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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.