Kumor

ROBBINS Abbos
Fousto
ASrc Mitche

Patholog

t
SAUNDERS
ELSE\]ER
Chapter1

CellInjury,CellDeath,
andAdaptations

Introduction to Pathology
Oveaview ol Cellular Responsesto Stress
and Noxious Stimuli
Cellular Adaptations to Stress
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Overview of Cell lhiury and Cell Death
Causesof cell Iniury
The Morphology of Cell and Tisrue Intury Examples of Cell Iniury and Necrosis
ReversibleInjury lschemic and Hypoxi(Injury
Necrosis lschemia-ReperfusionInjury
Patternsof Tissue
Necrosis chemical(Toxic)Injury
SubcellularResponserto Injury
Apoptosis
Mechanisns of Cell Iniury Causes of AooDtosis
Depletionof ATP Mechanisms of AooDtosis
Damageto Mitochondria Examples of Apoptosis
Intluxof Calcium
Accumulationof Oxygen-Derived FreeRadicals Intlacellular Accumulationg
(OxidativeStress) Pathologic Calcification
Defectsin MembranePermeability CellularAging
Damageto DNAand Protein5

INTRODUCTION the latter examinesthe parricularresponses

of specialized
TOPATHOLOGY organs.In this book we 6rst cover the broad principles
ofgeneralpathologyand then progressro specificdiseasc
Literaily translated,pdt olo6l is the study (/ogos)of suf-
processes in individual organs.
fering (pdrros).k is a disciplinethat bridsesclinicalprac-
tice and basicscience,and it involvesthe inv€stieationof
the causes rcrraloeyrof disearea. well rr rhe underlying
mechani\ms qatbogenesist rhar resuhin rhe pre.enring OVERVIEWOFCEttUtARRESPONSES
IO
\isn\ and (ympromsof rhe parienr.Parhologrsrs ure.r STRESS
At{DI{OX|OUS
STtMUtl
variery of molecular,microbiologic, and immunologic
techniquesto understandthe biochemical,structural,and Cells are active pa.ticipanrsin their environmenr,con-
functionalchangesthat occurin cells,tissues,and organs. stanrly adjustingtheir structureand function to accom
To renderdiagnoses and guidetherapy,pathologistsiden modate changing demands and extracellular stresses.
tify changesin the grossor rnicroscopicappearance (,rol Cells tend to maintain rheir inrracellularmilieu wirhin a
pDology)ofcells and tissDes, and bioch€micalalt€rations fairly narrow range of physiologicparameters;thar is,
in body fluids (such as blood and urine). Traditionally, rbey maintain notmal homeostasis.As cells encounrer
the disciplineis divid€d into generalpathologyand sys physiologic stressesor pathologic stimuli, they can
remic parhologyirhe former focuseson rhe fundarnenral uodergo adapiation, achievinga new steadystate and
cellularand tissueresponses to patholosicstimuli, $hile p.esenins viability and function.The principaladaptive
 z 1-
CHAPIER Celltnjury
CetlDeatl
andrdaptatioB

hrpertrcpby, hfierpLasid, dtrophy, and

netdplasid.lf rtu adaptivecapabilityrsexceededor ifthe NORMALCELL
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 per-
sistentstressresuksin 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
s.ner'. rhede'elupmenr of org;n'. rnd the mainrenance

The relationships between normal, adaprec, ano

reversiblyand irreversiblyinjuredcellsarewell illustrated BEVEBSIBLE SUBCELLULAR
by the responses of the heart to different typesof stress CELLINUFY ALTEBATIONS
(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 NECBOSTSx APOPIOSIS
increaseddemandis not .elieved,or if rhe myocardiLrm
is subjecredro reducedbkxd ftow lrschenial t'ron an Figur€ l-l
occludedcoronary arrery,the musclecellsmay undergo
inju.y. Myocardiummay be reversiblyinjuredifthe stress 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.-
ll".I};::iJll^"":-f.l:-\,'lis:*y.:,i:fli:j,:ld.JlT ii.elelsibre
injury
i,.6chemi..o"s"riti"e"".-,i,1r" tt" *i,pie.i.y.ca,riri"r
hypertrophy {/ower/eit).the eftventricurarwal isrhickerthan
2cmdofiar, i_t.5.;) R;;;;tji;;;;;;;;;:;iilH;,iljffiffi
grr,qhtmi(o5<opk
-"I^"_*-yi'11,.:,:iy-sj:T .hdnses. orreveribre cr,anseiIkeceir,t,,i"'eiffiJiliLtty ;r,"neeGhownhe,;).rnth;
riehtareain theposteroraterar
reftve;t.icre.represenis
anacutemyo.ardial
;#lil'1i1il:".,*T:#::"i,:fli:il""j:::jl*ar chroide' anenzvme
coro6viabre myocadium masenta. Fairu,e6 stainiill:f""""""#: i:::#i'i,::lihenvrtetraorium 'ubsiatethat
 C H A P T IE R C e l n l ! r yC e l D e a t a
hn, dA d a p t a l o n s 3

