Document 6733

Introduction to Pathology
Oveaview ol Cellular Responsesto Stress
and Noxious Stimuli
Cellular Adaptations to Stress
Overview of Cell lhiury and Cell Death
Causesof cell Iniury
The Morphology of Cell and Tisrue Intury
of Tissue
to Injury
Mechanisns of Cell Iniury
Depletionof ATP
Damageto Mitochondria
Intluxof Calcium
Accumulationof Oxygen-Derived
Defectsin MembranePermeability
Damageto DNAand Protein5
Literaily translated,pdt olo6l is the study (/ogos)of suffering (pdrros).k is a disciplinethat bridsesclinicalpractice and basicscience,and it involvesthe inv€stieationof
the causes
of disearea. well rr rhe underlying
rhar resuhin rhe pre.enring
\isn\ and (ympromsof rhe parienr.Parhologrsrs
variery of molecular,microbiologic, and immunologic
techniquesto understandthe biochemical,structural,and
functionalchangesthat occurin cells,tissues,and organs.
To renderdiagnoses
and guidetherapy,pathologistsiden
tify changesin the grossor rnicroscopicappearance
pDology)ofcells and tissDes,
and bioch€micalalt€rations
in body fluids (such as blood and urine). Traditionally,
the disciplineis divid€d into generalpathologyand sys
remic parhologyirhe former focuseson rhe fundarnenral
cellularand tissueresponses
to patholosicstimuli, $hile
Examples of Cell Iniury and Necrosis
and Hypoxi(Injury
of AooDtosis
of AooDtosis
of Apoptosis
Intlacellular Accumulationg
Pathologic Calcification
the latter examinesthe parricularresponses
of specialized
organs.In this book we 6rst cover the broad principles
ofgeneralpathologyand then progressro specificdiseasc
in individual organs.
Cells are active pa.ticipanrsin their environmenr,constanrly adjustingtheir structureand function to accom
modate changing demands and extracellular stresses.
Cells tend to maintain rheir inrracellularmilieu wirhin a
fairly narrow range of physiologicparameters;thar is,
rbey maintain notmal homeostasis.As cells encounrer
physiologic stressesor pathologic stimuli, they can
uodergo adapiation, achievinga new steadystate and
p.esenins viability and function.The principaladaptive
hrpertrcpby, hfierpLasid, dtrophy, and
netdplasid.lf rtu adaptivecapabilityrsexceededor ifthe
ext€rnalstressis inherendvharmful, r"1/ t',r,ry devetops
(Fis. l-l). Wirhin cerrainlimits injvy is reuersibte,and
cells rerurn ro a stablebaselin€;however,severeor persistentstressresuksin irrcuersibLe
iniury ^nd dea,thoI rhe
affectedcells-Cell dcath is oneof the mostcrucialevenrs
r! rnecjirrpuol or dr\ea\ern rn] tr\\ueororqrn.lrTEittis
cru\e\. Inctudrngr\hemra (h(k ot blood
fk)w), inf€ctions, roxins, and immune reactnrns.Cell
death is aho a normal and essentialprocessin embryo
of org;n'. rnd the mainrenance
s.ner'. rhede'elupmenr
The relationships between normal, adaprec, ano
reversiblyand irreversiblyinjuredcellsarewell illustrated
by the responses
of the heart to different typesof stress
(Fig. l-2). Myocardiumsubjectedto persistenrincreased
load, as in hypertensionor with a srenodcva,ve,aaaprs
by undergoinshypettrophy-an increasein the size of
the individual cells and ultimately the enrire heart-to
generatethe required hisher contractile force. If rhe
increaseddemandis not .elieved,or if rhe myocardiLrm
is subjecredro reducedbkxd ftow lrschenial t'ron an
occludedcoronary arrery,the musclecellsmay undergo
inju.y. Myocardiummay be reversiblyinjuredifthe stress
Figur€ l-l
Stagesin the cellularresponse
to st.essand inju.iousstimuli,
Figure t-2
Th€ relationship between normal, adapted, reveBibly injured, and dead myo<adial celh. The.e
ular adapratDn depicted here is hype.-
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myofilamentsper cell, which achievesimproved performanceand rhus a balancebetwe€nrh€ demandand the
cellt functionalcapacity.There may also be a switch of
contracrileproteinsfrom aduk ro fetal or neonaralrorms.
For errmple.during murclehyperrrophy.
rhe o-myo,in
heavychain is replacedby the p form ofthe myosinheaw
chain,which hasa slower,more energerically
contraction.Vhatever the exact mechanismsof hypertrophl, a limit is reachedbeyondwhich rhe enlargement
of muscle mass can no longer compensatefor the
incieasedburden.When rhishappens;nrhe hearr,serer!1
the myocardialfibers,of
which the mosr important are fragmentationand lossof
The variablesthat Iimit
hlperrrophyand cau.ethe regre*^e chrnge,
are incomplerel)
Therem,ryhe fin,rehmrr,
ot the vasruliturero .:dequarellsuppL rhc enljrged
6ber,.of rhe m,torhondriai",uppl' ;ieno.'* '"pio,
phate(ATP),or of the biosyntheticmachinervto provide
the contractile proteins or other cyroskeletalelernenrs.
The net result of thesechangesis venrriculardilarion
and ulrimatelycardiacfailure, a sequenceof eventsrhar
illustrateshow a ada?tdtiaftto strcss.dn ptoxressK)
fi,nctionally signifuaftt.ell inia^' if the stressis tlot
(Chapter 3). In this process,grofth factors are p.oducedby white blood cells (leukocytes)respondingto
the injury and by cellsin the exrracellularmatrix. Srimulation by growth factorsis also involvedin the hyperplasia that is associatedwith cenain viral infecionsi
for exarnple,papillomavirusescauseskin warts and
mucosallesionscomposedof massesof hyperplastic
epithelium.Here rhe growrh facors may be produced
by tbe virus or by infecredcells.It is important to note
rhar rn rll rhete-rruarion!.rhe hlperplasricprocess
remainsconrolled: if hornron:1or growth factor stimularionabrrrs. rhe h!perplasiadisappears.ltis this sensirilitv to normrl regulator,vcontrol mechanismsthat
disrinsuishesbenign pathologic hyperplasiasfrom
cancer, in lvhich rhe growrh control mechanisms
or ineffettver( hrprer6t. Neverhele\\. p'tth'rlogichyperpla\.rLon,r'rule\a rerrile
soil in which cancerousproliferation may eventually
aris€. Thus, parienrs wirh hyperplasia of the
endomerrium are ar increasedrisk of devetoping
endometrialcancer,and cerrain papillomavirusi;fec
tions p.edisposeto cervicalcancers(Chapter19).
As discussedabove, hyp€rplasiarakes place if rhe c€ll
population is capableof replicarioniir may occur wirh
hypertrophyand often in response(o rhe samestimuli.
Hyperpla\ircrn be ph!roloqrcor parholog,c.
. The two rypes of pbysiologichypelpldsia zre tl)
howonal l.ypprplasQ,erempl6ed hy rhe prohferrron
of rhe slJndularepirhelumof rhe rema,rD'ca{ rr
puberty and during pregnancy;and l2) .ompensahry
blpetpldsia, thar is, hyperplasiarhar occurs when a
porrion of the rissue is .emoved or diseased.For
example,when a liver is partially resected,mitotic
activiry in the remainingcells beginsas early as 12
hours later,eventuallyrestoringthe liver to its normal
$eighr.The rrimul for hlperpla.raIn rhr( \ettinBrr(
polypeptide growth facrors p.oduced by remnant
hepatocytesas well as nonparenchymalcells in the
l;ver. Afrer resro.ationof tbe liver mass,cett proliferarronis "rurnedoff' by v:nou. growrh Inhrbrtoh
. Most forms of pdtrolog,chyperplasiaare causedby
ercessivehormonal or growrh facor srimularion.For
example.after a normalmen,rrurlperiodrherer. a
bur\i of urenneepirhelirlproliferanon
rhar ir normatty
tightly regulatedby stimulationthrough pituitary hormonesand ovarianesrrogenand by inhibition through
However,if the balancebetweenesrrogen and progesterone
is disturbed,endornerial byper
plasiaensues,a commoncauseof abnormarmcnstruar
bleeding.Hyperplasiais also an imporrantresponseof
cellsin wound healing,in which proliferating fibroblastsand blood vesselsaid in re-pair
Shuakagpn the stzeol the cell bv the lcts,o7 rcll subttanccis hn6wn as dttoprl U hen I .ufncrentnumber.f
cellsis involved,the entire tissueor orsan diminishesin
size,becominsarrophic (Fis. l 4). Ir should be emphasized that abhough dtlophi. cells nay haue diminished
function, they ale not dead.
Causesof atrophy includea decreased
workload (e.g.,
immobilizationof a limb ro permit healinsof a fractura),
lo* of innerva"on.d'mini\hedblood,uppt).in.rdequare
nurririon.lo$ of endo(flne\iimuld on. andrs,ns {,en,te
atrophy).Ahhoxgh someof thesesrimuli are physiologic
(€€., the lossof ho.monesrimularionin menopause)
others parhologic (e.g., denervation),rhe fu;damental
cellular changesare identical.They represenra rerrear
by the cell to a smaller size at whicli survival is stilt
possible;a new equilibriumis achievedbetweencetl size
and dirninished blood supply, nutrition, or trophic
Arrophy resultsfrom decreasedprorein synrhesisand
inc.easedprotein degradarionin cells.Protein synthesis
decreasesbecauseof reduced metabolic activity. The
of rellular prorernroccun mainty by rhe
ubiquitin prctcasomepatbuay. Nr\ttie denciencyand
dr'u\emry rcri!areubiqui0nhgr\e\,\^hrchaFachmurtiplecopre,of the ,mall peprrde
ubiquirrnro cellul.:r
prorerns dnd rrrger the\e prorernsfor degradarionrn
Thi\ pdthwayi\ rlso rhougl o be responible !.r lhe ffcelerrledproieolysi\,eenin a varieryof
.rraholc condiiion.,.
In ma,y siruations,atrophy is also accompaniedby
increasedautopbagy, with resulting increasis in thi
nu.nhet ot autophasic uaruoles. Aurophagy r..retfearinB-li' the proce+in which rhe srarvedcell eatr irr
own componentsin an arrempt to find nr:trients and
survive.We will describethis processlater.
. , Norma brainofayo!ng adult.
B, Atfophy of the brain in an 82 yea.old
male with atheroscleroticdisea5e.Atrophy
oi the brain is due to aging and .educed
blood supply. Note that lossof brain subnance natrows the gyri and widens the
sulci. The meninges have been stripped
from the right half oi each specimen to
revealthe surfaceof the brain.
may alsooccurin mesenchlmal cells but lessclearly as an adapriveresponse.
For exarnple,hone is occasionallrf(rmed in soft rissues,
p:rrricularhin foci of iniury.
is a reversible
changein whichone adulrcell
t_vpe(epithelialor Dresenchymal)
is replaccdb) anorher
adult cell typc. In this tvpe of cellular adaprarion,cells
sensitiveto a particularsrressrre replaccdbv other cell
t l p e . b e r e ra h l er o u r r h . r . r " d
r h e . r d r r n e, n l n r r m e n r
Meraplasiais thought to arise by genetic "rcprogram
ming" of stem cells rather than transdifferentiationof
is exemplified
bv thc sguarrous
changethat occursin rhe respi.arorvepirheliumin habitual cisarette stlokers (Fig. 1-5). The normal ciliated
cellsof the nacheaand bronchiare
focally or widely replacedby stratifed squamousepithelialcells.Vtamin A de6ciency
in thr respirarory
The "rugged'
.rrrri6eJ\quJr,'d. eDrthelummr) I-e .lble ro srrnir.
under circumstancesthar the mo.e fragile specialized
epirheliumwould not t<rlente.Ahba gh the netdpldsti.
.q!n4out qtth.luh ha' rtuiutl ddua' dRc<.tnltut,tdt
fn tettruenTl dntsusa'p /,'st..urh .r\ mucu\n\ relr^n
and ciliary clearanceof particulrremarrer gpithelial
metaplasiais thereforea double-edged
sword; morcover,
tbe influeft.esthat indu.e metauldstictra sfolmatlfi, if
pe/sistent,ndy predisposeto ndligndnt trdnsfalnation
ol the e?ttheLium.ln fact, in a conmon forrn of Iung
cancer,squamousmeraplasiaof the respirarorvepithclium olten coexistswith cancerscomposedot malignant is thoughr thar cigarcrtesmokingini,
in someof rhesealreredfoci. MeraplasiaDeednot always
Figure r-5
occurin the directionof columnarto squamous
liumi in chronicgastricreflux,the normal stratifiedsquaMetaplara of norma columnar(/eft) to 5quamous epithelium
of the lower esophagus
may undergo (rigrt) in a bronch!5. shown (A) (hematkally and (B)
nrcraplasricrransformati()nto g:rstricor intcstinalrype
Cei nturyCeitDearh,
. 6 ' ,
CellularAdaptationito Stress
. Hypertrophy:
In re\pon\er,,,n.rer\ed $,,rkloadr inducedb)
,ffe$ rnd by ero*rh facron;,'.cun.n
tissuesincapableof cell division
. Hypelplasia:increasedcell numbersin re5ponse
ro hormone.rnd ,,rhergrowrh {actor.i,,crur. in
tissueswhosecellsare able to divide
. Atlopb,: decreas€d
cell and organsize,as a result
of decreasednutrient supply or disuserassociared
wirh decreasedsynthesisand increasedprot€olyric
breakdownof cellularorganelles
. Metdplasa:chrnsein phenotypeof d,fferennarcJ
cell\. ohen a re\pon\ero rhronit r-ntationrhar
makes cells better able to withstand the stress;
u,uJll)indu.edb) Jltereddrfferentiarion
prrhwrl of
ri*ue nem Lell\imJy re.Lrlrin reducedfrn.rrurrror
inc'er'edpropen.It for maLgnrnrrranrformatron.
' ',c]t
-'' ''
.f:^ a
,"_rl 9
A . , r . r |d, , i r r h eh F g i r rn q^ t r h , . h J p r e r . . , jnt i u r , , . , J i r \
w h e n( 1 . d r e . r f t \ \ d . o , c , . r r l y r h . r r h r \ . r r en , ,t , - B e r
ableto aclapt
or whencellsareexposed
ro inherenryoam
agmgagen!sor suffrr from intrinsicrbnormatiries.
ferent injurious srimuli afiect rnany metabolicpathwavs
a ' d . e l r u h ro r a J n e l h .I.n , u ' t n ' , 1 p . o q " r , , , , , " . . g n,
r e \ e r . r eh ' r J B e. ' n d , u l r r : r . r irne, e l ld e i r h, , e eF r g t - t . .
. Rercrsihlecel! oiutt.ln earll stagesor mild forns
o f . n i . , t r h ef u n . r r , , n .r r n dn , , , r f h o l n gct h r n t r , , r e
r e v e ^ , h 1, r. r h ed r m J t s , n s . ' , m , ,i1. ur ;. , , , r e d A ' r \ , \
srage,althoughtheremav be siBDilicanr
rhe injury hastypicalll nor
progressedto rnd nuctea.
