execution to

integration of upstream factors thatregulate survival/death decisions

Stress

Adaptation

Cell/Tissue Injury

Injury

Cell death,Impairedtissue fxn

ORFunctional trade­offsDysregulated repair

What does not kill me...Pre­conditioning

n Increased functional demand, growth signalsn Hypertrophy and Hyperplasian Cellular preconditioning (minor injury needed)

n Altered functional demand, irritationn Metaplasia

n Decreased demand or nutrition/energyn Atrophy

nLoss of functionnMetaplasianAtrophy

nGain of undesirable effectsnCardiac hypertrophynHyperplasia/metaplasia and cancer

Adaptation: new state of homeostasisAdaptation: new state of homeostasis

Myocardial hypertrophy

H&E, Image courtesy of Dr. Jennifer Hunt

Tonsillar hyperplasia

Ki­67 proliferation Ag

HypertrophyHypertrophy vsvs. Hyperplasia. Hyperplasia

http://biomedicum.ut.ee/aran/Poster/hypertrophic_myocardium.htm

NormalNormal

PhysiologicPhysiologic vsvs. Pathologic. PathologicHyperplasiaHyperplasia

n Physiologic ­Regulated & Reversiblen Hormonal or growth

factor stimulusn Breast at puberty

n Compensatory toloss of functionaltissue massn Liver, Kidney

n Wound healing

n Pathologic ­

n Disturbed hormonal orgrowth factor stimulusn Endometrial hyperplasian Benign prostatic

hyperplasian Viral infection

n Papillomavirus (warts)

n Increased risk ofNeoplasia (“cancer”)

Still Reversible!!

Increased risk ofNeoplasia (“cancer”)

MetaplasiaMetaplasian Chronic irritation converts one cell/

tissue type to anothern An adaptive compromisen Protection from irritationn Loss of normal functionn Gain of susceptibility to other pathologies

n Infectionn Cancer (although this may be due to chronic

irritation rather than metaplasia itself, thecancer often arises from metaplastic cell type)

Squamous metaplasiaSquamous metaplasia

Trade­offs?Loss of ciliatedcolumnar epithelium>> infection,hacking cough

Continued irritation>> squamous cellcarcinoma

H&E, Lung images courtesy of Dr. Tim Oury

ProtectionSquamousepithelium istough

Bronchial irritation, smoking

IntestinalIntestinal metaplasiametaplasia

ProtectionIntestinal type columnarepithelium is more resistantto acid than squamous

Trade­offs?Continued irritation >>glandular adenocarcinoma

Barrett’sesophagus

Acid reflux

There are also less defined examples of mesenchymalmetaplasia ­ including osseous metaplasia

Image courtesy of Dr. Antonia Sepulveda

Barrett’s esophagus, acid reflux

AtrophyAtrophy

ATPase, Image courtesy of David Lacomis

n Loss of stimulationn Disuse atrophyn Neurogenic muscle

atrophy (left)n Loss of support

n Diminished blood supplyn Malnutritionn Loss of growth factor

supportn Pressure atrophyn Idiopathic ­ aging,

neurodegeneration

Atrophy: TissueAtrophy: Tissue vsvs. Cell level. Cell leveln Tissue level atrophy can be accomplished byn Cellular atrophy (shrinkage in cell size)n Cell death (apoptosis)

n Cellular atrophy likely due ton decreased protein synthesis andn increased autophagic degradation

cellbio.utmb.edu/ cellbio/ser.htm

Benefit.sER “hyperplasia” allows more effectivedetoxification of ethanol, barbiturates,corticosteroids and their conjugation for secretion

Trade­offsResistance totherapeutic drugs

Some chemicals aremade more toxic bythe P450 systemmodification (CCl4,Tylenol)

The smooth ER contains detoxifying enzymesincluding the Cytochrome P450 system.

sERsER proliferation in liverproliferation in liver

Sequestration from dangerSequestration from dangerTissue leveln Elimination

preferred(liver, kidney, innate and

adaptive immunity)

n Sequestrationn InflammatoryEpithelioid macrophages

and granulomasn Other?Asbestos bodies

Cellular leveln Elimination

preferred(detoxification enzymes,

autophagy, exocytosis)

n Sequestrationn Membranous

n Vesicular uptaken Lysosomal

n Aggregation?

LysosomesLysosomes ­­Importance of garbage disposalImportance of garbage disposal

n Oxidative stress, protein and organelledamage

n Pathogenic organismsn Destroy organismn Used by organism for life cycle/replication

n Protein aggregates (+/­ ubiquitin)n Expansion due to undigestible remnants

n Lysosomal storage diseasesn Drug induced deficits ­ chloroquinen Lipofuscin ­ lipid peroxidation

MajorMajor DegradativeDegradative PathwaysPathwaysn Proteasomal

n Short­lived proteinsn cell cycle, transcription

factors, apoptoticmediators

n Polyubiquitinationregulatesproteasomaldegradationn E1, E2 and E3

conjugating enzymes

n Lysosomaln Long­lived proteins,

organelles, membranesn Nutrient or trophic factor

deprivationn Ubiquitin­like

conjugations bring Atgproteins to membranesto initiate sequestration

n Selective targeting ofcargo?n Chaperone­mediated

autophagy ­ KFERQn ?Damaged mitochondria

Altered protein degradationAltered protein degradationn Proteasome inhibitors elicit apoptosis

in primary neuronal cultures (yetproteasomal degradation of IAPs may be necessary)

n Lysosomotropic agents or agents thatblock cargo delivery to the lysosomeelicit cell deathn Chloroquine myopathyn X­linked vacuolar cardiomyopathy and

myopathy (Danon disease) ­ lysosome­associated membrane protein­2 (LAMP2)

n Autophagy: clears aggregates, but canmediate neurite degeneration

SummarySummary ­­ Part 3Part 3n In multicellular organisms, cellular

adaptation can be a double­edged swordn Poised to activate Cell Death programsn Functional trade­offs

n Hypertrophy, Hyperplasia, Atrophy can bephysiologic; as with Metaplasia, sustainedstimuli can make them pathologic

n Similarly, tissue adaptations may come at acost >> Chronic Inflammation &Dysregulated Repair as mechanisms ofhuman disease

A better understanding of adaptiveresponses to injury and the factors

that tip the balance to favordysfunction & cell death are

needed to guide development ofeffective therapies.