i s n r l d o r t h i . r t o . r L t c l u ' r r n r \ I n r o r n t l r r .o r ! ! i h Hypertrophy
e r c r r l r h r t i . r , r r m . r r u n r i c r g or r r o c r r l n c i n t u r r L i a l . r r r
| 1 \l ) t l t l t ) t ) l : \ i \ . 1 ) t 1 r 1 . h \ t \ t 1 t l ) . : j : t t ) l , . l 1 s h ' r l t t I t t t l
, , r / r r i r . r . , r f t l f r r , , r f ! ) l n s . d r ) . ! l u \ r ( ' r .\ i ) t ( . t { ! ) .
, 1 . 1 . , t : . h t l r \ ! : . t l t 1 , , , , , r , 1 . uI r . r d r t r . r s t . h r p r r p h s r r
r h , r i \ r ( \ \ . ! r f J n t u r \ r i i c . r r r r x r r r l r t l t t r r r o r p h oo g t
h u r r l v , r h r i o f . r r f r . r l \ t . r I ! ' o t t L l r . r r r r l r l s r u c sT. l r r ' . i r l l r c r r r r l r r i t , ' c h . r r , , r t t , , a rhl i . , r i n . r ' . r ' . , r r c l l
r ) f i n l ) ( r 5: r . r r { Jr f , , r h . r \ . r \ . r p r r r ch r p r r t r , , p h rt h c r c
n rrrihlr rrlurtd
..ll\. i$r brgAir .fll\. .fl.rrs.rl hy rir
r c s r m b l er r o r r r r r lr r r r t r t t ' r n . r p h . L , g r c . r l l vhr( , * f \ . f .
r n r r c r s i d. r r r r r r r rir, r \ r r r t u r r l f r 1 , r . i r r .\ r r r l , n ! : . r r r ! l 1 c \ .
r l , . \ . rr . . . rl . ' .Il ..,", r'r.r'. .'l
ll\tutl.r\rr i\ rrr .rJrptlrrrcsp.rst ir.rlL'..rIrlJe {)l
n r l c l i n j u , \ ! . r r h . r . t r l c t h . r lc , n L . r l , n r j ) . r . r .\ \ 1 h . r h . r r
t p l i e . r r r o n s. h c r r l h r p r r r r r p h r , , i t u n s h c r e r L l r . r r c
spc.fir Irnrr ,)i \tr$s r(lLi..s .rtl.rptrr,n rr eeusrs
n c . , 1 . . , l rol ci d , r , r l L , , r t 1 \ t \ l t t , , t ) l ' \ , , n l t / , \ s r ) 1 , , ! k t ,
i c \ . , \ l l J l . , , r r r i , r c * r b l c L r i L L r vr l r r . n r l ' n ( , r ( , n l \ ( , n r h .
i r . r t u r c. r n ( ls ( , \ f r L r !o a r h . \ t r . \ \ b u r r l s r ) o n ' . \ . l ,)rh.l tnlr)L)sk rrl lr eru'ttl L tIc, i)|rr.r(.r\c!i turirri(nr.r
J o r r n l , , r b \ s p t . i l i el r o r r r o r t , nr Lr i L , r r r , r . l l \ t ) ( . r n )
r . r r l . r l , l c s . , n c l r L L J i.ncgl l r r L . , rn , c t r b o l , ' n , . l , J u , J s r p p l r .
p h r . r r r t lh r p e r p l . r r i r t . r r . r l s o r t . u r n i r ( r l ] ( i : , r r r l , ) h \ ,
. r r d n ! r r i r L ( ) n . rsl r i r u \ .
< , u s h b o t h r c r u t i r r . r r r r r L , r r , * r li / , \ ' / , , , 1 1 1 , 1 ,r/ ,(ri,r ! . r n .
I n t h r s r h r p t c r s c d N c u r ' f i r r t l r r \ \ . c l l \ . r , j . r 1 ,rri )
l l r u : . r h t r , . , s n c p h r ' i r i I r g , rm l . , r g t n , m t , ) ir h . ' , r . f ' , \
strtscs rnd thc,,rhr.i!sr\.,,,cth.r,risr,'..trrl rrnrr
( 1 ! i . i t r f i r n , r f . \ ( i . ! L L f \ . r s. r . ( i r \ . { t L t r i r f ( ) f c d r ( i g . n
q U . n r c \ ( n r h . \ x r i o u s k ) r r ' o i . r ( ! t r . . L l ( i . r N . r g ( i.f c r i ( l