Q,) "
ot apoptotic
celluar featuresof necoss (/eft)and apoprosi5
(.bhO (Adapted
from Walker Nr, er al: Patternsof cet death. M;thods A;chv
Exp Pathol13:18-32,1988.with permission
of S. Karger,Baset,
os!, ncdtdnnns, an.r robs n diseasednd physnk,sy
(liis. I 6 andTable1-l). \(hen dam:get<,nrembranrls
c!toplasm,and digestthe cell,resuiringin zerrosis.Cellular contenrsalso lcak our through the darnaged
plasma membraneand clicir a host reaction (inflammatur). Necrosis
is rhcmajorpathwavofccltdeathin
many comrnoDlyencounteredinjuries, such as thosc
resultiDgfrom ischemia,
exposurcio roxins,vanous
inlections,and rrauma.!(hen a cell is depfivedof
qrolvrh lJrrol' "r rhe ,ell\ DNA .,r prore.n,rre
d.rmrgcJI'eyondrepJ,r,rhf cell l,ll, ,r,etrt'r ,nlrher
. Cell death. Wirh coDrinuin8damage,the inlurv
becomesirreveBible, at lvhich tinre rhe cer carrnor
recove.and ir dies.Thereare two typesof cettdeath
netrcsisaftrl dpoptosis tuhichdif[er in tbeir mo4lhot
rt_ilr l
of Ne(rosisand Apoptosis
Pyknoes J k:ryoiihcrr
tragmrn!anon no nu.leosom.n,?elrigDcnb
Intacti altrcd $ruduc, spaiallt orien&non of
l'hvnolog'. o. f&ho1.g(
Eozvnrr.c d'ge$1oni nril lerk ou( ot cetl niil br rele.sedD aD.pron. bod,e!,v pdrholosr. l.ulnrnrnon
Olrcn phriologr., merns.l ct,m'.anng un*,:nied
cells:tr[r he f]thoL(aj( rft.r y,fre nrnj! ol
.eLlrDrur!.c\peor lr D\A dinrtrsc
CeI InjuryCeI Dearh,
typc of death,callcd dpoplo$r, which is characrerized
by nuclear dissolution without complete kxs or
mernbraneinregrirl. Apoptosis is an acrivc! r,,crsy
dependenr,rightly regularedtype of cell death that is
'een in .,me .pe.ifi, \lurrion,. $rc,cds lr.,/,^^ r5
alwav'.a fath"].u, t'h\'ett. ap,,p!.^tttctuc, ftany
nuthal lu't, tn n' dnd E h"r neccssanlya':,riaral utth
pdtholoei. ell Mftry.The rnorphologicfearures,mechanisms,and rignificanceof thesetwo dcarh pathways
are discussed
in more derail larer in the chapter.
arino acid,rh,rrutun in hemoglubrn
\ grung n.e ro
\ i . k l c . e l l r n e r i J . a , e n e t idi e f e , r r\ r a yi . r L l er r l l r r r l u r r
becauseof de6c;encyof functional p'oteins, s'ch ai
in inbornerrorsof metabolism,
or accurnulation
of damasedDNA or misfoldedpnrteins,both of which
triggercell de:rh when rhevare beyondrep:ir. Variati{'rs
in the geneticmakeupcan alsoinfluencc
the suscepribiliry ofcelh to iniurl-by chcmicals
and othcrenvrronmenra1insults.
Nurritional Imbalances.Even in thc current era of bur
geoningglobal affluenle, nurritional deliciencres
a major causeof cell injury. Proiein-calorieinsuffciency
among underprivileged
popularionsis only the rnost
The causesof cell injLrryranse from the gross physical ohviour crlrple: ,pe.,ii. \,rrmin drfir,e,rre,arc n,r
in devek)pedcountrieswith high stanrraumaot a moror vehiclraccidentto the singlegcne
dardsof living(Ch:rpter
8). lronically,
defecrthat resuhsir a defecr;veenzymeunderlyingaipcexcesses
of nutriron are also important causes of morbidity and
ci6c merabolicdise:se.Mosr injuriousstimuliian-be
Drortality;f(r example,obesiry markedly increasesthc
groupedinto the following caregories.
risk lor iype 2 diaberesmellitus.Moreover.diers rich in
Orlgen Deprirarion.HV,,rtt. o. ,,r1gen deri,irncy. rn mrl
f.rr;re,rr,rrgly impl,(JredIn rheJev,.topmenr
$irh derobrcn\rJdrire re,prrrrron,rnd r, rn
arh(-u\clero!.a' well ar n rn.rer,edr.rlncrrhilrttro
andcommoncauseof celliniuryand
rnany disorders,includins canccr.
d,JrL. HlpovJ rh,,uldbe Jr,nnguirheJlr,,n rd..nta.
$ h , . h , \ - ,l o $ n f h l , , u d \ u p p l n
1 a r r s . udeu cr o r m p e d e d Physical Agents. Trauma, extremes of tcrrpcrarures,
arterialflow or reducedvenousdrainage.n0hileischernia radiarion,electricshock,and suddenchangesrn armosis the most comrnoncauseof hypoxia,oxysendefici€ncy pheric pressureall have wide ranging efficrs on cells
canalsoresuhfrom inadequatc<ixvgen
atn,n-o I rhe blooj,
r . i r p n e u r . o n i i . , , r e d u . r r o rnn r h e o $ g r n - a r r y i n g Aging. Cellularsenescence
leadsto altcrarionsin replicac r p J . f l ), , f r h eb l o n d J, , I n b l . o J l , ^ . a n e m , ,rr c r r b o n riveand repairabilities
of individualcells
(CO ftrms a stablecomplex of rhe,e. hange.
monoxide(CO) poisoniDs.
rc,uh ,n a drmrni,h,
J rhrlrryro , e,1,,nd
wirh hemoglobinthat p.eventsoxygenbinding.)
r o d J m r g eJ n L le. r e n r u a l lrlh. ed e r r h, , f L e l l .r n d o f r h e
,trgJIi,m.Tl-, me.hJni,nr urderlving., )lubr ,rgingrr
ChemicalAsents.An eDormousnumberofchernicatsub,liscussed
ar rhc endof rhrrrh,rprer.
glucoscor sah,ifsufficiendvconcentrated,
canso derange
rhatcellinjuryor dcarhresults.
Oxygenat sufficiendvhigh p:rtial pressures
is also roxic.
Agertscommonlyknown as poisonscauseseveredamage
at the cellular level by altering mernbranepermcabitiin
lr is usefulto describerhe basicalrerationsthat occur in
osmotic hofteosrasis,or rhe inregrity of an enzymeor
ccllsbeforewc discuss
ihe biochemical
cotacror!and exposureto thesepoisonscan culrninatein
nisms that briDg abour rhese changes. All strcsses
the deathof the wholeorganism.
agenrsare encountereddaily in our cnvironment;rhese aDd noxiou! intluencesexerr rheir effecrsfirst ar rhe
mole.ull ,'r
le\el.Lplluldrluncttonnay be
includeair polluranrs,insccticides,
CO, asbestos,
losr lons b,l,.re cclldearh"ccuts.and the nuryna,,st.
social srimuli"suchas ethanol.Eventherapeutic
drugs chancesof ce iniury
lot dedth)lds fdr behindbo,b tFiE.
L . r n , , r u \ c , eolrl r i , ! r ci n i u r yr nr s u s c e p r r p
l rr r e nnrr r f
1-7).For examplc,myocardial
cellsbecomcnonconrracu,eder((\\i\elr or inJnfropri:rrl1rr h.rpre-8'.
'rlerfrer I ro 2 rrlrute. ot \ hemu.Jlrhnutsh
rnel oo n.l
Infcclour Agenr\. fhe.e rrnge trom .ubmi.r,,,otic
die unril 20 to l0 nr nure'of i* heria hrve(rJp.ed.Ihe.(
vrruscsto meter'loDgtapeworms;in betwcenare rhe rick
myocytesdo not appeardead by electronrnicroscopyfor
ettsiar,bacreria,fungi, and pmrozoans.The diverseways
2 ro 3 hours,and by lighrmicroscopy
for 6 to 12 hours.
by nhich infectiouspathogenscauseinjury are d;scussid
The cellular derangements
of reversibleinjury can be
in Chapter9.
and,ifthe injuriousstimulusabates,
n , r n a l c 'P , r n . r e n r o r c \ r e ' \ i v e i n . u ' ) . h o $ e v e r .
Immunologic Reactions.Although rhe imnrunr sysrem
cJu,e\cell' ro pa.. rhenrbulour"p,rnr ur no rerunr"rnro
defendsrhe L,odyagainsrpathogenicmicroocs,rnnrune
nrcuersibleiniury ^nd rell drarb. The eventsthat derer
can alsoresulrin ccll and tissueiniury.Exam
minewhen reversibleinjury becomesirreversibleand pro
ples includeautoimmunercacrionsasainstones own
to cell death remain poorly understood.The
and allergicreacrions
of this quesrionis obviousiif we can
in generically
an'werit rr mav be ahl( ro devi,e,rrJregre\
Inr tre\e t
GeneticDefects.ceneric defectscan result in pathologic ;ng.ell inluryfrom harrngperm.rnenr
as conspicuous
as the conseniral
malfbmmr;ons querces.Although rherearc no definitivcmorphologicor
with Down svndronreor as subtleas the single biochemicalco.relaresof ifferers;bility,xuo phenomena
The two main morphologiccorrelatesof reversiblecell
iniuty arc ce ulat swelling and fatty thange. Cellutar
rwellingis rhe resultof failureof
pump\in rheplasmamembrane.
leadingro an inabilnyro
maintainionic and fluid homeosrasis.
in hypoxicinjury and variousforms of roxic or merabolic
intury.and i! manife*edbr rhe apperrrnceot \mall or
largelipid racuolesin rhecyroplasm.
Ir occursmainlyin
cellsinvolved'n and dependenr
on fat merabohsm,
as hepatocytesand myocardialcells.The mechanisms
fatty changeare discussed
later in rhe chapter.
C.llul.r 3w.lllnt (Fig.1-€B).th6 first manitostationof
almost all forms ot injury to cells,is dif{icultto appreTherclationship
cistewith the light microscope;it may b€ more app6rmoryhologic
of cellinjury Notethat cetkmayrapidty
snt at the lsvel of the whol€ organ. Whsn h affects
aftertheo$er of injurvatthougtfthey
manycellsin an organ it causessome pallor,increased
ttill viable,with potent'ally
dam;9;;a tong durarion
turgor.and incraasein weight of the organ.Microscopic
or In,urymayevenludlly
leadto irreve4'ble
examinationmay rsveal small, clsar vacuoloswithin
Notealsothat celldeathtypkallyprecede5
lhe cytoplasm;theseropresentdist€ndsdand pinchsd,
andgrsrly visiblemo.pholoqi.
off segm€ntsotthe ER.This patternoI nontethalinjury
is sometimes called hydropic ch€ngc or vacuol.l
dog.n.ration. Swelling of cells is r€versibte.F tlY
consistefltly cbaracterize it/eyercibilitf: the inabili, to
chrng. is manifestedby th€ appearancsof tipid vacuolss in the is principattyencounrsredin
rcuersemito.hondlial dystlr.r'b, (lackof oxidarivephoscells participatingin fat metabotism(e.9.,hopetocytes
phorylationand ATP generarion)even
afrer resolurionof
and myocardialc6lls) and is also reversibl€.Iniured
rhe original injury. and profound drsnrbancesn mem.
cells may also show increasedeosinophiticateihing,
branefunctio . Ls mentionedearlier,injury to rysosomar
bocom€smuch more pfonouncsdwith progresmembranesresults in the enzyrnaticdissolutionof the
6ionto necrosis{describ€dbslow).
injuredcell rhat is characreristic
The ultrastructurslchangssof reversiblecell injury
Differ€ntintudousstimuli may inducedeathby necroers illustratodschematically
in Figure1-9andinctude(1,
srs or apoptosis(seeFis. l-6 and Table 1-1). As menplasmamembran€alterationssuch as blobbing,btunttioned aboveand detailedlarea severedeDlerionof ATp
ingordistortionotmicrovilli,and tooseningofintorcetand lo* of membranernregnryrr€ typicilly assocrated lular attachments;l2l mitochondriatchangessuch as
wjth necrosi5.Apoprosrsr. an ,c !e and reeulared swellingandthe app6arance
phousdensitiss;{3)dilationotthe ERwith detachmont
procesr nor assocratedurrh ATP depletronand n har
whrchwe wrll describe.eparatelv ot ribosom6sand dissociationof polysomss;and (4)
nuclsaralterations,with clumpingof chromatin.
larerrn the chaprer.
Figurt l-7
Figurc 1-€
Morphologk(hdngesin t€veBible.nd nreveBible(ell injury{ne(oris),A Noftat tidney tubuteswrth v'ableeo'theti.t (e r. a. Eartv
rrelenrore,6oem( Inlury3howrngsurtacebrebr,increaeed
eotnophiliaof q/,and twellingol o(csionat (eth, C, Neooria{nre'vereore,InJuryor eprthelral
cerk,with rossof nu.leiandfragmentation
ofcelk andleakageol(ontenti. Theuttrdttructuratfearu,s ofthere
stage or.ell injurvde ehownin F'9.l-9. (courteryof Dis.NealPin(kardand M.a. v;nkatadatam. univel'iryot TexasHeatthSdences
I -
Cel lnju44Cel Death.andAdaptalons
, r \q{i:,v/
, -*l-'
f l ) o _ i , . - : i i
N<oss -'_r
, .. :o-'^ -3
A normal.el and the.hange5in revereible
and i.reversible
cell injury(ne<roris)
The term narroslswas first usedby morphologisrsto refer
to a seriesof changesthat a.companl cell death,largely
resulting from rhe degradativeaction of enzymeson
l,i hJll) Inrured
cell,.\ecronLtell. rre unabler,,mrrnran
membrancinregrity,and theircontentsoften leakout. Thc
enzymesresponsiblefor digestionof the cell are derived
eitherfrom thc lysosomes
of the dying cellsrhemselves
frornthe lysosomes
of lcukocytesthat arerecruitedaspart
of the inflammatoryrcactionto the de:d cells.
In onecommonpatternofcelldeathresulting
of oxygen, the necrotic cells show increased
eosinophilia1i.e.,pink stainingfrom the eosindye, the
"E" in "H&E").Thisis attributable
in p6( to increased
bindingof€osinto denatured
in panto lossofthebasophilia
thatis normallyimparted
by the ribonucleicacid (RNA) in the ctloplasm
is the bluestainingfrom the hematoxylin
dye,the "H" in "H&E").Thecellmayhavea moreglassy
than viablecells,mostly
because of the loss of glycogen particles. When
enzymeshavedigestedthe cytoplasmicorganeiles,the
cytoplasm becomes vacuolatedand appears moth
eaten.Deadcells may be replacedby l6rge,whorled
phospholipidmasses,called myelin figuret that are
derivedfrom damagedcellularmembranes.They are
thoughtto resultfrom dissociationof lipoproteinswith
unmasking of phosphatidegroups, promoting the
uptakeand intercalationofwater betweenthe lamellar
stacksof membranes.Thesephospholipidprecipitates
are then either phagocytosedby other cells or funher
degradedinto fatty acids;c6lcificationofsuch fatty acid
residuasresults in the generationof calcium soaps.
Thus,the dead cells may ultimatelybecomecalcilied.
By electronmicroscopy(seeFig.1-g),necroticcellsare
characterized bv discontinuiti€s in Dlasma and
markeddilationof mitochondria
with the appearance
of largeamorphousdensities,dis
ruptionof lysosomes,
and profoundnuclearchangesculminating
in nuclear
Nuclearchangesassumeone of threepatterns,
due to breakdownof DNA and chromatin.The
aell niurycellDeathandAdaprarons
b a s o p h i l i ao f t h e c h r o m a t i nm a y f a d e ( k a r y o l y s i s )p, r e s u m a b l y s e c o n d a r y t o d e o x y r i b o n u c l e a s e( D N a s e )
activity. A second pattern is pyknosis, characterizedby
n u € l e a rs h r i n k a g ea n d i n € r e a s e db a s o p h i l i a i;h e D N A
c o n d e n s e si n t o a s o l i d s h r u n k e n m a s s . I n t h e t h i r d
pattern, karyorrhexis, the pyknotic nucleus undergoes
f r a g m e n t a t i o nI.n 1 t o 2 d a y s ,t h e n u c l e u si n a d e a dc e l l
c o m p e t e l yd i s a p p e a r s .