\rifrulrt((l \nr(!,th nrrrsclt hrprrtfuphr .rn,1 \u(rith
i r g u c r L b l c e r l l u j u , r . s u b t e l l u l . r. r l t . f . r i , ) , , \ . . r ncd( l
r r r u ' t l ch r p t r p l . r s , ri l : r { . I l l . l n ! ( D r s t . r h . \ r f i . r l . J
J o r h . \ V c e o r r i l u J cr i r l r t h r . c , , I 1 r r rt , , ) . ( t s f \ r h . r (, r f i f c r
n , u ' r l t c e L l si n h r x h t h e s k t l e r . , Ln , u s c l c. , n L tl h c h c r n u n
c c l l s r n J r * u e r : i r r r r , r c c l l u l . r r . r e c r r r r L L l . r r rf .nrrr\h. { , l o g L .
rrrtltrgo rnlr hrponophr ir ruston\f nJ rroc.rs.J
c i 1 e i t i . . r t l , n .. r r r l e c l l . r g , n g .
rltn,.,rJ btrusi in thc rJult ths hrrc Llnltcd trp.,rrl
r , . l L ! i d c . l h c r r t o r c .t h c . \ i d s c r s h t l r t t etr. r r r l e v c J orp
r p p l c J p h r r r l u r r I l r b r h r p o l l . p h r 0 i , r r r l r U d u .\,ll. . l c
CEttutARADAPTATIONS
TO5TRE55 n l , , , u s e l ct c l l : r , L l u c c db \ . , , rl , , . , r l ' c d \ 1 ) r l l i u ( 1 . l j \ . r , r l
llcs ot plrho|r,rLi rcllul.,r hrpcrrroplrr rfelr.lc rl,c
A J r t r . t i o n s . r f r . \ c b r h l r . l r r r r s c rr r t t L c n ! n r b o . \ , 7 c . e r r J L r cr n l . r r g c r n c rrth i r , t r . u ^ \ i r l r l r r l . r t c n r , r r , , r
p h r n r n i p c .r r e r . r b o l l re. r r \ r r \ . . r l ! , r ! l i , ) n s( ) r e ( l L sL f , r ( i r I r r\ . r l \ c l i \ . . r s f 1 \ . r f r g . | - l r .
fu\l]l)rr\r t,, .h.rrg(\ if rh.if ..\Lronfr.nr. /'r\v,1,,(r I I c r r e t h . r r i s r r lrrsi \ i , r s r . r ( l i . r (l r r p r n f u p l r i L n r o l r r
. r , 1 4 , 1 , r / ' , r -r r\ ! . r l l \ r ( ' p , f ! n t ( \ t o n n \ o i r . l l s t o r o r n r r l . r r I c . r \ t( \ ( , r \ t ) ( s , , i l i t , r . r l r : a r , , /, , . r r r r ' . rt1r r r s l r s , s u , : h. r s
l t l I r ! l r t i ( n r b \ h , , r d r n ( \ ( t r ( n ( l , A , i ( , ' r r h e m i c . r ln r r l ' 1 , . ' , / . . i : ,
. r ( ( t r \ 1 f . i . . ( h L h o r n r n r n t h r r c L lo r l . r g c n r o r t o i t h c r r l r t n t r g i c r L ' c L p t r r s .l h N ' s t , n r r : l L r L , n r( ) n $ g f . r l l r , r n s
b t . r * . r n d L L t c r uJsu r i n g p r c s n r n o 1 . / ' . r t r r l , , . ! a r J r l , r . r J u i r r o r p . r r h s . r r st h . r t L r . r rrl o t h i r n r l r r , : r i l no i . r n L r n r b c r
1;,,rj.rr'f.st)(!ri.\ k' \irf$ rhrl ,rll(^\ ..lls n) nrod!l.rt. ' j ; , . . . r . l '
t h f r r \ r ( L . r L L frcn . l h r n . r i ( , ni r d r h u \ . ' . r t c i n l ur r . S u r h i c l l L L r r p i , t t , r n s .i r c r r r l r n gg r N t h a , r . r ( ) r \ . r f { \l r l , ! l | L r . r l
, r r h p t . r t i o n sc r r t r l c s o c r r l r l r s tr c t i o r r r . p n r t t , n s .I h r , ( \ u r \ r h f \ \ r t l r ( r s ( ) f m o r i p l , t , n s . r r J

,...; i
'r
- Y-t'-:--.
.€--'....
c

p h F o l o q i . h y p e ( r o p h y o t t h e ! t e r u 5 d ! r n q p . e q n a . . y A , G r o s sa p p e a r d n . eo l a . o r n a ! t e , ! t { / , q h 0 a . d a q , a v i d u l e , ! i ( / e / t )t h i t
w a s r . m o v c d l o r p o n p . . t l m b . . d i n g B , l m a l . p n d l e 5 h n p e dl t e r n e r m o o r h m u s . . . . r l r . n r a n o r m a l r c t r f c o m p . r . t h s w i t h ( c )
a r g e ,p l m p h y p e r i r o p he d s m o o l hm ! ( e . e s i r o n r a q r a v d u r e r u s( B . n d c , s a m em a g nn . a r o n )
4 1-
CHAPTER CellInjuryCellDeath,
andAdaptation5

myofilamentsper cell, which achievesimproved perfor- (Chapter 3). In this process,grofth factors are p.o-
manceand rhus a balancebetwe€nrh€ demandand the ducedby white blood cells (leukocytes)respondingto
cellt functionalcapacity.There may also be a switch of the injury and by cellsin the exrracellularmatrix. Srim-
contracrileproteinsfrom aduk ro fetal or neonaralrorms. ulation by growth factorsis also involvedin the hyper-
For errmple.during murclehyperrrophy. rhe o-myo,in plasia that is associatedwith cenain viral infecionsi
heavychain is replacedby the p form ofthe myosinheaw for exarnple,papillomavirusescauseskin warts and
chain,which hasa slower,more energerically economical mucosallesionscomposedof massesof hyperplastic
contraction.Vhatever the exact mechanismsof hyper- epithelium.Here rhe growrh facors may be produced
trophl, a limit is reachedbeyondwhich rhe enlargement by tbe virus or by infecredcells.It is important to note
of muscle mass can no longer compensatefor the rhar rn rll rhete-rruarion!.rhe hlperplasricprocess
incieasedburden.When rhishappens;nrhe hearr,serer!1 remainsconrolled: if hornron:1or growth factor stim-
"degenerative"changesoccurin
the myocardialfibers,of ularionabrrrs. rhe h!perplasiadisappears.ltis this sen-
which the mosr important are fragmentationand lossof sirilitv to normrl regulator,vcontrol mechanismsthat
myofibrillarconrractileelemenrs. The variablesthat Iimit disrinsuishesbenign pathologic hyperplasiasfrom
conrinued hlperrrophyand cau.ethe regre*^e chrnge, cancer, in lvhich rhe growrh control mechanisms
are incomplerel) under,rood.Therem,ryhe fin,rehmrr, hecomedrrregulared or ineffettver( hrprer6t. Nev-
ot the vasruliturero .:dequarellsuppL rhc enljrged erhele\\. p'tth'rlogichyperpla\.rLon,r'rule\a rerrile
6ber,.of rhe m,torhondriai",uppl' ;ieno.'* '"pio, soil in which cancerousproliferation may eventually
phate(ATP),or of the biosyntheticmachinervto provide aris€. Thus, parienrs wirh hyperplasia of the
the contractile proteins or other cyroskeletalelernenrs. endomerrium are ar increasedrisk of devetoping
The net result of thesechangesis venrriculardilarion endometrialcancer,and cerrain papillomavirusi;fec
and ulrimatelycardiacfailure, a sequenceof eventsrhar tions p.edisposeto cervicalcancers(Chapter19).
illustrateshow a ada?tdtiaftto strcss.dn ptoxressK)
fi,nctionally signifuaftt.ell inia^' if the stressis tlot
Atrophy
Shuakagpn the stzeol the cell bv the lcts,o7 rcll sub-
Hyperplasia ttanccis hn6wn as dttoprl U hen I .ufncrentnumber.f
cellsis involved,the entire tissueor orsan diminishesin
As discussedabove, hyp€rplasiarakes place if rhe c€ll size,becominsarrophic (Fis. l 4). Ir should be empha-
population is capableof replicarioniir may occur wirh sized that abhough dtlophi. cells nay haue diminished
hypertrophyand often in response(o rhe samestimuli. function, they ale not dead.
Hyperpla\ircrn be ph!roloqrcor parholog,c. Causesof atrophy includea decreased workload (e.g.,
immobilizationof a limb ro permit healinsof a fractura),
. The two rypes of pbysiologichypelpldsia zre tl) lo* of innerva"on.d'mini\hedblood,uppt).in.rdequare
howonal l.ypprplasQ,erempl6ed hy rhe prohferrron nurririon.lo$ of endo(flne\iimuld on. andrs,ns {,en,te
of rhe slJndularepirhelumof rhe rema,rD'ca{ rr atrophy).Ahhoxgh someof thesesrimuli are physiologic
puberty and during pregnancy;and l2) .ompensahry (€€., the lossof ho.monesrimularionin menopause) and
blpetpldsia, thar is, hyperplasiarhar occurs when a others parhologic (e.g., denervation),rhe fu;damental
porrion of the rissue is .emoved or diseased.For cellular changesare identical.They represenra rerrear
example,when a liver is partially resected,mitotic by the cell to a smaller size at whicli survival is stilt
activiry in the remainingcells beginsas early as 12 possible;a new equilibriumis achievedbetweencetl size
hours later,eventuallyrestoringthe liver to its normal and dirninished blood supply, nutrition, or trophic
$eighr.The rrimul for hlperpla.raIn rhr( \ettinBrr(
polypeptide growth facrors p.oduced by remnant Arrophy resultsfrom decreasedprorein synrhesisand
hepatocytesas well as nonparenchymalcells in the inc.easedprotein degradarionin cells.Protein synthesis
l;ver. Afrer resro.ationof tbe liver mass,cett prolif- decreasesbecauseof reduced metabolic activity. The
erarronis "rurnedoff' by v:nou. growrh Inhrbrtoh degradation of rellular prorernroccun mainty by rhe
(Chaprerl). ubiquitin prctcasomepatbuay. Nr\ttie denciencyand
. Most forms of pdtrolog,chyperplasiaare causedby dr'u\emry rcri!areubiqui0nhgr\e\,\^hrchaFachmur-
ercessivehormonal or growrh facor srimularion.For tiplecopre,of the ,mall peprrdeubiquirrnro cellul.:r
pro-
example.after a normalmen,rrurlperiodrherer. a rerns dnd rrrger the\e prorernsfor degradarionrn
bur\i of urenneepirhelirlproliferanon rhar ir normatty proreaqJme\. Thi\ pdthwayi\ rlso rhougl o be respon-
tightly regulatedby stimulationthrough pituitary hor- ible !.r lhe ffcelerrledproieolysi\,eenin a varieryof
monesand ovarianesrrogenand by inhibition through .rraholc condiiion.,.rncluding<anrercrcheria.
progesterone. However,if the balancebetweenesrro- In ma,y siruations,atrophy is also accompaniedby
gen and progesterone is disturbed,endornerial byper increasedautopbagy, with resulting increasis in thi
plasiaensues,a commoncauseof abnormarmcnstruar nu.nhet ot autophasic uaruoles. Aurophagy r..retf-
bleeding.Hyperplasiais also an imporrantresponseof earinB-li' the proce+in which rhe srarvedcell eatr irr
connective-tissue cellsin wound healing,in which pro- own componentsin an arrempt to find nr:trients and
liferating fibroblastsand blood vesselsaid in re-pair survive.We will describethis processlater.
 CHAPTER
1 Cellnjury
CellDeath,
andAdapta
ons

AtrophyA . , 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 sub-
nance natrows the gyri and widens the
sulci. The meninges have been stripped
from the right half oi each specimen to
revealthe surfaceof the brain.