MorphologiaAlterations in Injured Cells
. Rcrcrciblecell iniury: cell swcllins,fetry chansc,
plasmamembr.rneblebbingand l(xs of mic(,
villi, mnochondri:rl
s$cllins.dilarionof dre Elt,
(dueto decreascd
. Nerrosa'increased
:nd dissolution;
plasma membrrne .rnd orgrnellar membranes;
and enzvmatic
. Ar(rn)s's: nuclcarchnrnrnnncondensation;for
mationof apoprotic
of ruclei.r d
of TissueNecrosis
\ , . - . , . r ' , ' f r . , ' l e . , , , i . e l l .r . r r r * r r c , , , , i , B , , . r i r
i n s r a n . c ! n r h f , s c h c n r l cm r r r . r r t l i u n r . r c r r h s i n r l c r r h o f
r h e e n r i r . n s s u ei n d v r l r e t i r e s . r l rc l r t i r eo r g a n .T h c r c a r e
s r l c f . l n r ( t r t h o l o g i c l l l r d r s l n c r p : r t t c n r so f t r s s u cn c c r r
s i s ,\ ! h i c h n u I p r o ! i d c ! l n e s . r b r i r t t h e u l d e r l r i r r s e r u s r .
A l t h o u g h r h e t c r r n s r h r t d c s c f l b er h e s ep r r r e r r r sd o n o r
r e f l e c tu n d c r l y i D sn c t h a n i s m s . r h e t e r m s . r r e u s e do i r c l
r l d t h e j f i l D l j . ! n ( n r s r r c u n r l c r s t r r r db v b o r b p : t h o l o g r s t s
Coasulativenecrosis is a form oftissue necrosisin which
. t h ec o m p o n e n tc e l l sa r e d e a db u t l h e b a s i ct i s s u ea r c h i
tecture is preseNed for at east several days (Fig. 10).
The affected tissues take on a firm texture. Presumably
t h e i n j u r yd e n a t u r e sn o t o n l y s t r u c t u r apl r o t e i n sb u t a l s o
e n z y m e sa n d s o b l o c k st h e p r o t e o l y s i so f t h e d e a dc e l l s ;
a s a r e s u l t ,e o s i n o p h i l i ca, n u c l e a l ec e l l sm a y p e r s i s tf o r
d a v so r w e e k s .U l t i m a t e l r t h e n e c r o t i c c e l l s a rree m o v e d
b y p h a g o c y t o s i so f t h e c e l u l a r d e b r i s b y i n f i l t r a t i n g
l e u k o c l t e s a n d b y d i g e s t i o no f t h e d e a d c e l l s b y t h e
action of lysosomal enzymes olthe leukoc},tes.Coagu
lative necrosis is characteristic of infarcrs {areas of
i s c h e m i cn e c r o s i si)n a l l s o l i do r g a n se x c e p tt h e b r a i n .
Liquelactive necrosis is seen in focal bacterial or,
o c c a s i o n a l l yf u
, n g a l i n f e c t i o n sb, e c a u s em i c r o b e ss t a m
u l a t e t h e a c c u m u l a t i o no f i n f l a m m a t o r yc e l l s a n d t h e
e n z y m e so f l e u k o c y t e sd i g e s t( " l i q u e f y " )t h e t i s s u e .F o r
obscure reasons, hvooxic death of cells within the
c e n r r a ln e r v o u ss y s t e r no f t e ne v o l e s l i q u e f a c l i v en F c ' o s i s ( F i s . 1 1 1 ) . W h a t e v e r t h e p a t h o g e n e s ilsi q, u e f a c t i o n
c o m p l e t e l yd i g e s t st h e d e a d c e l l s ,r e s u l t i n gi n t r a n s f o F
m a t i o n o f t h e t i s s u e i n t o a l i q u i d v i s c o u sm a s s . l f t h e
p r o c e s sw a s i n i t i a t e db y a c u t ei n f l a m m a t i o n t, h e m a t e
rial is frequently creamy yellow and is called pus
( C h a p t e r2 ) .
Although gangrenous necrosis is not a distinctive
p a t t e r no f c e l l d e a t h ,t h e t e r m i s s t i l l c o m m o n l y u s e d i n
c l i n i c a lp r a c l i c e .l l i s u s u a l l ya p p l i e dt o a l i m b , g e n e r a l l y t h e l o w e r l e g ,t h a t h a s l o s t i t s b l o o d s u p p l ya n d h a s
undersone coasulative necrosis involving multiple
tissue layers. When bacterial infection is super:mposed,
c o a g u l a t i v en e c r o s i s i s m o d i f i e d b y t h € l i q u e f a c t i v e
action of the bacteria and the attracted leukoc!,tes(so
called wet gangrene).
Caseous necrosis is encountered most often in foci
o f t u b e r c u l o u si n f e c l i o n .T h e t e r m " c a s e o u s "{ c h e e s e l i k e ) i s d e r i v e df . o m t h e f r i a b l e y e l l o ww h i t e a p p e a r
a n c eo l I h e a r e do f a e L r o s i s{ T i g .' l 1 2 ) .O n m i L r o s c o p i c
e x a m i n a t i o nt,h e n e c r o t i cf o c u s a p D e a r sa s a c o l l e c t i o n
o f f r a g m e n t e do r l y s e dc e l l sw i t h a n a m o r p h o u sg r a n u
C o a q u l a t v en e . r o s i i A , A w e d q e s h a p e d k i d . e y n f a r d ( y e l o w ) w t h p r e r e r v a t i o no f t h e o u t l n e s . B , M r < r o t c o .p v i e w o t t h e e d g e o i
the infarct, with normal kidney (N) and necrotic ce k n the nfarct (l). The .e(roti..e k show p.ese.ved outlines w ih lossol nuclei, and
an inf ammatory lnf ltraie I prete.t (difiicult ro d s.ern at th s maqn on)
j ":l
:i".,. .'-'
';"' "i'u: ': ,1,.
i r lt
: Ji f .
1 : - . : ,, :
-., ,
utn prorcrns,hdush
rhr drn,s.d
'h. cncuhnon,ro
lidB ' n.'n5 ',fdfl(rn8 n$ucsp(,f( nrtrou5u,ns
arr,li:( DUeh, fnr.rimoh.
a unlqkrornm ofthr mzrn.(etiD. kim!
?id of'h. lonkd . mo.e'nrotu";. "hei.rsh.or .
hile dud tp+€lilm onirn',
kmFi,r,r R,;rut
roforh of rhe.nzym.ikatin. pholphnzr, and h.p,
6ibl. initrs ind 6tl
deed in ih.n isues rrt rtne(d in incm*d 5!run
lelels ol !u.h pror.'ns, ind m.asurcmcnroI erum twek
n uedclini.allyrc s!.$ damrs.b .* issues.
S||br.llubrrerponr.sro Inl||r!
rhus f2rv. h:ve mrnt fo.ued on ihewh.teissur or
lh. ..ll as , u.n. HolBer! .eit in z*.nb znd jr..*s
ntt,l!ns ony sub.dtuhr
ol8,n.rh!. Ar+oleh em. ot 'hG;tk
ron, (cur,r
rd.rdharinruq,o .EJE(rn,nLhrontrru,morrdl
iniurn and ,ill.orl'ds arc id,pl1y
n :nd 'ntr.nine o'
ther rtnion! arc d\o^w.l
Aubptisy EG6 ro tvsos.naldisenion.f
rh. c.ll\ osn .onponenr rnd is .onm$.dtnh ,gr
suberi.o hom rh€cdriJc for i,riicd/uta! dsruqioi
lFis.l-15).Aurcph,syn rhousirb L. a suryi!, n nm.s or d.privarion,su.h rbar thr
fiflrd cll liy6 br sms ib own .oftns, tn ll1r
prtu!$. nr,cdtuhr o|e?nr s Jd
ir< hrslfqu{rcrd fr,,mlhe+'oolz'nn
,,. {o/. fomrd trcmnbo,on! fft,4'on\ of rh. rc;h
ER LRERrTh€lr.uok tu*5 wtrh y,o",-s b brm;
c,tdthasatya'an4 :nd rh. c. trl, .omlon.ns re
di&*.d by lysdonll.nzyms. Auhphasyiinni:Ed by
ev.Er prckrsihr$nsenrntntd.pnv,.on. tf nis nor
(o arcd,aroph:8) m4 resisnrt.d drnh h) rpop
hn.d ellrh,r Lrlrn
n,, ions.imp. br Inins on B"$n or6ndL!.
Thr.i4n6 n lr5o, brcrl do\n msr Do
rii!,nd crbohydrua, at'housl sohr tiD& rcrfu,n
uidicdEd tF6on6 wrh und&{.d,s mr *.
n{ wtrhLn
alL a! E &,16,,&., o' m! b. -;ud.d.
Liort..i, prr44 3hnul6 r.prckft md,s6nbL€
rur rt5drnB hom frc. Dd,c,t_m.dDEdhDd Ddo",
d,ion. cddn indisKnbtc pisnrn( 5uch ,s i,rhon hhd.d fom rh. .rmosphei..r incul.ted
,i pL2sotrsosom6
mr.ophasesrar (disus.d tarrr.
rh,r dtsade v,irousn.cromoh.ut*. Rsultin
:bnorm.l 6l1.dons of int @.diar iQ a.
Irsoson6of als,
.v.r fi. b.dy
d2nr :us.ptibl. rt, l.thaLLriua lrcm suchdhuta.
Indtroion (H}}.drop[y) of Smoarl'ER. Th. smoorhEt
(SER)is'.volnd in thend,h.lnm otvaria!.ch.miak. qFrd to rh6. ch.mi.abshowhyrrt.onh!
of rh. ER a! .' ldipiv! Esp..s. r[n oa], h;v. idorr
n$nc€, b$birur.tes
arc nerabolized ir tllr llve by the crehrcme p-1J0
m,xedfundon oxidl* sstem found ii the 9ER. pn,
r2&d useof brhnuEB hi& b a $r
wnh a in fi. dlfr6 oI rh. drur ind d. natl b
ur inci.rins dotrs.TIn:daphrion ddue to incRz*d
eorun. th)p€tuophy)of $e sER ot h.Ddo.yr.! .nd
in(osed P450 .n4m ( nr!trr. Ahh;ugh p.
4so-m.dftJ mod'filrnon6oh.n rhoi, r"f-jit-",
ai€ rcnd.d,o/. inMi.6
by rhn prE q on! exanpk n.rboo ter'chtorid..dis.
.usd l,r.i In addnion, d! p.oduc6 forn.d by this
oxidrtiv. f.tabotism in tud. recrvr oxyeln !;f!
rRosr, qhrh cin r!ft rh. ([ .rrs adji'ed ri, om
.rrbotr,{her !on
poundshrndl.d hy th. sE. syn.n. Thu5.if DdmE
hkins ph.nobarbndIq.Dit.Dsr rncrt1srhff ;Lohol
rblc, rh.y m.' hrv. subiherip.ud. tev.h ct th. .ntib..ruit oI iDducaonol sFR r
Mi'qho.lrirl Atlnrimr. A! t,kr, mrGhon
dier drrrundon Fhy. :n ,mpon,
inruryand d€aih.ln en. ronldh.t Dnholmicd,!di
iion!, hou.v.l rhG n,y b.,h&aioi,s n iha lumb.i
si-. shrF, 1nd presumrbly
lundion oI nirrhondni.
ror$rnpk, ine uLrhrFnoph
in 'hr fumbn oI m, miro.
lhondnr d..rtas. 'n nunb.r dunnr cdlutar irioDhr
rrob,bb !E arcphisr. MtrEho;d.r m4,,s;-;
elftmlr' ri'3f ,nd ;hnomrt lha
,ous,dri,t,r, drti
..noa,nd i.ohotic tivd dk..5e
mer:bolic di**6 0I strtdal nusb. thc nno.hohdtidl
nlotdltE', d.ks in mirEhondn.t mdrbotjf n€
oAdnr rsri,rd
wnh iicr..sed rumb.6 of u.urui y t2is.
rnchondn. conr.inilgebnorml trnb..
rctin rnd nlsrn ril,mha. nnrotubuks,a v.riour
d *..t iftlmldi.E 6lan.n6t svd,lorh.r nonpl,lyn.r;cdandronfiLmenrous
fomsatonr,.ih Drorein5
.ko cornibuk ro rh. cdluhr siffolJ. Th. .rlosLddon
is impoit ni for n,ny c.llula!Iundions.inctudns
. lnfec.llulrr hnsDort [email protected] .nd nokcuhs
. Mirhli.i
oI 4.5i. cdt;rchn durc 1r.g.,
por,rirr,,lierinsunhiqup enddcsn)
. THnsmissionof rtll{.l| 2nd err<xnaallul,r
. Miinrtftn..
of mahanical $rtnsth tor i55u.
cdls ,nd rstr6 i..pond b .nvnonm€.tt sis.ts
k.3.,she,rsca in bk,ody6skor iD.Fdtd prtsuc
ii .l'!an) by con$antlyrtmad.linsdtir inrac.llular
$:ffotdjns.Abnorm.tnmof rh. qbskd(on oaDr in,
vrri€ry oi pitholosic $1r!. Tij.e abnom.lri6 har 6.
mn1i.s.d s r .b.ormataDF3rrne 'nd lundi.n oI
.d15(hrp.nophic cardiomyop,rhyt
cl'.pEr l l), 3btr.
:nelks.d.fdi!. ftll
ldonomn. dr inr..dlula
ccuinuhiicn oI 61,!irh,
nrnri2l ,s in ,coholic tiverdiksr (c[apE 16).p4.
o.h.rionsin th. ol8rnianonof,nrtubuLscane *
*erility by ,.hibnins .p.m honLty, s uell s d.fnaiy!
mobirn'of!irr in,h. 15pnrory.ptrh.t,um,Kat ns,n
!hronr nfld nn5d!. ro 'mFrr.d !qEnc oi rnhrLfd
6.ckia lkrtuseEt, or t\. idnotile dlir, stndrtdzr.
Mtrrcrburs,i. rrn,.s$nnrt Ior kIL&rr m,4En,'n
,nd phrg,r)tosi5Drussrhr prc\.d m.i{ub!1. Fly.
m{ft rron1e3...okh,!,ntr,r.d.fu
€n' of mroph:g6
ro*ard ui,r.ftyi*
unh subr'tue [email protected]
it ,h,*o+osis .nd inflanmrtion.sii.r hicrorubul.s
r.rm ih. mnoic spmdl.. dius. d'2r bild b microrubuhs
(e.s..vincr rlk,lods) ,i. 21o .rtiDrotileHtive
,nd m.y
thercfor.b. u{Iul .s.Dtnumorr*.nB.
Iru r,trr
Slbclkl$ Ahdddr i. <.ll hl{E:
Elld ol r4udoBA!.it oi ds.;cl6.nd
SoD. iorms ol ..n injury 'tu*
olgimlr6 ,nd hay! uniqu. mrnilsbriotu.
. ,4!rrra3'r In nurienr d.priv.d alh. olsanells
n. .nclosd in vicual8 thar fu$ with lKo.on6.
Th. are,nclI6 ar. digsrd bDt in .on.;as
indis.ii6l. pism.nt(..s. LNtusjn) rh.ins.
t l|.rntl'y
of strli c.ll6.rEd
to bnrs drt
rrcn.hboh?d,n,h.5tR 5howhy!.ndph, of (he
meh,ntrn h m.vm,z
.d hilrartu!! rd^&er6
. Mnuhontrkl
albatioas: Chsrgs in
.umbri, si4, and sh,ts oI mirNhordii ar Fn in
div.c ad{t iions rrd r.$on$ to chrcnic i4ury.