Metaplasia columnarepithelium. Metaplasiamay alsooccurin mes-

enchlmal cells but lessclearly as an adapriveresponse.
Metaplasia is a reversible changein whichone adulrcell
For exarnple,hone is occasionallrf(rmed in soft rissues,
t_vpe(epithelialor Dresenchymal) is replaccdb) anorher p:rrricularhin foci of iniury.
adult cell typc. In this tvpe of cellular adaprarion,cells
sensitiveto a particularsrressrre replaccdbv other cell
r h e . r d r r n e, n l n r r m e n r
t l p e . b e r e ra h l er o u r r h . r . r " d
Meraplasiais thought to arise by genetic "rcprogram
ming" of stem cells rather than transdifferentiationof
alreadydifferentiatedcells.
Epithelialmetaplasia is exemplified bv thc sguarrous
changethat occursin rhe respi.arorvepirheliumin habit-
ual cisarette stlokers (Fig. 1-5). The normal ciliated
colurnnarepirhelial cellsof the nacheaand bronchiare
focally or widely replacedby stratifed squamousepithe-
lialcells.Vtamin A de6ciency mayalsoinduccsquanous
meraplasia in thr respirarory epithelium. 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 respirarorvepithc-
lium olten coexistswith cancerscomposedot malignant
squamouscells.lt is thoughr thar cigarcrtesmokingini,
riallycauses squamous metaplasia,
in someof rhesealreredfoci. MeraplasiaDeednot always
andcancers ariselater
.*:la*-'--L
occurin the directionof columnarto squamous epithe Figure r-5
liumi in chronicgastricreflux,the normal stratifiedsqua-
Metaplara of norma columnar(/eft) to 5quamous epithelium
mousepitheliurn of the lower esophagus may undergo (rigrt) in a bronch!5. shown (A) (hematkally and (B)
nrcraplasricrransformati()nto g:rstricor intcstinalrype
6 1-
CHAPTER Cei nturyCeitDearh,
andAdaptatons

SUMMARY . 6 ' ,
CellularAdaptationito Stress NORMAL
. Hypertrophy:hcreased cellandorgansize,often
rt_ilr l
* "\.,,
In re\pon\er,,,n.rer\ed $,,rkloadr inducedb)
mechJn,..rl,ffe$ rnd by ero*rh facron;,'.cun.n
tissuesincapableof cell division
. Hypelplasia:increasedcell numbersin re5ponse
' ',c]t
ro hormone.rnd ,,rhergrowrh {actor.i,,crur. in
tissueswhosecellsare able to divide -'' ''
':"4': I

. Atlopb,: decreas€dcell and organsize,as a result

of decreasednutrient supply or disuserassociared t
wirh decreasedsynthesisand increasedprot€olyric .f:^ a
breakdownof cellularorganelles
. Metdplasa:chrnsein phenotypeof d,fferennarcJ ,"_rl 9
cell\. ohen a re\pon\ero rhronit r-ntationrhar _{.)
Apopror,c
makes cells better able to withstand the stress; @rild
u,uJll)indu.edb) Jltereddrfferentiarion
prrhwrl of
ri*ue nem Lell\imJy re.Lrlrin reducedfrn.rrurrror l"
^t.)-
inc'er'edpropen.It for maLgnrnrrranrformatron. / Q,) "

tt ,,^".,ieit'
Enzymalic
drgeslion Phagocytoss
OVERVIEW
OFCELLINJURY
AND andleakageoi ot apoptotic
cets
CELLDEATH cer!larcontents anotragmen$
NECROSTS APOPIOStS
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 celluar featuresof necoss (/eft)and apoprosi5
(.bhO (Adapted
agmgagen!sor suffrr from intrinsicrbnormatiries. from Walker Nr, er al: Patternsof cet death. M;thods A;chv
Dif Exp Pathol13:18-32,1988.with permission
ferent injurious srimuli afiect rnany metabolicpathwavs of S. Karger,Baset,
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 . .
os!, ncdtdnnns, an.r robs n diseasednd physnk,sy
. Rercrsihlecel! oiutt.ln earll stagesor mild forns (liis. I 6 andTable1-l). \(hen dam:get<,nrembranrls
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 \ , \ c!toplasm,and digestthe cell,resuiringin zerrosis.Cel-
srage,althoughtheremav be siBDilicanr strucrurarand lular contenrsalso lcak our through the darnaged
lunctionalabnormalities. rhe injury hastypicalll nor plasma membraneand clicir a host reaction (inflam-
progressedto severemembranedam.ge rnd nuctea. matur). Necrosis is rhcmajorpathwavofccltdeathin
many comrnoDlyencounteredinjuries, such as thosc
. Cell death. Wirh coDrinuin8damage,the inlurv resultiDgfrom ischemia, exposurcio roxins,vanous
becomesirreveBible, at lvhich tinre rhe cer carrnor inlections,and rrauma.!(hen a cell is depfivedof
recove.and ir dies.Thereare two typesof cettdeath qrolvrh lJrrol' "r rhe ,ell\ DNA .,r prore.n,rre
netrcsisaftrl dpoptosis tuhichdif[er in tbeir mo4lhot d.rmrgcJI'eyondrepJ,r,rhf cell l,ll, ,r,etrt'r ,nlrher

T.bret-i Features
of Ne(rosisand Apoptosis

Pyknoes J k:ryoiihcrr i kirvol\,s tragmrn!anon no nu.leosom.n,?elrigDcnb

Intacti altrcd $ruduc, spaiallt orien&non of

Eozvnrr.c d'ge$1oni nril lerk ou( ot cetl l.b.tr niil br rele.sedD aD.pron. bod,e!

l'hvnolog'. o. f&ho1.g( rt,le Inv.r.bl,v pdrholosr. l.ulnrnrnon ot,treve6rbtc 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,
andAdaplations

typc of death,callcd dpoplo$r, which is characrerized arino acid,rh,rrutun in hemoglubrn \ grung n.e ro
by nuclear dissolution without complete kxs or \ 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
mernbraneinregrirl. Apoptosis is an acrivc! r,,crsy becauseof de6c;encyof functional p'oteins, s'ch ai
dependenr,rightly regularedtype of cell death that is enzymes in inbornerrorsof metabolism, or accurnulation
'een in .,me .pe.ifi, \lurrion,. $rc,cds lr.,/,^^ r5 of damasedDNA or misfoldedpnrteins,both of which
alwav'.a fath"].u, t'h\'ett. ap,,p!.^tttctuc, ftany triggercell de:rh when rhevare beyondrep:ir. Variati{'rs
nuthal lu't, tn n' dnd E h"r neccssanlya':,riaral utth in the geneticmakeupcan alsoinfluencc the suscepribil-
pdtholoei. ell Mftry.The rnorphologicfearures,mech- iry ofcelh to iniurl-by chcmicals and othcrenvrronmen-
anisms,and rignificanceof thesetwo dcarh pathways ra1insults.
are discussed in more derail larer in the chapter.
Nurritional Imbalances.Even in thc current era of bur
geoningglobal affluenle, nurritional deliciencres rrmarn
CAUSES OFCELI.INJURY 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
rraumaot a moror vehiclraccidentto the singlegcne in devek)pedcountrieswith high stan-
defecrthat resuhsir a defecr;veenzymeunderlyingaipc- dardsof living(Ch:rpter 8). lronically, excesses of nutri-
ci6c merabolicdise:se.Mosr injuriousstimuliian-be ron are also important causes of morbidity and
groupedinto the following caregories. Drortality;f(r example,obesiry markedly increasesthc
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 or
rFrertere\ $irh derobrcn\rJdrire re,prrrrron,rnd r, rn
arh(-u\clero!.a' well ar n rn.rer,edr.rlncrrhilrttro
!xrremelyimporranr 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 armos-
is the most comrnoncauseof hypoxia,oxysendefici€ncy pheric pressureall have wide ranging efficrs on cells
canalsoresuhfrom inadequatc<ixvgen atn,n-o I rhe blooj, (Clhapter 8).
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 replica-
c 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 andtissues. Al1
monoxide(CO) poisoniDs. (CO ftrms a stablecomplex of rhe,e. hange.
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
ChemicalAsents.An eDormousnumberofchernicatsub- ,trgJIi,m.Tl-, me.hJni,nr urderlving., )lubr ,rgingrr
srances!an injurecells; eveninnocuous substances suchas ,liscussed ar rhc endof rhrrrh,rprer.
glucoscor sah,ifsufficiendvconcentrated, canso derange
theosnnricenvironmenr rhatcellinjuryor dcarhresults. THEMORPHOTOGY OFCELL
Oxygenat sufficiendvhigh p:rtial pressures
A]{D
is also roxic. TISSUE INJURY
Agertscommonlyknown as poisonscauseseveredamage
at the cellular level by altering mernbranepermcabitiin
osmotic hofteosrasis,or rhe inregrity of an enzymeor lr is usefulto describerhe basicalrerationsthat occur in
cotacror!and exposureto thesepoisonscan culrninatein damaged ccllsbeforewc discuss ihe biochemical mecha
nisms that briDg abour rhese changes. All strcsses
the deathof the wholeorganism. Otherporentially roxic
agenrsare encountereddaily in our cnvironment;rhese aDd noxiou! intluencesexerr rheir effecrsfirst ar rhe
mole.ull ,'r hlochemi.al le\el.Lplluldrluncttonnay be
includeair polluranrs,insccticides, CO, asbestos, and losr lons b,l,.re cclldearh"ccuts.and the nuryna,,st.
social srimuli"suchas ethanol.Eventherapeutic drugs chancesof ce iniury
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
hal rr r e nnrr r f lot dedth)lds fdr behindbo,b tFiE.
1-7).For examplc,myocardial cellsbecomcnonconrrac-
u,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. repaired and,ifthe injuriousstimulusabates, thecellwill
Immunologic Reactions.Although rhe imnrunr sysrem r e r u r n
r , , 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 .
defendsrhe L,odyagainsrpathogenicmicroocs,rnnrune cJu,e\cell' ro pa.. rhenrbulour"p,rnr ur no rerunr"rnro
reactions can alsoresulrin ccll and tissueiniury.Exam nrcuersibleiniury ^nd rell drarb. The eventsthat derer
ples includeautoimmunercacrionsasainstones own minewhen reversibleinjury becomesirreversibleand pro
tissues and allergicreacrions gresses to cell death remain poorly understood.The
againstenvi.onmental sub
stances in generically suscepriblc indjviduals (Chapter.s). clinical relevance of this quesrionis obviousiif we can
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 deleterrou, r,,n,e
changes as conspicuous as the conseniral malfbmmr;ons querces.Although rherearc no definitivcmorphologicor
associared with Down svndronreor as subtleas the single biochemicalco.relaresof ifferers;bility,xuo phenomena
 1-
CHAPTTR CellInjuryCellDeath,
andAdaprations

Reversible
Iniury
The two main morphologiccorrelatesof reversiblecell
iniuty arc ce ulat swelling and fatty thange. Cellutar
rwellingis rhe resultof failureof enirgy-deprnu.nr ron
pump\in rheplasmamembrane. leadingro an inabilnyro
maintainionic and fluid homeosrasis. Fattychangeoccurs
in hypoxicinjury and variousforms of roxic or merabolic
intury.and i! manife*edbr rhe apperrrnceot \mall or
E largelipid racuolesin rhecyroplasm. Ir occursmainlyin
cellsinvolved'n and dependenr on fat merabohsm, such
as hepatocytesand myocardialcells.The mechanisms of
fatty changeare discussed later in rhe chapter.