' clioJtslsal clrd,.rbzr son. druss ,rd roxinr
:isnbly r.d lunaions ol fiLmens or rcsfi in .6nodal rau.
r ruRy
I rEctatttfls of cEr.L
Now thr s. h,!. dieu5*d rh. cau$sofRllinFry rd
narasis.nd .n no.pnotqic'nd tun(oni.orEtaks,
w. ie{ considerin norc d.r,il th. moreutar ot
cdl i,iury rnd lltd illun,ar rh. impoit nr prin.ipt.!
wiih r r.w krr,.d "xanpr6 orcommonryp.sofiriury
Th. bi&hrhicn mehanismslinkinemy sivm iniury
with ihe rcsukiq c.lltrlii rJ Gsu. mnife$.iions,ie
complex,ifueKonndEd..nd ishrly nrrwoytn wnh
mrny nhc.lluh! mdaboh. paih
aft.n dil6.urt r pinroinr 3Deri6.mohculrr akd,
rionscau$dby r pini.ular insuk.N€venh.lsi nlcral
s6d,r prin.ipl.s:r. rct.vrnr ro nai f.ros of cdl
. Th. eltulo ft:panr to i,i',h,' n'nuh d?p?n&oh
the ,p? ol inj,4, it' dyn o\ and * rfu?7ifr. rhus,
low da*.aI!xi!5 ora bn.fdunrian.Inchlm; nav
LrJ $ Beribl.ellniurx wl'e.:s lars*toxn dok;
sult n trrcv.sil'r.
iniuq rnd e1ldeft.
. rh. a,[email protected]
ol dr k)u,ius n'autrs d?p?h!t
" th. ttp.. iat"., ddnphhnt. cnd zdan tua.ap
at th. inPnd .,r. rft en. ntq\ h's ! tr J ftqrnr
ourona d.tsndins on th. c.1t 116 thun *tuEd
sk.l.El muele in dr 1es"<omnodaks .onDltir
i$hemir for 2 ro r hou6 ynhout rak6ibt. inlury.
wh.r,s c,rdi2. muste dies rfrft onir 20 h t0
nintrk.. Th. nunnio'rt (cr horhonat)naiu5ca, rlso
b. impon,, ? sj.osen.rcptd. h.p,r{rk
w,[ ror.r,rcn( mrh bflkr rh,n "nr ${ h]!
run brm.d n! hrslu.or molRul..ccndcnty d.tcr
nin.d diy{siry i' mdrboli. p.r6way5can .Ls b.
'mpoftznr.For inr2n !. whenexpord rc rh. s1m.
dok or i raxin. individ$tswho lnh. yariancin
s.n s .n.odrs crtchrcn P 450 n.r crabotiz the
'oin ai differcnrfira,l..diir b diff.rcnrourons.
Mu.h.ffofl is nowdir(kd tosrrd und.d.ndircth€
rot. ot Fnd. potlmclph',m\m (spon*. ro d,,uAi
:nd rnh5:nd in dn.'( 5u{.otibitiF.Thr sudr oI
5uchinrmctio,r ir.dr.J Dh:;ase;omis.
. inqry ks\ns hon f,rctiorul dnd brrr.nnal
cbhandhn' in ote ot rat o{ sr{al .seanat dqt
tat .onpo"nB \Fie. l-16). Th. Do$ mponrir
i:4dr or rimuli aG lt) mne[.ndria. rh.
sita of ATPs.r*arion! 12)rtllnchbBn ! on *hl.h
rh. ionicand ormdn hoi(Ebsn
olg.n.llcs dtptndi 1rl prorin s)nrhsiq i4) rhe
cyt6keleroirind (t) ihe sndic app,i B oI th€cdl.
r -
dr ntq .d M
B.Mlbdod.bribiE" nry kd b;;;bh;iryJ;-;
ATP, ,h. .n.ry) 3rcr ot e s, ts ,rodlcd m,nn bv
a\id?,n. ph6phootrnon or adtro,ne dDhos;hri
IADP) du,inc rlucion oI oirsen in d. d.d;on ;,ns
por syirrm"r mndhondna.In rddr on. ,h. rtvcothc
pflhv:,.rnE n.tur. crr '' rh.ik.rc.oroxv6
slu.,* dtrtreddrh.r lDm . ciKuhron o.lilm rh:
hydrcrr* ofintr{€ uhrc|og.n. T}. m.or (ruc oa
r vesen ind n(n.
trL. mn(hondn:l d.m:s., rnd rh€ ,c;,ai! of 5om.
, o d n 5k s . q a n d . ) t i s G $ r h , s r t : k r e t y . o t F .
.rprcfy i..e..rh. hs) r. rbk ro 5urvilrto$ of oxv!.!
ind dni.r*d ord
. phosphoqhon b€nd,hr;_arc
t Pr.rd8.d f {trfn,ns d+knon or aTp (ruer
,a. tun] dB,upran ot th. prct an s
or ribo5"m6 fom th.
rcDsh.ndopt,*icr.ricutumIRER).nddrri,ion of
pdyen* nro honoen.q wnh a co6.oue rcdr
tion in prckin synrhsis. utrim.klx rh.. i; iftv.Bihl.
d,mis. b mn(hondi,atrnd teemrt mnbEn.s,
phosphr<rn rhr rom of AT? r
(qu,red far yinually ill syn$eac ind dcqriddvr
ror ohosDhot,Dd
nmov.t. D.ptehan a[ afP ta ter &ca t4c ta ]o9r ot
"mct t"Ek h^ vdnp2ad 4frd, u ia4
.The rcnlrr of th. phru ddb,an. dd*
dAd.t nt so.tua przp E i.d(.d. rEuhrc i,
iir,lr ut.r rclununion of ,odiqm ,nd .ftu\ or
por.s'uD. Th. nd s'in oI5otur. is,.comDanird6v
rio.o$di. eir oI qn(. a6ms @ .41/,s {j
! Th.r. k : ompdn6q, dare in ,tudobn
..'r5r In r .lhpr
to n.'nhin rht et|n .n.rcv
e!ft, A5r.onr,,,nr3e !h,;
rft Bprd\ d.ptd.d, .nd tidr .fld ;d;Eu|JA
r.idins to dri.lid
inr'c.llutar DH md d.crikj
activityol @ny cdlul,r .nzvmc.
. F.ilrn olth. C., p'-nte2dstoiniuxolc.l.wnh
dim"cins dftr6 on c uhr conmrn6.
cyro$li. t ..i.iuh n nom:lly n,inbintd 6y AT?
depsd.d calciumr: nspoftr ar.orc.r r onsfiar3rc
,s nu.h rs l0,000rneslowertia. d..onc.nt,,Dn of
.ft,cdltrh.rLiun orol*quaErtd inrlrllubr dno
chondill .nd tR sLium. latumia .nd ..nain !,in5
cau$ a! increa*h cyGolicqlcium .orc.rnnion. ini
arlly b.c,Ds of rcl.rk af Crr' trom ihe intrftllul,r
ioi.i ,nd lzr.r 6u1dnc 6oa iicr,*d innux ldos d.
ptasn n nbtane, lnoa*d qtasali. Cl a.rvtt.s a
,!rD.r ot r.ymeJ. wi$ potenmllrddd{ious allular
lvhi.hclu! m.obr.ned.m.$), prctes* {-hich bEaL
down borh nembran€ and qroskd(t porins),
cndonucle*slwhrch.i. rtspo$ibl.Icr DNA rnd.hre
nrin tisndbrionr. rnd ,Jdo!in. riph.sph:m!6
IAII:*5, rh(.b) hrn€ninBATP depl.'ion Incer.d
,p.prcsn,by dnN z.iv,bon of.spsa ind 6y ind.i!
ins nno.londri:lpqhc,biliry.Th. inpon.nccoI ci.
in c.ll inlun wasesablish.,lbv rh. firdin! rhr,l.Dle!
ingexna;eliul,rG' d.hys cdi de,rhilitr_hypoxi,,nd
A.armllatlon ol Ory9.r.oe.ived FEe
R:di.ab {Oridative5t|6)
Frc. r:d,c.ts,i. ch.mi.,tsp.da wrt , sinsttunpiirtd
.L.r.n in rn ouE orbnal.Su.h r.t s ar
.*Emdy un*abk rrd rcr'lilynctutrh inoqrnic,nd
D.rag. to ilito.hondria
Mnahondi. aE rhe cdlt supplicdoI lif. s!$rinins
.n.Ey in the fom of ATP,btrtrh.y in i.o.riri.i
in e injuryandde,rh.Mnehondnl .an b. d.mas.dby
incr.{a of .yroeri. ca-, E.div. oryen sF .s ld$
cu$.d bdowl.nd oxys.ndepi!,!on. d so rl'ty r.
snsnivero vntu'lly rll rypA ol injuiousnihuli. irclud
No maior otr+* of hnchondlial damse lFig.I-13)l
. Mndhondfil drmrs. ofteniauk in rh lom1non
of e hlgl.onducrinc.chinn.l in ,h. mircho.di.l
m.nbhne,..lhd rhennrthondrhl Fm..biliry knsid.n por, Th. op.ninsof ihn ch$ncl l.ds io rh.
bs of mnEhondi,t membran.pordii,t and pH
cnaas.s,rtstrtnnqn [ritn 6l diddti. prosphotyh.
toa cndprsn,,i
datdaz d ATP(qtm'nrnnsn
. Th. m(chondri, ilso .onDin 5&r.l Drcteins
rh,r ,ir c,p,bh at 2diy.nrg apoFoti. p3ihw2r,
includins ./khtuh.
. khe m.jor prckr invclv.d
in d<.rcn r:nstsn). lncrs.d tsin ibi|nr of ih.
mirchondrirln mbbnt nry r.sultin ol rh.*
p6t ins inro rh. .rrcor .od de,i, &r,"toprosi Thus,
.yi(hrt,h! . play!. k.y ,lu2lol. ,n cdl ruiviv2l2nd
d..thr in i6 norml lc,mn insid. nnchdndn., ft k
6snti,ltor.nergys.n.n o!andth.lifeof rh.cdl,
bd -btn iiftrhond.ia r. danzs.d so ev.rly drit
./r(hrom. . l4ks our n rismh cdL ro di..
[email protected]@
[email protected]
ft..o. or rcrdEorye.i 'Bi6 (R6) h
ar m!ry or n @iEdd ro {tsrdid. loj)
3,o, b1drndn d md ikft! ro d.r rh!
c,rc orrzd
Fldd ddai
Bi, B
oren in! hn tu.rodo,444!
n (etk 4 aldty
rnr(I nucl.,ca!id5 n well* a \:n.D of! ut.r Dro
teins,nd ripids.In rddiinni fR bdn.L intrirt .i!t,.
cdrrync r..ciioE motlcuks rh,r r..r vnn tft adicri
,ir n tqrnmiv.d(d nto ne Dd'cn5.rhui D&D.crunr
rh. (hrn or damas..r.,Ju.
orys., "p-,;, tio.-,,;
r iyp. ar oxysendoiyld fR hdigt whosercI. in crtl
'niuo k"ell6b6lsh.d Tho r(!.d normalvm
!.lk dunnsnr,{hondnr rts"ahin rnd -{E c;r
rion. bu' rr n. d.sEdd rnd rcn"\ld bi ; un
dd.dn srtem' wh.i $. produd,vnofRos,na..*5
ai rh. saveryins rn ms $. in.#ctiv.. rl1t 6uh n,n
.xa$ of rhd. fc ndisls, l.adim to a
ti.s_ Cjll iniuq in maiy circumsD(A
'nvalv* drmrsr by fc rrdrcd.: d.s snu'dons irctude
1dieu5*d b.lou). .h.mist inJ
mED. roxl$
ellulirrs,ns,m(rcb:t rilrnsbipf]sqr^
Th.,eunularion of nr adicds r d.unin.,l bv ih.;
Earorpddu.tionrndEmolallF€. r-20J \r!.p r.n.
non!,F Espon'bt.r.rrhe8da,rn4 d h4 [email protected]
r Th. rcdudion.oxidaiion
l.doxl r.rd6ns thatBur
dufln8 no.mi mnmhondnrl fr.hbotisn. Du.iru
(!r eumol(, ssk \hr .*ks
Fqrnri,lrrrd(ed nniGhondnibr'h..ddrionaf
th. Drcss. m1ll
,m"uns otro.r ntem.d':k 5rE,e5ri p.!saE,l bv
p.dsl rcdufinn or oxy*!n,d;f rn.tud;rFrcrd:
ndn,L loir, hvdia3d p.fid. lHror). rid oH.
vr do,r. fE dfr'rcil dunns .(D n mriedrut;r
readlons2nd ihercby.:i.tyk Ift rudi.atformition.
sf,h. F.nto' ftdnr lt.!+H,o, j Fcr + oH.+
rojor r4roidn
b |n d
! Th€ .bicauuo d rud,inro{cy le.s.,ut,Erot.r
rcnr, \ ny(). lonirns Edir'ion !rn hrdrotya ur.r
ii'a hldro\rlLoHl andhrdrcc.niHl fre hdioL
. TXr.n4mii( n{,b.1'rm oir.oFno,s.h.o,.rts
(..s.,crrbonGr.chtoidq * tai.n
.,naation, bft,u* t.e mdic,k rE Drcducd bv
l.ulcytes dit or.r tisstrB he Cn:oF lr
. Nitriccridc lNO),rn inponant. tirni.rt -.db ro.
normlly rnthB'kd byr,;nety orcttbD6rlhrDrcr
2), crn rfl 13r fk cdi(Jt or !,n b. .onrert.d;b
highly rcadrv. nnnt sFls
Gll, hilrdr(lop.d naq zer,,n,,h, h, tno!. h2.
rddral and ' hnm,. ,nrury Fre nd k rE
inh.cnrr urirbl. md dery sponrnsudy. Th.rc ,i.
are ev.r,r ion.nzyn i. and .nz',n.ric sysrDs rh,r
.onr,b,r. b inad'v'doo of fft ri/ r.ediom {*.
. Th. hrc of iFnmn.ou! d(ay or suDrord.6,c
n'66n'ly n(i.&d bl rh. :cucn af,uFordr d;
m u h * 5 1 t o D r L t u u nmd n i n y < q p ; l 6 h t , . n q
rh.Krdoi ro;2H - H,or+ O,l.
. cruEdiunelcsH) p4o\rdee il
'niuo br crrltnnr fEe+rdor bft;tido"n, roH.+
1CSll - lHlo + CSsr ls\uD,n,on. hmud,m(r .th.
inrlelluh, ntio of aiidi-d duhthion. ICSS(jlro
rtd(.d sluiathioft(CSH)i5r rtfl(tion of ih. ondr
!y. shk of d. ..ll an'l rn ihrotunt rsr.n ol r!. .e r
ab i$ m..tabolir t. r.dicats.
, dc6 the dtE .
dationof iydr.Fn pdoxd.l2H:Or + o, + 2HrO).
miff E, A, ald C. .nd Fc.locnel mr lithq bick rh.
romdo! of fF adicrs d s*ds. themd.. ih.y
. As m$tior.d,bov., toz .nd .oppd ei.arzlrt
rh. rjormrion of Ros. The l.vds of d.* rcrive
mdrl. .r Edued by bindine oI rh. bns ro *o$se
andtnnsDodFrat ins(..*..Ensf.rin.
f€rn, /nd ftrulopsm,nr, rhsebr d(ls'nc rh. roF
. Dut.Lan ph.sOhobA ,nthe'k The ,rcdmioo
of ph6pLolipidsin €]ts m,v b. rJulrd urr.D.vs
rh.( n a Gll in ATPlevels,Lidjng to d6rc&d enersy. .nzym1ft ,c.iyni.s. Th. rcdued phasplo
.ff€d '[ a JI n.hbr.!.s
indudi4 lh. mn€hodiii ih.n*lv.!, rhus.x.ft.