Morphologlt

Figurt l-7 C.llul.r 3w.lllnt (Fig.1-€B).th6 first manitostationof

almost all forms ot injury to cells,is dif{icultto appre-
Therclationship betweencellularfunction,celldeath,andthe cistewith the light microscope;it may b€ more app6r-
moryhologic changes of cellinjury Notethat cetkmayrapidty snt at the lsvel of the whol€ organ. Whsn h affects
berome nonfunctional aftertheo$er of injurvatthougtfthey ar; manycellsin an organ it causessome pallor,increased
ttill viable,with potent'ally
reversible
dam;9;;a tong durarion turgor.and incraasein weight of the organ.Microscopic
or In,urymayevenludlly leadto irreve4'bleIniurvandcettde.th.
Notealsothat celldeathtypkallyprecede5 examinationmay rsveal small, clsar vacuoloswithin
uttranructural,
tight lhe cytoplasm;theseropresentdist€ndsdand pinchsd,
mi<roscoPic andgrsrly visiblemo.pholoqi. danqes.
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 vac-
rcuersemito.hondlial dystlr.r'b, (lackof oxidarivephos- uolss in the cytoplasm.lt is principattyencounrsredin
phorylationand ATP generarion)even afrer resolurionof cells participatingin fat metabotism(e.9.,hopetocytes
rhe original injury. and profound drsnrbancesn mem. and myocardialc6lls) and is also reversibl€.Iniured
branefunctio . Ls mentionedearlier,injury to rysosomar cells may also show increasedeosinophiticateihing,
membranesresults in the enzyrnaticdissolutionof the which bocom€smuch more pfonouncsdwith progres-
6ionto necrosis{describ€dbslow).
injuredcell rhat is characreristic ofnecrosis. The ultrastructurslchangssof reversiblecell injury
Differ€ntintudousstimuli may inducedeathby necro- ers illustratodschematicallyin Figure1-9andinctude(1,
srs or apoptosis(seeFis. l-6 and Table 1-1). As men- plasmamembran€alterationssuch as blobbing,btunt-
tioned aboveand detailedlarea severedeDlerionof ATp ingordistortionotmicrovilli,and tooseningofintorcet-
and lo* of membranernregnryrr€ typicilly assocrated lular attachments;l2l mitochondriatchangessuch as
wjth necrosi5.Apoprosrsr. an ,c !e and reeulared swellingandthe app6arance ofphosphotipid-rich amoF
procesr nor assocratedurrh ATP depletronand n har phousdensitiss;{3)dilationotthe ERwith detachmont
manyuniquefearure\. whrchwe wrll describe.eparatelv ot ribosom6sand dissociationof polysomss;and (4)
larerrn the chaprer. nuclsaralterations,with clumpingof chromatin.

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/topl.sm,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 -
CHAPTER Cel lnju44Cel Death.andAdaptalons

-.a
o
ei+=N
+ES\
, r \q{i:,v/
.-66d
I
ffi
ow
,",rt\

.!.
;c , -*l-' '@,
Clumping

FEomenlaiionol

d6
::iffJif*'t.;-ai
'.o -r
). -. -!
f l ) o _ i , . - : i i
N<oss -'_r
e
64
2 / , .. :o-'^ -3

|;ru*.-",t:,"
EI
d;
E3

A normal.el and the.hange5in revereible cell injury(ne<roris)

and i.reversible

Necrosis homogeneous appearance than viablecells,mostly

The term narroslswas first usedby morphologisrsto refer because of the loss of glycogen particles. When
to a seriesof changesthat a.companl cell death,largely enzymeshavedigestedthe cytoplasmicorganeiles,the
resulting from rhe degradativeaction of enzymeson cytoplasm becomes vacuolatedand appears moth
eaten.Deadcells may be replacedby l6rge,whorled
l,i hJll) Inrured
cell,.\ecronLtell. rre unabler,,mrrnran phospholipidmasses,called myelin figuret that are
membrancinregrity,and theircontentsoften leakout. Thc derivedfrom damagedcellularmembranes.They are
enzymesresponsiblefor digestionof the cell are derived thoughtto resultfrom dissociationof lipoproteinswith
eitherfrom thc lysosomes of the dying cellsrhemselves
or unmasking of phosphatidegroups, promoting the
frornthe lysosomes of lcukocytesthat arerecruitedaspart uptakeand intercalationofwater betweenthe lamellar
of the inflammatoryrcactionto the de:d cells. stacksof membranes.Thesephospholipidprecipitates
are then either phagocytosedby other cells or funher
degradedinto fatty acids;c6lcificationofsuch fatty acid
Morphology residuasresults in the generationof calcium soaps.
Thus,the dead cells may ultimatelybecomecalcilied.
In onecommonpatternofcelldeathresulting fromlack By electronmicroscopy(seeFig.1-g),necroticcellsare
of oxygen, the necrotic cells show increased characterized bv discontinuiti€s in Dlasma and
eosinophilia1i.e.,pink stainingfrom the eosindye, the organelle memb16nes, markeddilationof mitochondria
"E" in "H&E").Thisis attributable in p6( to increased with the appearance of largeamorphousdensities,dis
bindingof€osinto denatured cltoplasmic proteinsand ruptionof lysosomes, intrac),toplasmic myelinfigures,
in panto lossofthebasophilia thatis normallyimparted and profoundnuclearchangesculminating in nuclear
by the ribonucleicacid (RNA) in the ctloplasm
(basophiliais the bluestainingfrom the hematoxylin Nuclearchangesassumeone of threepatterns,
all
dye,the "H" in "H&E").Thecellmayhavea moreglassy due to breakdownof DNA and chromatin.The
l0 CNAPTER
I 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 - Moryhology
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 Coasulativenecrosis is a form oftissue necrosisin which
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 . 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
'l
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 tecture is preseNed for at east several days (Fig. 10).
pattern, karyorrhexis, the pyknotic nucleus undergoes The affected tissues take on a firm texture. Presumably
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 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
c o m p e t e l yd i s a p p e a r s . 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
SUMMARY 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
MorphologiaAlterations in Injured Cells 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 .
. Rcrcrciblecell iniury: cell swcllins,fetry chansc, Liquelactive necrosis is seen in focal bacterial or,
plasmamembr.rneblebbingand l(xs of mic(, 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
villi, mnochondri:rl s$cllins.dilarionof dre Elt, 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
eosinophilia(dueto decreascd cltoplasmicRNA) obscure reasons, hvooxic death of cells within the
. Nerrosa'increased eosinophiliar nuclearshrink' 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 -
age,fragment:tion, :nd dissolution; breakdownof 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
plasma membrrne .rnd orgrnellar membranes; 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
myclinligures;leakage and enzvmatic digestionof 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
ccllularconrcnts 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
. Ar(rn)s's: nuclcarchnrnrnnncondensation;for rial is frequently creamy yellow and is called pus
( C h a p t e r2 ) .
mationof apoprotic bodies(frrgments of ruclei.r d
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
Patterns
of TissueNecrosis undersone coasulative necrosis involving multiple
tissue layers. When bacterial infection is super:mposed,
\ , . - . , . r ' , ' f r . , ' l e . , , , i . e l l .r . r r r * r r c , , , , i , B , , . r i r 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
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 action of the bacteria and the attracted leukoc!,tes(so
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 called wet gangrene).
Caseous necrosis is encountered most often in foci
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
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 -
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 . 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 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 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
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 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
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 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 f.ai on)
 I