ROShavemny dlves..ft b on c€Islnd hiv. a.n
b.en inplicd.d in &.ivaion of cdls by i vri.B ol phy'
idlogic rimuli. Hq.v.4 rhirt €dioff arc tsnicDlidy
cwlnr 6 .an ntw! h,llidkA la h.e tk Fi*.
. I|.t%.d
phosphnlip'd bt akdoan. s.!n
miuy r "$Gnted wiih mcrc1*d /.gr.d:non of
p66.bly duero ectivrtion
of.ndos.noxsphspLolipas by LveL of
. roriddtiaa af nmbft, 6ondsi^
n.hbG!. pol)unsruEr.d lipids .E vulnd,bl. ro
.ftack by oxys.nddi!.d ,r4 ndic,ts_Th. lipid,
ndicrr intfurions yi.rd Froxides, *hict' '. them.
nlvaunsabl..nd rcad,v.,"rd,. rurG:hlyticciar
. (ns hnrt4 ol p'nt.ur
5ultydivt mrdEEdprckL' *6, Lntrn& Guhrns,n
rcrctionmy.hodnetly suk p.lyFp.
. DNA t ace,hror. Fi.ebdiel edions sri
rhyoin. in rnd niu*ondrial DNA produc.
nnsl..nruid br,l.5 su.h DNA din:s. hn b(n
mprlrkd in <i d€rh, isms. ?nd mat€n:nrrrii
. ros. Oxyc.r t* rrdftt sue injuryto cellmem
br.n.s by tipidtsroxiddon.di$u$€d.rrtff
. clb:ldtul
db,omlitEs. cytoskeld2l 6lh.nb
sfl. iMncho6 connetinsrh. Dt,sm,n.mbnn. ro
d. ..ll lnErioi Adrvrion oI proEa$s by incrcakd
cllosl,c car. n1/ cau$ d:m8e io dend6 01 th.
. Lipid btahdoa ptod"*. T\.r! inclu,l. unaren
lild hE h'ry icd!. nrlarnr'nr, rnd \,aphoiph"
lLpids,.r,bolk orcducB rh,, rrt Lrou ro
r..umut?k in,nrqrt:dalsfi
aut! !f Dho5DholDd
dcsEdnion Tr.y hiv. : ddlrsld .fh:cr oir man
br.,d.Th.):re rrhtr inqtrinro 'h. hpd h GFr ot
,h. mdbEn. or.:.hrns. wrt' mrmbtsn€pho5Dhc
lipidr,p.knirll) .,ueng .hans6 Lnp.rm.rb'ltry,nd
Tht m,&,mpofttrersar h.mbrrft drmsedur ns
crr,niuq ei. . ni,*hnnd'i.t n.nbdn., 'hr pG5Dl
m.mbmn,,nd n.obnnes oI tysosonn.
t.rlr 165 of *i.h{
ftmbnnr p.trob,tir katlns
. Mnothandnat nmb E l,es,,
As di$uscd
ratuE vr m6r fomr ol <ll nruD k:ftphFptuys)
2bov.,d,masrb mn&hond t meDbrr.s 6utu ii
The ph,Di mrm6En. .,n b. d.mia.d by ,rh.nB.
ds.rsrd piodudjon of ATq cuhin2tins in nEosiq
v.riour n,cbbi:r bxilr, tyticconpLm.ntcomronens, did trkJft llf prcre'Bfi,' r'es.r rFprotr. deerh.
. Ptdsd' 4erbrale 4,44.
rid , !eri<4 of phFut ,nd (h.mraLrFnL. s.vrBt
r,hrmr nehbEnr
h*h.m..l mtrh:ntrm! m4 .onr'bureio m.mbEm
dama$Lrds b 16. oI osnoic b,l!r..rdinflux of
lluidsrnd ionqsEll rs los ot cdlularconrns. Th.
cdL h1y .ko lcak ndzboliis rhn arc vn,l lor ft.
E.onrnurion of a]?, thus tunh.. depldng .i.rsy
ttelect In il.nbrane
. thir4 to lt$etul
..s 6!ksii
rhu .nzymB inro rh. rnd ..tivlrioi oI the
&'d h,drclij6 n ft n'd'c nr,!.lul?r pH of rhe
inrurcd ks. i*h.m(l e . Lrs,{,,ms conn,n
nNr6. DNrr! prorcraj stuc6dai,, ind o,hs
m 6 t . a d rn , . n a .
mn. dis6tion of cdl compordb, .nd lh. alls die by !o Dl|A
hjury redi{
c.ll\ ha( m(hrn6ns 'fr KFird
il ihk drmrg. r 'oo 5-{. ro br lofthd
ke, rhn
mdi,non intury or oxitlative$6.t.h.cdl
lunid. prnsDn Jd d,.! b, rp{'o
k ris{.d
by 'momFny loll.,lmo,.'ns.*hrchnar b€
Ih. rcsukof,nh-,Ed nuurcii or.r.nn
r'*er 3u!h
er ry au* rpopro3lj 'h!y n. d'*u,qd hEr n rh.
I 'Uflf
L<n-kfr of cdl niury
. Mibchoa&id arws. AIP dqlLrtd : i.i,tt€
e['nrr tusions + Dlti
Drery, nd6'q und.r lm. .ondnioq t..t4. ot
. I'nlB of aLir,:
oi 6zyr'
drm,e. allul.r comporcnts.nd n.y 'ts Eiss.r
. Acdr.t'tid
6l urw
axwd $?e'.s. .ovl.
r.n, of.. uhr pmru5j Lp,d5,nu!t.r
. [email protected] tmabiltt
.l e.lqtat nmbrr"6:
my affet pl,sm n.mbnn., ly$sn.t
m.nbr.n6, mitchandial ftmbrrnst rypiglly .Dlmi
. ^affiahtiot
af &tuE d DNA and hllotdd
EI fPrI5 0f Clu |l|{rtY
To illusEar tll..volu o! an'l biel'tiic.t neh,nnh!
orcdliniury,w..oDdudeihiss(n'n by di$
comndry 6n{nised d"nd6 of rcv.slbt. c.1tinjury
Th. tund1on,l .on*quen.s niy b. $v.F ar ihij
n.s.. Forin*rnc., h.:d musL ea
60 smnds ot corcmry(tueion. Hou.!.q to$ of6.
,.djrry dc nor n€i cdtd.rth. rt lyFxia co,tintrs.
wnh bsolmicrovirri rnd th. formitianot ""ce
Fis. r-9r. Ar rhi5ime, Jh€cnrf.tll and ns [email protected]!
inrehondria, tR) ,ir n,i<.dty s*o en, wtrl
..n.mnations or srEr. sodiun. ,rd .hloride,nd :
d(rcr{d lonrhrEion oI Nir$run. , 6?.,
E orta,alt Ltth-. dLtuia;atak kAt;bt.'
II inhnn t 'sk,q nEr-rble nitt dna neoa'i:
krcv.slbr. ioiury r ssi2i.a
wnh sv,.
smll,n8 at inchond'i,,
dmrc. ro Dlimr
m.mbBn6. ind 3*ell,naor |lsom3 i!4. h!. !9r
MassiE,nnuroro ! u;'nro ihe !t[ hr Go; D€5rh
n n:inly by mrtEit blt iF rs,..lrc;ndbu6:
b$ty by d.a$ ot
prcrpdproric moleul.r fioh t..kv mirehondnl The
(rlr5 compomii, ,ft |rosrcstrel' d.scd.d, and .r.
n wrde.prt:dkaL;s ote u[r.n4me5,nto
!p{e. Iinally, rh. d..,1 elk my
rcpr,lcdhr ha n,,!6 (,mNfd or ohosDhohDd5
rh. rom orm'dm riBd.5 rh.,t rR rh.neilhd;hrco
.,rordb) kur.(y'e, ord.srJJ?diqnh.r ohryn;5
l*ieni..8.perft,rion Injury
It cells ,rc rtvd5ibty iur.d, th. E*orrtion ot blodd
flow.r r.$rt in ft i..ov.a. How.v.i und.r etuin
.unenrc.q ih. rtsbGion oI blmd flav to ishenr
bur orh.fl ( L rbt. ri5su6 rtluE, prrudou.,ly, r
.\4*bakd rrd r.etehd riuD
lt hemi. andtlypoi. tniury
lh. lo$ of els ;z r'ddl,o, ,o tr.p thd M nrc
w6ih, d'aed dt th. dtt oj th. t\h.nL @Lod.. rhb
k.h.mi,,ordimi'ish.dbtaodfloy ro. tissu4n th. mo*
olm.n q6. ai en iniury in ctini..l medici,t. rn \o.el| d r.h.dur.pnratoh nBry 6r.t,i,i,tt,,mpoF
.onFa{ ro h}p.!a. m whtrh oq$ senehnonby t.t prees ftr m,y .ondbute si8. i.,nrly b issue
d2naF in myEfdiit and erebr,t hfdions.
rnaeDbl 3ry!ur15n
an.on'nu. lalbcr t6! cl6..ndv
s.vaal D{Mnnns nav ,rou{ ao' rhc .xrctrb2iion
tnrn by okjdanv.prd*1yt,,,hd comDromie:
of cdl miury rcsultins fr;h EFrlusicn ino irhmrc
rlr d.livery oI strhnEi.s for sly..trsis. Consiquonr
,Frd poFnii,l subsrars ,r. or
rl'i6iEd by th. ,ccumubbn 01
mchhvrn6rhr Eoltd normith k (mor€J b\ bttld
Ha' rh.rt'orc. E ^da tnp6 n,e4 jasq i,n do6
:nd nruc0r,t ch3D!6 rn
b?dir. The bici.nic.l
oxys.nJ.piived .e s -.rc discursd in d.tait .anii ind
rh! aquene s ft,pnubrd b€lo*
Ihe rundan.nhlbnh.micat lbnormtis i, hymi.
elh th,i rea&to cdl iriury n rdurtd i"r.;€[ut;; k,
mn,{ of ATr, r I uf rdKd sooh of
A! bed rbo!.. t!$ of Arp krd5 ; the
hrlua ol qdy a,]
ta.hdta? ltl tM punps lerdhs tu crt 5w.t'ne.rnd
rcn, hn,6Leicr , by
r.duld 5hLn'nsror drbohrdnns 1.ts. by 'he p.nodc
rnd thir'rn),
wtrhr(murnit{ ofhcn! rud, rhu5
th. inrac.lluhr pH\ .nd tJt flau4io. in
. Ns dr mcc tul b€'ntrri'.dd!
b! 'nr.iid *rn.n'ion or RoJ rromNr.nchrdn rld ..lls andtan inFlintinc titrlcy;.
rhl supplr of arys.n is increakd, tl.E mri b€ r cor
r.5pondi4inaq* in . produdon of Ros, 6F
lirny b.our
mtrdhanJnn drmrft had5 rc rcdud.n ui oxlsen,,nd beru* or ,h.
:don or o\jdr*5 in ku!&}16,.n,lorh€tu kk. or
prrc.chynll cdh. Cdlul,r.nioxidr d.f.n* hEh.
,nnns mar,:ts b€conpomi-d by ishrhia. hvor
ina tb. :ccunuliti.n of fF. mdidL.
. rsheff iiiuD is isri.rd
yith ,r&,e'1o,,
whrh mr inr$(
w(h r.Frfuion b<:ur or
mlEs.d innu\ olhut()re5rid pL!tu erokrG.rllt
prcducbof2dvaFd l.uldyr! frav..u; rddnlonal
tissr inrury lch2 d 2). Aaiv.tion ol t6.
may 3ko coniribur b ish.mi, co.6sion
r!ry' boJ,6hrrr prornjryrc;.6trm
i(h.m,. r,iu6 t,{ unt'owi rt:!n::nd *hei btdd
flos r rtsumtd,..mplciot prori$ bin'l ro thr
d+osn d antihodn!..!eactiv.kd.' nd .x,arbik 'r
elliriuryand i!flrmndrn.
([email protected] (loxi.) Iniury
[email protected] indua atl inify by ont of No s.q.ral
rh,, ih. rtl1 rd n! 6asm.n6 b.come avid blgds for
116 hav. kal.d ou+nd ih.rttort .rll &.rh by rhis
lrthury des nor tlnn an indam4roq rcactionm rh.
ho*. Thu\ .poprcis diffe^ fron ndosn, which n .hf
.ddized by los of ne,nbrdr inteln( dzymdi! drs.'
aon ot aLtr.hit,3e ct.r utrr !frn15. rnd tr.quen,y
r hoe rtFon Ge Fiq 1i rnd l:bte t-1. Howd.(
lpoptosisandnercsn enetin(.mxnr, ind rF,pn\ir
induce,l by en prdolosic *inuti m1y proeGs ro
. sone .h.dkrk rtt di4tly b .o,binnE uith r .n
nd nob.qlat !'nporent at eelhht otpn L. F.l
ex.n ph. in m.rcuic chtoridt poison,ns,h.(u ry bi.d s
orhe,utnrydry sroup!ot,r,ff crl m.nbnne pc
knr. lasin! inhihirionof ATt.d.tsnden kanspun
ud in(.ed m.nbmne p.mei5it,rr. Mdy .!ti,
siiuenons, dk a
r.oplastic.h€nodd"pt'tic ,! ar{ indue cdl
b dimin.t poEninllyh.rmfulcdlsrnd..lls rhr hrlc
d.magtby dnR cyron;. eff($. In suchrn*,nes,
ou ived lhdr ukIuln s. k tr ,te, a paihotosic
rft srtdb4 d'dar. is ssi.'nen b! th. t lk tlint 'n,
*h.n rtft 1r dflased b.yond reprq 6p..nllv wh.n
obsoft, exoek, at bndnncte th, a,nt,aunds.
$c damac..ffec ih. cdlt DNA or prorin! iD rlsc
nt4,.a t bblast
rhetrrcprmblydime.J d1 k.liminai.,l.
att cdn . bqt 4u! b. fi,.t ,o4v.nedta 4'.hu to'n
-.tdhotits ehch thea.d an tuts.r ./i
I1)n mtd,
Apoprsc in PhFiokgi.sirurioB
ificaionis usm kdompli.h.d ty rh. p 150 mix€tlD"oth bt tpopto3i' t a noffil ph.notutur that s.e6
ru,ction cxi&*s in d. smoothendopt.smrcrcticutuf
to .li,uak elk ttat . rc kns- 4..ta1 and to nain.
or rht rild,nd ods oB!s. Ahhou*nd. mhbdna
",hh{ ofwno$ett pop a,ons intsu?s.
miehrcrur mrmbiine dim,s. rnJ \.ll niuq bt
ItG iEpotunrin rh€follo*ns physio
los,.lnu*iq s:
n,l lipi&,,he m6r
inpon,ft mahannmof cdl ,nitrryinvoh.srh. tor
. fh. ptovann?d tuatudn,n ol..tts d,inE nbno.
hnion of fc r.di.ak. t /ro, ,rrd.bLniL taa]!,.
ss,,$. indrding inpraninion, ors.n4eneri delel
lhich -as ukd widelyn ih. d4 dcaDins
irduf) bur
opndnrrl indution. md itrn
"prcsnnm€d Rll d.,,1" *r! lrieinily
is m* binn.d) ,nd $. anate.sic aetuntnott.n
oined to
hdong in rhn c.Esory. cct , lor .xrnph, is .ony.n d
tl.roit d.dh oI 3ptci6(cll 9p.s .i defin.drnes
t, rh. hxn frceHdielccl, pincipnly in the livei
dunnerhddcllropD. of3n os
The fre radlcrlsc,u$ ,uidararyticmembnn phcs
1 B"n.ric G'n for rhis panemol d1l dtrh. rcs.dl.$
photipidp.roxi!,ion. wnh cpi bekdown of rL.
ofth€conkxr,br r i!.ft.D usedinkrch..s.rb! wnh
ER. ln 165rhrn l0 mnuiesrhd .xFsur. to CCL,
-prarinhld..ll d.arh."
lheE is a ddft
in Ldpltic q,nth6r of
. ku,tqho4 of tanotu d,t."d.,t
tissr.s utan
€nzyn.!rid prr3hrFftinr wnhin2 houu,3k ,ng
h,,one d.ptildnn, sn h x d,tt nnnr atl b'eak.
or,ht lntu,h m,r,ph5mi.rcKutumrnd da!*Do.n
dow. duringrht nd$ruar.ycte.ud rcsirsDnol rh.
or ihleo*
lion tn. smoorhtndoDlIEi. diculum
h:ve NurrJ
Th.r n r.duc.d lipid expon from rh.
. Czll lo$ in ptoli[doinc a topubhn'
s$h as
h.p,rNyt q i.2 r5uh of lhcn Ln,bil1ty
io synllaia
rp.p!.t in b tom .onptex6 *nh ristyc.nd.s 3n,l
th.icbr fa.ilr,k lipoproitid s(Eion; th. rcsult is ih.
. of alls th$ hrv. *i.d $c; urrul purp.r,
"Iatq liv.r" .l ccl
F,ierins. MnEhonddil iniury
lnd r)mph&y6 d th..nd otan in
'ndrfK € 'on n;nrp.n ind prcgrc$ry!(ll 5rell'rsr
d.* snu{ions,.ellsundnso.pcptosnh&:us thry
,JrmaFdby Lrt
aE d.priv€dof n(a3zry luiiyar sisnak.suchis
,rd.hyd.! pddu(rJ hy rip'd Fjo d*,on n 't( ER
Th.tnd6uhqn b..alciDnnfl ux2nJdlniuallyell
. Etinituti.r at natdtnb h.,,ful ltttzddive 1\npro.r't J, .nher b.forc cfufie
'!y hay! .ompl.ted
ih.n matunaonj in od{ io preven
on \ ovn dsu.s (chaptn 5)
. arl d.oth 'd4.a1 by .ttob'n T |tntho.rts. a
d.f.n$ m(h nm r*iini yirues and &mo6 ihar
,{potrdk n 2 pnhy.y oI cdl d.rtfi rh ninJu..dbya
s Bto kdind dihi!& ynulinf€d.d rnd n oplis
iishny rceulartl suicd. pm*sn in which alls d6tin.d
ro die ,ctiv.rc .n2yda c.pabh of 'l.gidns tl'..1115.
ownnu.r.ft DNA andnud..r:ndcybDt,smicp.orirs.
Apopb* in Prd'ologkConditms
rhg!.ds of lh. apoproticrtl1srld b!.ak oft. sivins fi.
.pp€amnc. rhd r rsponlihl. for rhe.rme l,r"rrdsti
Anotbrs.linut?s that dre !.r.r.allt alt red ol
"fllhs olf). Thcprasm.m.nbnne oI rh. lDoForic
'aiuted be|ond q.n urhout ctrnns a 3.8re ha! rta.
rmiins inbd. bui ft. m.nbnne r rk.r.,l io luch a qay
tion, thts r..pin3 th. danas. as.antun?d B Dosibt .
I |'oPlosrs
D!.th by apopiosn n rcsp.nrbl. lo! to$ ot cdG h :
YrEry or prtholoqic iaks
. DNI /,zqs. Rrdi, r,cytoioxicrndcanardruss,
DNA.etrh-d,Ed ) or \D h{ -d sl,.
rh ,h<mNri 'h.
r I r & r ^ n f t i n ! n m d h r n i 5 m 5 , h in d u c . : N ! , 6 b .
ihecettmavbiilxft r
alrmaive rhr risk'nsnddois r ih. danaFd
DN^. trhnh mn poeE$ rc mit'sDni FaFbl'ii
I on. I hN 'nrunou!,nmuti
.run rtuDrci5if rhrf3u/r
i! mild, bur l,R! dons or rh. $;i*i.uli
--h h
Jqrh liduuo!rpoFo,rof .:n..i clr 6
r d6 Ed rffn of.h.mdhsiDtur
!h,rh B!,k br d,hrsrs DNA
. A.,un,tatua ut ar{otlta! ,D,.,,J. loDroDertv
roldedpuEns m4 rnr h..rur oi h,Er;,;
rh; o.odins ih.!d pror.ins oI h&1u* of exrtinsn
r&ro6i sNh * drnaBecaukd6y rEemdists.rra,
ste..cumul,iion oI ther prt,Einsn rheER t.adsb
rmndnnrsll.d ERrres, whichcutnin:6 in rDo,
. a niury in eia'a '{,as, DaiticuLny vnal
inf.dio's, in whi.h lcs of irleted caltlii t.rc;h dF
ro,poproticd.rth r[rD:y b. indu.d byrh. !rs 1.5
in\trr rnd humrn ,Fmunodfi.,hq \,ru,
Dk(non,)or br rhehoe,mmurcrc
..rdth losnatbphn pa2t.h\wtv'san,.tk
n rh. DJG
. Dro!,1
r|ethanismrol ADoptorii
Apopro,sn 2Dadiv. en,vh.ti. pr€ss in whichnuctco
pDreinsaE brclcr du-!
d dd the cdt r fBg,
m.nrd. 8€for disrusinsd.
i5u*tulrD rc\r$ ,hemoroh!r,arofrhr orhwry orlrtl
asim9hlb cnQhrm (Fio,1-22).Nat.r rhd rdou;
cld pi*6'. rh. 6n. .rpidrv IrnnL iom doobmic
bud!. lnd r[gftnr im .r.crdc bod-
h.. Frs r-a). B*[email protected]
Tl. tund,nt!.al .v.n in aDoDror
of €D2ynescarhd 6p,s5 Go n J b43uk ihey aE
ih,r cteeve pr.r.ins rfiu 6r.ftjc
i.sidtral, Adiv,rd .asprsesct..Y
cdnranns in riy.tior
of nu.Lr56 th.r d.snd. DNA
and orh-
'hr prtam.btt dnror nld.oDro
k ,, rnJ crol.t.rit pruEins Th.idrdddusD,*j
drFndr or z fine1viu!.d bahnc. b.
ipoproiic mol(ular pathwiys. Two dis;.t
conve4. dn .:sDdr .ctiv:inn ctled rk -ro.han*bt
prthwd lrd thc dzdh re..pta, patru,l Ahhough ,hE
.r.tb ,ndu!.d und.i
n!ot!. d /tircn, motKut$. rnd
I nt),
rh. Mi,udond;.t (tnbiosn) rrtl*ry of [email protected]_
Mroth,ndflrcono n nlerrlprcr.,n5 rhl n.!i;bror
'nducins.p.pmliri th* pmrins inctud. ctr4tirome.
,ntl enHsrnk oI .idogrriu5 o'oetc ,nhrbro6 ot
epop,oJ! Th€.hoK b.sRn.r
lu^natrnd d.nh 6
dtismin.d by rh. Dgm€:b nr of mnchcndri.. which
is conirohn by : frmity of moE th" l0 ,rorins. dr
prora*p( of !h!h ! B.l.!. vh.n.c , nadeDnkd ot
stu$rh fa!'Durnd rophtr hahi{.5, orrr..\p"(d
nut,r uia.ceorabt.
,mounE of ni+otd.d proE tr,; snpaf $rio6 B1d
;r. memb.6 0t rh€
Blr 2 hm, n m rum anvirc N" pro.aDodoucn.rb€r
,,frhe fim,b !rled B.] ind Bar;whih it, ru.n
,n,o ih. mir(hondfl:t m.nbmn., rnd form !h:in<t5
,holsh sh(h r/chDft
. :nd orhtr mrehondm
pror'ff elF
inro rht labsot. o6tr iJ.t d $nsos
,nh,btrrhl ad'.rpop'ou. mo (! s 3.t2 rnd B.t \ L!rt
bdowr, rirh 'h. hn. .nd rcru[
. t.rtcc oI mib.
dondial prckin5. Cytahroht a i%edtr;th
coiados, rclvaks cr$&.9,
whnr othn D.otcins btel
rhr i(ni,i.r or 6+re
.,esaiDh rh:i funft,un 5
phFero8ic inhrbituF ofrpoprd5 Th€ nd 6utr , rh.
a(iva'ion of 'h. .npr( !*ad., ulnh,Ety k.drm o
tI .dt5 'i. .\Dord ro so;h
ric,o( and dh.. $ntrn nstut\ rho ,n,hc;
; r.
lpoploti. n.Db.G oath. Bcl 2 f,Eit{ rh. rso nai ona
orwhich,it D.L2 ndt,rd &lxL.Thd.poEinsanb*
.ll^mr BE
d n4crM,ddi{ah
onia Bar .nd B.k, .n,l thur Lmn $....2p. oI mnochond,ial prc.rpopion. pbi.in5. Cdl5 deprived of
growth, 06 io' on|Jadiqc |h
i . . n r b d J r ! , 5 h o qr . d u ( e dk f L o f & t 2 , n d & t \ ,
ihur tunhq tihiry fi. b,lrn.. ro!,/ d.lrh, The mnochon,lrial prftw,y kms o h{ th. p3rh*ay th* is
rtspomiblr ror md
mrDm of rpopt6n, 's w. !I.11
i* calle,lFLlr,b|ck
rctiv,lon ot osp*$ down*rcan of d.rth
nslr em. viruks pbdurt homolosu.soI FLIP,
:nd ii is su*ned rh lh6 is r m.cha.isnth.r vnu$
c.lls .liv.. Th. &rth Geptor
pdw,y is irvohed in d'minaiion of alt rt2lriy. lyh
d i. killns ol blgr <ll5 by em. cybrxic
Tl. D..rh Ra.pror lExh.n.r
cld.n r or ,^poplotic C.lls, Apaprctic cdls unJqso
nvqal chans.sin tnar m.nbnn* rh promoEth.;
ph.sE)tusn. h nom,r .dl5 phcphatidylsine ts
prtrt,t on d. inn.r band of th. phsm m.nbi,nt. hur
in ipoptori. alls fiis phospholipld"nip." oui .nd is
.xpced on the out r Ly.r oI d! D.mbrane, *h.r I
is ftor,rtd
by nacroph.s*. Glls lh ft dring by
apoflo5n.l9 solDbl.fuo6 thr Edun ph.eo.
cn6. Thn f..ilitrr6 pronF.Lrnn. ot th. d.rd cdls
b.forcrhe' und.€o *."ndaa m.mbcn. drn,se ind
rcr. . .nlrlurarconk'6iwhrhsnrsutr,n,nnrm
manunl \om. rpop,d( bod'.!.,p65 adhFnr sllco.
b phrs&rrs, ,nd
mrophlsa rhrmells mr prcduRFrodns,l'n h,nd
roepiiptutic.dhlburno' 'ol,!.(lltaid hrB(th.d€rd
c[. for .$uLfmmi. Num(us mraophrs. R.p'cs
t u h r n r o l Y € 'dn ' h . b ' n d n e , n d
.nsulrm. or apoproti. cells.Ih[ pu.s oI phae{q,
Prrlwry of Apop'on,
s,c:lled'lsA Grp
tcr, ih,i riss.r aFpbsn. Mo* of th.r ,rt ndGc ol
rhl runor nercsn hcto' ITNF) r.Plor tamil) rhrt
s: con$fled"d.rth
dom,i,." so nin.d b.qu$ it ned
od.r proEins. Th. prctorypic drlth r.ptoc arc th.
typ.l INF K.!br hd F.5(CD95).Fzsliprd lF*Lln
e meDbiin. ptukin m'i.t) on ,c v2rd T
rynph&yi.r. vLc! lh6. T cdts rc.qniz F,s*xpr.sins
DBdsj F:s moLcuLs rrc crcs linl.d by rh. F:sL ,nd
lh.y binddrpri pid.insrwhichin tum bmd.,sp,* 3.
chsring or iany c:sp:s.moL.ul* t.ds to $d .cti.
y2iioAlhusinitiatinsih. ssp,*.,$rd.. In m
] all
np.5.rlpJq 3 m,y !|aE:nd adi
m.mbdar,h. Bd 2 frm'ty.rl.d B'd,as Gdrsrb
th. nn(hordi:l paih%y.Dr canbin.d.dvarion of
6orbprhq.ys delivns1 ldhil 6|0- b thecdl.Cdlul,r
$ .firdc,t lhr dradrttL Jn
rla. and Lnfl,nnddi i5*.
ahMushw. hiy. .mphisird lhr dktindionsb€Nen
n<rels :nd :pop'un!,'h!\r Nv fomsafklld.rh mry
!(!trrr,d & rthkLrmchJn nrr t). Fof,nshn(. DNA
drnasr rftn ,n 4)ptosi5) ad'v,r6 :. .nuym€c.ll.d
polr ADPkibos) polym&,*, which depl.G .dlula!
5upph6or n'corimnjdrad.!ined irucl.od., l..dins io
i hllnATPl.yrls anduh'm:kly ndosn. h h.i&n
i,,.onnoo siE.tiors suchas ikhcmi.. ir hd bc.r suc
psEd thar .any cdl d.,il can b€ panly rftbcd
apopbrnirnd drnEn n rhedomimnNprolcelldsth
hr., wtrh,.*nine i$hemir
dF,$q inrluding
ard prrkinson
dinass, ald los
iiblr aF IId rb.re5Depn!r.n,,l g ucor rnd o:ysri,
rnd s($ suchA ht,r.?ry, Esuk in proHn nlt"tdms,
culmmtinain.rllinlury andderh.
ap.ptnir oI s.lf-R..div. Lynpiocyk, Lymphqi.s
.rpabl. of Goxn,zng ltf rn B.n
d4rd ii rll ndiyidurlslf rh.k l' nph&r4 .n.ounkr
nft riris<n5,rh. e 5 d'e by ,r,pi4k 8olh ,h. nro
ind 'h. Fa,dorh reRplorpnh4?r
hav.ben impli.,Edid thn prE s lch.pir.J). Fitu(
ar rloposn of rtf.rcr.ii!. lynpL(yt s is on. of lhe
T LFp[cn-Mdi{d
ap.poen. cytoror.I hmphoqls lr-rln h,B
cdLd.ith in m,nr liruarions
r lnown m h..auFd bv nE*nEd on ,heinr< , f nri(ed han c r rnd tumor
(lh l(hiprrsr up,{ r.n,rron,cT
rpopions.inJ the $t.d.d ex'mpt.sli*.d bdow i[!r'
hftrhr rc|. ofthid.rth p' wry in nomat physiolos, c i [ . d 3 , , . r ] z . . . n E r r h f r i r s d < l 5 . c r a n z r m . , . k r .
pnrons.t asFrt,r. rtndua andai. ablero,tiyri...l
run cnprs. rn,hn 4:r, Ihe (TL L' ! hrts{ (t5 by
cronh Fdor D.p,ivarion,Hcrhon.snsniye alls
d,R'ry Lndu!inB
ft rff{ror phi!. ufap,,r'ons.wtrhour
depiredofrh. claart homon.,llfiphan6 th:i rr
en8lsig midhondflr or dtrh
nor i'huhEd by rnra.ff ,nd qtokines. rnd n.u.ons (.p65 tr3r an ,hdr artr(
rnd mrr l, hrts{( 5by
del)r ed of ne r ero-d lador d1. by ipop.6is. In 3tl
rJ by th€ mtrcllon
Ennple. ot Apoptcij
r pr,h4!r
rnd r irflbfahr
'ii rflnr,on
oI prf
rp,,phtr( m€mh.6 or 'hr 8.1.2frn'ly rnd d(r.5.d
synihelsoI B.l 2 rnd B.!x.
ol .dlls r' cdirtio' or
.henoih.Ep.uti. i3.n6 indu<s DNA dam4e, dd it
when DNA ! drm:e.d,'h. pst prukr:(unutft!
cdh. h rid f.$s th. R .r.|l kr rh.c, phrk)ro2llow
ntu n' r.pan lchrpE 6r. Howvei n rh. damag.N
id B(r' ro br npincd su(c.sfutl
r irrr.
Bi\ JnJ Brr. ind by j,mubrns an,h6D 'n Dro.
1poftrrc n,e,nbss!f d. 8ct-t t 'nni vh.n p5r is
nuhted ofub* (ar n k in cdrn gn..6l. r ia ind
p,bl.afindu.ins rp.ltosn, !, thar.etk *iih d.m.s.d
DNA arc allow.d m $ryiv.. tn suchrtlh rh. DNA
re,d to nedprdn ..ndonnltun (ch.ptn 6).
A.cuddlrion of Misfotd.d prd.inr. Dtrri.g nomal
.h1Fror.! in th. ER .onnol thr
nrop.i Iad,ns "t n.prr 5)n'hs,4Llprok,r, rid nD
rordrdplrrncoridFrrc ubquhnaEd :nd 6Qdrd for
pn,k, )ns lf, hoestq unfoldrdor m',rot,lJprckn!
aamuhr f lh. ER be'u! of in
.ork rt, at.d
r rny' /r?/
6ponn r!"vrs 'en'nBFrh
of .hrp*oia rnd
rcbrdDbt r!rh. ltvclsotmn.
folJcdprote'nsi', ih..dl. How.v.i I rhn Eeotr. r
u!:bk io copt wnh th€a.cunut,riono! misfodrdoro
idni rhr 6uh is rhe:dlv,iiq ofcaspNe rhr t.a,lto
ipoprtxn. Irri..llul,r a.cumulanonoI ahDom:ttv
6ld.d pbkL's,ciukd by nuhtionr, rsiis or unknow;
.d .s: t iitrr. ol
I surrurY
. R.srlat d mrh"nio otc.ll d.rtl' ri{,F.s
ehf, unlrnEd ard trramblt d.m.Ed elk.
wtrhd. kd Ns,bl. ho{ ;.Kio;
' ChrnRi,r.d 6y, m7yruh. d.sird,honorprc.
kins rnd DN{, inniaFdby !.stsqt rnd [email protected]
don :nd Enonl of ddd ftll! br ph:sr)rs
. Mto.'.rlr;al
nrhB.) pcthM, B he$ red
by rx or rurivil rdniL, DNA drmra. ind
:(unul,i,mor mist6ld?d
rsrnnd rnh |e|('s. oI !6:poptonc pG
troprnm. sh.rt 'hq insEa ctrp:k mq.
tion: inhibn.dby anii..Doprod!mrm&r5 of
,hr B.r f.nitr whi.[ ,i. ,nducd bt 5uvrvrl
,isMk imludir. *ro*d hdoR.
. Ddh n.pptor t4mas4 pcthwt . r.teonibl. for rtLninn'onof *lf !ffia tDoh;qs
iid by cybbxi. r tmptuir;t
n iii
trrFd by .4as(m.n' oI d.:'[ E.oro6
lm.mb.d of rh. TNF i.c.Pbr hnity) by
1'3m&on adirc.nt..lls.
pnr.t '.,porn.Ih!
rhn d<ripnon ot ,p.ptulk .nnctu
"r ([ iniu4 ind (tdo(h. A5B. hrr {.n, rh.r
.d rhn .h4E wirh bIi.I .oi sid.rarionscf r[ft oih.r
pd6!s: inr,ellJr
ac.umul.tio.sot v2iou5 sub.
n{c.s:nd exucllul., deDosnion
whi.h .i. oft.n sfiard
wirh ..ll iniury,and rsra.
m i f t i { r d f n \ ' \ { ) r r n . L l n h , ii s N l $
(ill\ \!^di$r.,tr
| (h( iuJus. rrJ r ii,! [( \,d,h!
!/(J l,r rh(!lr\r!J !( \ or m., h( I
rh{r.u. rh( mrD rrL\r!
of i[rrmi
or rqtr r.J J.f.G
r n)l,lfs. Nrhri,,s.
. An nrofmi
Di o, org.n, rrLrnr
r L $ ! r r 1 n 5n p ( d i l r ( . r ! D
{,a q
. Ll.N!r.d iJ
mr!h,ns, n, JL8nJ. rhr n,hn.D.. rr
sli.i fJ.r$.ifu.r
.h(r tr it!]
. a11nht,11''r,hl
nrtd* J$,trirnl,r,
,lL!^ ,r( t|\ qd 4nubl
'l l,rtr tt\Dx( or th,: L'4 |
ltuc hr\
.ft $r(ri(J
! f!n
iJiNsr hs!
x) hsr,.sJ$.
J ro.Msren,l
k, tddr( t,!Jn5 rri,s.
N . \ l i J i . t r ! . , b 1 !r l
D.,, burr f0n !rcfc
. .hus r..qini,lg nr
Th! nantlinq or fn$.h.rise dqitrrn o
{\tr{\ oi rtl r.druir
on. \\
(.(.t. trrJ
lk !!$(
rdr. [trr un-! !, (
, t i r r i r . i r l J L (s . D
a3) a
ccl. po&nins).hq.h
Ee6 ir!e^'bh In fh. rv$e
toi,n, frny chr,sr nrr prt.edr rtlLdatrh,rid n$ ht
3tld"). TM od'$ pmsm ol tutrv .
hdi. nqohenatnn rahapie'r5).
njury 1.,c.,diphrhaia)a.d shos morc unlromly
cholen.rolrnd cl'ol.ndyl Endr- ctlLul,r .[ol$rnn
rit l.r micrc$opi
rh. o4.iic $ v.i6 tpi€ny 63d i
F odic Eid-s.hin lfiich d
viord).Ivlcuola donord:in]Y$3ninlh.|iwl:nd
rorha6rl Fiph.ry lFiq.r-2531.oe$ionrllv6dieu
wnho('Enili.:nr nn:clLular
i(umulanon. How.v( phisNyri. ftlk mi) b-om.
orerlo.dedwnh Llpidlr.elrindA,.hdl.i.rol,,nd.ho
in lrwn Jirrqo, p
srh ft Lrpiddebnsof
idonc .elk o' ,brcn,l te.e.,ordtrd) Iorh. of
lipiJ. Thcr manorhag6 mar b. 6lled !trh mrruk.
Dembcn€.bouidvicuotesot tipLd,rnpairL,si formr
rpperrr.. ro ih.n qlopl,$ lrrn .,1k\ h\ atr?.)
!LnM, \moothmu5dcccrkrnd rusophasesarerirL€d
wnh\omposd or .hole$nolij,d .hol.r
ie4Le$r5;ihen sNer$erorkrorr phqus rhtn.[]r
trrtdsn. ytllo! colord'l $nn,6utun,ihr rrhoBcn$^
or thc{D lchaprr r0l. h hredtrry ind a.qutr.d
hyp(hp,de'nL.srndrams. n,.rophtrsn,.rnulr.
iN .elluhr .hole$(.li 'htn rr$rnt ,n thr \ubrDnhr
tentloDs.du(6 or
rhN f,nm,\mr{.rhi3s ntrnrmrf s.rtkd a.d,.,,,s.
rrot ins.MonhaLoFtrll! ri6lr ituhuGhis
o< r. prernkd (o$e.elko' beciur
$e.ells slndstrerr..*r. rnounB.ln thd!]ddq, nr
hv pncnGn h.he
I)nxjmal(nduted n'bul.s.Ho*.!ei Lrdsodenwrh
h.r$ hrl,$ ,tn* ih( Fl,fr{uLir 6hs rc.s.,
Glyosm. Exesile rricdlul,r drposns sly<,scDae
jiscilrd wnh26normaftie5
in lhe mftb.lismoferh*
sluos .r Blycoso.ln poorlyconmollcd
ttrs.rh. prio. txrnpk ofrbncrhil glu.o* n.,6.1nn,
mrcyks. end9cdls orrh. il.$ of Lrnserhrns.
sroup clokly
relakds.n tic rtt ii.d tu i\ d.o
lchapkr 7). In
s., tnhs. dk nss, o, xr.os.nos
rh.s,.nzyma.c ,LIe6 m d. srnih.ns cr
brcrkdow, of sty.4.n rtsuk f n$,.
wirh$.ond,v riurr :nd c.ll &nh.
.rosenous,com,n8non ou6id. rhe body.or .ndos.
nous,sytuh6n.dwrhin rhr b.dy nl.lf.
t Th. monconmon(!s.ious piEmsr k.,1601 lan
exampleG coal dus), a ubiqunous
atr polluiinrol
odchrh and womed| HqPir , sdq'
u6$ lif.. wh.n inh,l.d,n tr pLig
r.r mitroph,s.. fd ianlpotud rhrcushlymphnn
n.phrc.c srn'lrcmel, ths. is r mu.h |,fgft r.,bsordon
.hfn.l! r, rh. r.Fionalnach.obDnchiat tymph nods.
nBiniie dn |.oktn
Assrcsatesof the bl.cktn ihe dn,nins llhph
f u*wiih ry$om6, r.surn!Fin thehisiotosic
nod(,trdp monanp1ftnchrfre{dnthaatisl.Heavr
of pinl, hyalin.crrplasmi. ,lrople6lFia. r 26). Th.
.Da ora fibrcbhr
prc.s is revtrnbl.tifrh. proreimn2,b1E rhcpnn.jn
i. Eadlon rhat can rcn'[ 'r a s€rioDs
luns dn.i!.
dropla!1r ndlb.ltcd anddisaDFa
i Anoihqexanple
elled corl worldr pn.undonidij (Chapr.rr3).
r Endogd.ur pismlns indudeliNfu$in, mrlanln,
n fi. m.rk.d a(umulaiion Df fltwl) sytuiai?d
rh m.y uur in rllt RtR .f a,m.
and enain deivrivs of hemoslohn.
Lipofutk, ot
"q..r:nd{.rr pdmtni," s ,n inn,lu6l. hrcwnnl
pl,sm. .elh, fohing roundtd, <Einophirn R!$',
yellawsrin ' fr,..11urar m.teri.trhn a(mut.Gs
Aaumuhtionsof intraRllulf prot ins ir,l$
in. v .ry or n$ueslpanlcuh ) rheh.rd,l1v.i,rid
'n c.drin ryp* of..ll niur For.xinplq ih. Mrllory
bnin)as a fundionof.Be ofurophl. L'pofurin rp
bonn or -, hyalii," k.n.osinoDhili. qropler
rcsenis.anphxaollipi,ldd pn,.in lhr d.,iv. frcm
in liverelkrhr is hisll).nr cdistic ol
ihe rr.. ndicalra&lyud peroxitlation
of poljur$ru
ilcoholicLvd dff f lch,po 16).sucl,indusions.,e
nted tipidsof subcdtutrmrnbrine. ii il i(n iijuri
.Ed int m.diat 61.
ousb thr ftll but n impomn, ai
inha lhn pEsurubrr rcskt desnd on. Th. tr.u
rft ndn:r iniurr. rhc bn,wn 1ri3. t-17),
in rh. bmmr AD[.mei disr.
is rr r8sresakd ponr nclNian thr n,n&iis Dicro.
io the risue th:r r c,ll.d bron rt.pb
By .t<.
tubur.2smi,rd prodn5 and n.urc6tam.n6,r afle.a6 a! p.iriuchrr
i.i ola disrupEdn.urcml cytoskeldon
trd,ron dcn{ BEnuks1Fi8.t-2-Br
hrcwn-bh.t pisnhr
follow'rs rh. rrtr,fu{
c alyTedo\id ioi of twonn. b dihyduyph€ny.
lihirre. k n lmrhdkd Lxdusiv.lyby mdindvrs
ro.1r,r in ,hc cridsmn ard ads a; ";.*
hlrhfur u|fa{ord cdHtioi. Akhouahf.trn,trcs
JR ihe onlr eurce of mdrnin. 2di,.r hasr rcr
$. skr on a..umuhEthr pism.nt{..e.,
,i r.&kr.t,15!?n dermatnacroph4a.
. H.a,,,/.,i is r h"moctobm
m.n, rhr EAotd.i !. a$ ,,, tr,,En rnd i(!mutrrcr
Li rsues *h.n *.( n a tFat or ssrenN rxrts! of
;on. rroni5 nomnty nortd wtrhiicdtr Li js!)or!!r
wnh lhe proreinapol.rrl,, Idn,ns f{nin nicdles.
H.mosiddn pisme rprilcnE rars. assrcsresof
rhen reiinLi nitc[6, Qdit,- lisu:trtd br tish rnd
ideni6.d hy fi. Prusfn 6lu. hnnf,h€micitrci.rioi
tF,s. r 23r. Akho+h h.mosjdnn:(unuhnotr n
Lhir pichdr a..
n,nmalh rh. monofucle,iph,sorrk! or .he bone
marow.sph.i,rid 1!!.r,wh(E.h{. n.xGn'v. Rd
s($ivc ac.umuh.on.p,i.n.hrn,l.(11!,hrcushoui
rh. bodylburprin.p,ll! rh.liys. ranc.:s. heiit.and
end(rift ore,n, bdoh. "hronrd" sidr.ctrnut,r
o.cu6 in rh. rninsol lr)
of! ;on, l2) impan.dui.
rtsionof non.1r)hen.LFi.1ioias,.Dd t4)r:nstu
sionsld. u,nrlu{d cd cdk coni
bidornonr, ln mo*'nn:neof &ooidero.
.ells or mpff orgii fundiond6pn an 'mr6rivr
r.ctrmul,ion (Fis. r-23). Howve( nor. .-dsiyc
non,i.ei h r,tulitan hno.hto.
q,,cD 1(hipkr rb,, {rh n$u.,nFn m! ud'nah!.r
6bb, i. ht,d b,r.rc.rnd dBh.r* ne tu!
I P l||olo6K c tctf,c^no||
Prholosrc.aLdici .n ,\ i .ommonprc6s rn r wid.
v,itrry or dn.ri nr6: n impl'( ihe,bnorhrlJoo5i
rioi oI.alc'um $16, bserhtr wrh !hnF!.noun6 of
15.vho th. d€pDn
n is.altd4rtupri.
t ld!*5 0l ;on, and .ons.quendy
ol cdLiun n tabott.
siderir,rcsultnom h.noiihrs(. The b.$ examplets
um kYrlsofcilc'um).
rh. commonbrun.. afi{ rysnot thr {}drc.yB 1r
of c.tcrumshs in noffirl
rhr nr of hcno ase,rh. Ed c.I d.brn n ph2sGy- In conMn, rhe d.pniq
.,L,lnaiDr ana otna,
'.!cd hy @.'ophases:
thr hem.slohn.ofttu n ihen
i, tdla\n a.tabol'st
.rabolird br lysgona {ith a..unutanonof thr
y ol.cLonrhroush lhfi.rcakma). tt st lld h. natd rh{ rhrl. hyptr il
wh,.hdr bruis F$6 l.ll(h rhn. r,nsforh{ions. .em,r isnou prtrcqunn€n'd)*roph(.,td6oi.n.
Thc orisinalrc, oI h.moslobinis rane
fomedro v:ning3hdaols(n-btu. by$etN,t tor
Dylrophic Crlcifision. DyrnThi. calcific,iion n
m,rionof bjrilqdintq(n bLldandbrlnuhin1rd bite) €n.ounkrtdin ,.s or nEroskof
rrt,mrhc h.n. noier],rrh. non jonsoI h.moeobio r |n.lnibk jn rh. alr?rc"J otdvdrd rhqostF
rcuDular * Bold.r yello* I'tfrGldcrin.
rasn,i!!Eia&d vnh inrmtrniury in rtr rnta andtaF
r vhenerd is srncni. oye oad oftron, trmo
r({ies and ch.iidsizd 6r a..umulatjonof lirras
sidriinr d.p.!nd in Dan),o's:ns.ndrnsu.s.a<Ddi. lchaptd l0r. Ahhoushdynroohicc'lciti.l.on nay b.
i.n crled ,.zo'Lro$
{ch,prd lz). rr n found in ,n.dhhr rindna rndtrrirnc,ny*n 6!rrr Fn c.l
. hd in $e nononNl.,r phascyks of rh. |1vrt, , n i u n ., m r n Q b . i \ 1 6 . . t , t r F r n d , + u n ( o i . r o r
bon. maiioq $rrn. and tymphnDde*nd f Qr
.rampl.,.aL.,ri.rti.i c.n d.lerop'i asns or dlhrssd
r.rtd nicrcphaBesfircu3hour orherorsrn\. wnh ,rohe,n !,hd, 6uhrq in iv.fttv .onprt,ni*d vatle
or pndudion of pr*hy.oid
hornonrrcrairdFtran br oih- trrta'rn niioq c)
dsttudDt af bane dR rc rh. rtfd\ 01 k(]sr(d
I,ncrd*J honc .*ahornn snEHted rnh 'nuhLple
EFl,,m4 leukemia.
or d'ffur irehbl ndii2rnr 0l
rtbn'n t)-t?ht.d afoa$ nrltd
.anon d sr.d/orr iin !h'ch m
ubhr D pKutrod: and 14)r.,"/ /",hr. if trhth
trrds rc se.onla4 htp!4aath\-
ih.bdybure ncip.rvrn 6 r'a id4rit:trisu.6 ot
Eoinr. Dvnrorhi. .al.i6.aron of rhr hnL. !116 n
of ioni. {.nai
n ihc cueny
d6po.rr in rh. kidnry l4r'.ahhdr.)
6n 6u$
tufu tY
Ahnoml htEellul.r
. Abno.m:l deposiisoI mi.rirls in (ll5 ud
tissnaar.rh. rt k of.i!!*iy! irtal. or 'Lfetiv€
. tiit
r|1t prrl,.gd$ir of dErophic ..Ld6crioi i'rvohs
;,r!,roz i,r nud.anon):nd prop,t ro,. hdd ofwhich
may be €,iheri.riftlluhr or cnhtclluhrjhe uhrmrk
{aline dLun oh.s
,r,r.. InnDhn iD cxna.ettuhr sG drm r ii(m
h4n€ bourd vsi.le5 abor]00nm
in dianftr: in
.r.r. ,nd Li p,rhok4j. .aL.licatioi rhry tldve lrofr
d.gdq,ir3 crk. rt is ihouahr rh:r c,tcim n ,nnBly
lDcnrited 'n rh&vsicler hl n! rfiiDiryIqm€mbnre
phospholipidr.*hi[ pholph.cs a.cumuhk rs i rtsuh
or ibr nio! of Dcmbrao..boundpho'phrri\6. rnnB
,n oI iDra.dlubr .aL.'ficrtioi o.
d,ir old.rd or dlng.r1l\
{ hale ron then rbiLft ro
r.*uhk inratclurrr .ncium. Ah.
r{ariq, prcpagrDn otqst
d+rnd€ni on rh. coiftnrrrian ol(:r rnd PO. 'n ihe
exricdluhr sprrts, rhr p(vn.( or nineHt rnh bnoq
rid rhd dqtu !l .orbsenmtioi, w[i.h .nhrn.s $c
qer iD BrmaL issu6 shen.ver d.rt nlrrqel(nn.
The n)ur maiorc es or hrp.r.lrlcm; nc l |l 2 re"s1
pa thrtuil haMD.. nu. o siher pi'mrr
.r,,ce ,c.umtrliiio. oI lr.c riclyeid.s
rrom ex.esiv. mhke or
d.r.{iv. ranspod lohr. be,trk at d.t 16 in
lynd.sis of hn5pon prorinti h.nif6tarion
. Aohtdol
deto'tion: resuk ol delfrarr
casbolism r.d .xc.sik mDL.i jn maqo.
pMsesrnd snotrh iufl. ..[s of qilts
t D.poinion .f t'oe,t!
rcibsorbed pbRins in
kidn.) tubtrl.s! nDuncslobulitu in plasmaalh
. Deednioi or srlrosd, i! meroph,ses ot wiih der.G in ly$sml .nzym.s 'ai
b(ak dorn sly.orn l*ly.caen *o!,k dneast
. D€poltio. ol pis,e,aj typically indise*ibk pis
menr, such .s carbon, tlPotusr l6rt2lJow!
p.oductor lipidp€roxid:rion),
non Gsuallydu. b
ovgroad,asr h€nordebrn)
I Dt*n,pLn .ak'li.aho,: deposni.n.1 .2t i\o
* snc oI ftll iniuryinJ ne!trn
r Md,r,rr
ar./,rdrnr d.pcnion of ekiun
in ndm,l fisu6, eued by hrptftl..nir
a con$,tuencoI pf,rh rrcid hormone
lrl^ru r -
dr 44 Gr M
'o 4h.
n h!hd!
I Glruuf, AG G
t2nukt 'snq i5 th. rc,,h ol a ptat.4,v. dkh4. t4 th.
p'atile tiv. @po!^ '4d t'l? \pan at atk r4.t th. 4kd3
tt *oseta6 t'd,6 thatdue
c<y4rro|on .t .. uht ann d.hdl.t
d,hdp. tle
l-r0r. Thi prf65 or rs'ng R.onrn.d fromten ;
humin!,rnd<r krs n,motemod.
'o b. rcsurnedb,, , 'mtr.d'umbrr ofiens. rh. d€r
'hr r8inBb.on,rcl.d b' prn'cutrrsm6 rrr55puftd
ir hriplhte, pr6.s ihrt w,a onc. inexcbbl. S.v.r,l m<hanism ft tnon or
3uspd.d rc b. rsponsibt.Iorce ulft ising,
. DNA dam|.. ctltllr
as'nE is assjned with
n{.s ns DNA d:m:8., sh'.h roy hipFn dunm
nomrlDNA (ph.rion rnd (rn b.dh:nc.d bv t.;
Ddi.rrs.Alrhou8hm6t DNA drmas tr rF;d
r rid rt;umrh,;
.s alls5s.. sonea$n8syndrom4,rci.*iak,l wiih
dehcBin DNA repff n&hannms.'nd th. tift .brn
or mod.r:nimrkc'n !t incrtistnif rslonms o DNA
drmrserrc.nhrrc.d or prok,ns,hr j:b u. DNA
Ie inroducd ln t r, 'h. nFru.nhonrhr h,5 moil
conls.nrb, potons.d tire sp,' in mo* sFi.s G
r[,nf '.!rkrror. Renrln i hn b..n pbp,{.d rhrt
cron. rcnr(on iDts*5 a te\.t of *($ rh,r:rt
v*s proEi[ of ih. situin fimitn 5uchr sr2, rh.t
tunfton as hrron. d.aeotik.. TrEe DroriB mav
d.r.ryhte rnd dseby ictiv,c DNA rt;r mln ;
{hB jrb,ttr4 rh€DNAi n rh.,ben!.oftn.; dp
,eins,DNA n Fmn.In drmr.
. D.leued 1lhb aphatan A nom:tc ! h,v.
a limtredlrpaciry for trptnrtron,:nd :ft.r r n*d
numbdor divnion.c.1k beoni,r6ted in . (mi.
nilly nondividns n.te, kna*n .5 r.rliart
..'.. Ag'ns i.1$mi!rd wnh progGriv. rptic,nve
(lli. cn i lron.h, drtn haveih.cip{
,\ ro und.Bo ni{. Dund! of (!ti.ruon,h:n docdlr
kon ord.rFopte.In lodEr,c.l!
fton Drkm wrh
\ymr st dtm.. ^ a,. dn tk.!5ld4iz,l
bv De
n,ruE .sin& h,v. . mrkrdly r.dued m vitrc lili
ip.n. ln htrn.n celk, rh. n(hannm of crlicrtiv.
hvoh.i tn( rcpt,.r,on ,nd qm
shon.niig or Flom.r6, wh'ch 'tinrEty
E5u 6 in (lrrcl. nftr. LLz*.r
*.,hon r.Fned
equenG.r DNA [email protected] ar the tin.,r.,ds oi chro
n6om6 thr ft imtsdr,,Ior(n5unnc a. lonol.rc
Epr auon of.hron6om..nd5 and lor;!oE(r;,h.
.ndrrom run,,n:ndd.sredn'onvhd!,mrtr.;
Ep,cft, a 5m' R'i!n of ih. rcto
6'.d, and rcloh&s b€oft pros(snet, !h,d.n.d.
a5 rb.,dotuG beom. lhotr rrh..n&ut(hlomD
$Ds crnnoi b. p'ord.d and ft sn ar bbkh
DNA, whi.h5l3n,Lcettcych,r6t.Tt. tenqhsotrh.
t lon.Es ir nomall, miinnin.d by nuc[;nd. rddj
tion n di.rd by in h,yi. cald r.lou.r6e T.toh
.rak r. sp€bti*d RNA.prctin .om!l.x rh,r u$s
n! uw' RNA r a EmDhk for addmeiddrid-."
'h. endi of chomastu5 Tdom.;s rchv& tr
.xpr6..d in sem c.115.!dis Drtknr.t tou Lvii3 iD
$tn .dlr but n n usurlly,b*
in nsr 3.maric
Gsu.s(Fi& l lrL lh.ftfor,.5 ce[si*r th.n ktom
.6 eon. shonerrd th.y .xn ll). e rycL. i6uh.
ing in an mib't,D ro s.n.,k n.w e ! ro fetra
drmrsedon6. (o'\.et',
r 'mnoit:t qncs idlj.
rdomd,n n rcad'vded 2nd cton
.n.d. sgs6ring 'hn Etomftetongnio, mrsh,& ai
non.Thr D d,xus,ednor. t!l[ d
5uchiIunnsobk r,otr,howav.r,rh€;trflffih,;"i
rron{rr rd\ir and relatuE tmg'h ro as,ne
_ rnd
€nar h,3)d 'o h€fultr 6Db|Bhed.
. R?,1"4.1'q.nefttik @nad, at ti$,. t.n 1r..
R(.nt studies susg.n thai *nh ase, iI. pt6
I slfrI||I
! Rdul6 tmm .onbiution
oi rccumrtati'r
(.e, by fc 6diciL), rcdx.a
ell'Jrr do.e
€Paciry b divid. {rcplic,riv. b*rnc.),
rcdued abilig ro i.p1t it nu.d DNA
. Aeuhrkn.f
DNA d'ns.: d.lew. DNA
rtp:n nchannmr DNA rcFr my b. :a*:nd
by calori. E:ridion {LnlM to pr6lon! .ging i!
. [email protected] tuda
rcdtBd aprin ol ells
ro divid. b..auk of d.cisrq
imauns oI (16d,
.n! .nd DrcBcsiv. rhofr.ni4 ot.ircmmnrl
. ot .r fddd, posrcsiv. cumDlation 01mdl
bolic d.marj psibL 1016oI soqh futo6 rhr
prcmd. 13iry in sinpl. nod.l oq.nisms
w rh i(eiR
en dr ft;
lcDKN2Al pocin .ccumuhi.rm snn, andrh.y
prusr6i v.ll loF rhnr cip,ur, r, elf ff.q pt6 B i
prcB($ron!i, p.
mh,bbr "f..[.rk
di{s5 n chrpkrb, dctcuon
ort6i ot Iuid,ln muE.
rioli or Dr6 r. rsiar.d with.1
. a.t,uktia"
al n4.boln dn-q.. c.llilar tle
spanr rlsc dd.rminrd by a b:l:ne b.*en dim,e.
rtsurinefrom m.rahohc.v.i,5Nlrflng wlhm (he
!!ll rnd (olnEncnng molduLr rop,{$ th.r c,n
(p:n rhedrm8.. on. eroup,,I pohnrlly ror. pro
duci or nonirnd:bornm n Hc
A5 v. haE di$usrd .rdff in tl'. chaerr. fi.s
hyproduG of oxddivr phosrlD4l.tion du$ covi
tenrmod,ri!,ironsofptuFn',,p'ds,rnd nud.K tud!.
rnftx.d or d,iEdam.e..outd rc,uhfron ftF:Ed
. n ! r a n n . d r . r p o < ! a r o! u \ h , n n
tsdi.aon,ro4wrh proara! \! rdu(on ofrnrcu
dani d.f.6. mah, hs. D.msed (llul,r olgm.ll..
,.ctrnul.r * <llr ae. ThisDry,ls b. th.6uhof
d(linins tundion of d. prai.1ofr., th. prot olrlc
rr $ourd [email protected] h.$ torm ot cdlu
and adlphiians d.siibed ii rhi5
'n ell sia, eavth. d tundion:to tnr reve(ibl.,nd
tri.ydiblc ro.msof acur.cdl niuyr rc rht EBula&d
rrF or c.ll d.arh rcFrennrdl by ,poooa' is
mad€ b :I dre ik.ndons lhlolshoui tnis bm!
berurt rI orc?ninj!ry :nd utnndrty d J,'(rt daQ{
,rururc?nd iunrn,,n
)61 Fb, 4u4 enbd k. bai,.
irbt 64t'iRtu' at khd4. tu4!q.1
Dii! N/ r4qaq
16 zas. zaal
rttu E tq,r
@rb Qtu's
o, ttt 3d. h6ttt ot Piota j
n olei
rd oxd{r
. srtrdi8 i! modet osnsns, titc th. ,om
Genorhabdrs .l.eaE. h,( 5hown thrr soqh
hcro6.5uch,s iniuln 11,.8rc{h frdo(:nd nft
anubr signllins tsrhweF r.inrr.d 6y $!* IDF
nunlr knd b Edtrft tLt .prn. Th€ undstyms
mEhan',mir. noi illlr und{rmd,bur,hreEroMh
rFou n,r anrnun tn2 rceon(i 'o rtllGr !F.s
,nd du. Educ. th€ $rbiliry ct rh. DNA.
*tudt rt, ,,ryhhdd6i.bIrm
qd d{@t.t
ot $. rch ot 4o&&ra
r .d turtp,
n. Fd4t'd4t
r ni4rdin
!<8. !J 6e. ,B' /o,!fu.!
D4,11\ 16s [email protected] @<a'
A 4ens
d [email protected]
ot q4
at e,.
ad [email protected] [email protected]
[email protected] [email protected]
4 ltu [email protected]
4 tuftt
[email protected]
.* Fd.d e*
ot tk @
[email protected]@
d rw &;'
1 6 [ D .s L d ] M e ' c u . e B r e r ! [
Eo.Ic-. ,6t
[email protected]
au ot DN^ atqx
n au
ot h4rtut
rn d qad
rfr d
& h4hnna
d &nr an | | r:.r r. ,@r
ttutw al.a h6. 14 qtu
tu &@4
aL I