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iL.r' '
:i".,. .'-'
j ":l
';"' "i'u: ': ,1,.
,..-'.;..i..'..i.i
il, i r lt
.:i'.. r:',i.- -., ,
ii
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4 : Ji f . _
I
a!
:-.-:
 rqrrsfofmri.. utn prorcrns,hdush rhr drn,s.d ev.Er prckrsihr$nsenrntntd.pnv,.on. tf nis nor
'h. cncuhnon,ro (o arcd,aroph:8) m4 resisnrt.d drnh h) rpop
lidB ' n.'n5 ',fdfl(rn8 n$ucsp(,f( nrtrou5u,ns hn.d ellrh,r Lrlrn
arr,li:( DUeh, fnr.rimoh. n,, ions.imp. br Inins on B"$n or6ndL!.
.oDtains a unlqkrornm ofthr mzrn.(etiD. kim! Thr.i4n6 n lr5o,on6.an brcrl do\n msr Do
?id of'h. lonkd . mo.e'nrotu";. "hei.rsh.or . rii!,nd crbohydrua, at'housl sohr tiD& rcrfu,n
hile dud tp+€lilm onirn', kmFi,r,r R,;rut uidicdEd tF6on6 wrh und&{.d d.bi,s mr *.
roforh of rhe.nzym.ikatin. pholphnzr, and h.p, n{ wtrhLn alL a! E &,16,,&., o' m! b. -;ud.d.
6ibl. initrs ind 6tl Liort..i, prr44 3hnul6 r.prckft md,s6nbL€ n,i.
deed in ih.n isues rrt rtne(d in incm*d 5!run rur rt5drnB hom frc. Dd,c,t_m.dDEdhDd Ddo",
lelels ol !u.h pror.'ns, ind m.asurcmcnroI erum twek d,ion. cddn indisKnbtc pisnrn( 5uch ,s i,rhon
n uedclini.allyrc s!.$ damrs.b .* issues. p3rti.rs hhd.d fom rh. .rmosphei..r incul.ted
,i pL2sotrsosom6 of
S||br.llubrrerponr.sro Inl||r! mr.ophasesrar d.sd.s (disus.d tarrr.
L)sosones,r.akorepariroi.! whercretls*qu6Er
rhus f2rv. h:ve mrnt fo.ued on ihewh.teissur or mdribr\rhrc;nno'b..,,mpftbd.q,drd
lh. ..ll as , u.n. HolBer! .eit in z*.nb znd jr..*s HeEdrrr
ntt,l!ns ony sub.dtuhr .Dzymesrh,r dtsade v,irousn.cromoh.ut*. Rsultin
ol8,n.rh!. Ar+oleh em. ot 'hG;tk ron, (cur,r :bnorm.l 6l1.dons of int @.diar n.kh.tn6 iQ a.
rd.rdharinruq,o .EJE(rn,nLhrontrru,morrdl Irsoson6of als, .v.r fi. b.dy
iniurn and ,ill.orl'ds arc id,pl1y d2nr :us.ptibl. rt, l.thaLLriua lrcm suchdhuta.
n :nd 'ntr.nine o'
ther rtnion! arc d\o^w.l
auropbaSr. Aubptisy EG6 ro tvsos.naldisenion.f Indtroion (H}}.drop[y) of Smoarl'ER. Th. smoorhEt
rh. c.ll\ osn .onponenr rnd is .onm$.dtnh ,gr (SER)is'.volnd in thend,h.lnm otvaria!.ch.miak.
efopr,431, nwh,chrcdl andc.lk qFrd to rh6. ch.mi.abshowhyrrt.onh!
suberi.o hom rh€cdriJc for i,riicd/uta! dsruqioi of rh. ER a! .' ldipiv! Esp..s. r[n oa], h;v. idorr
lFis.l-15).Aurcph,syn rhousirb L. a suryi!,tm.th- n$nc€, b$birur.tes
.rrn n nm.s or nuri.nr d.privarion,su.h rbar thr arc nerabolized ir tllr llve by the crehrcme p-1J0
fiflrd cll liy6 br sms ib own .oftns, tn ll1r m,xedfundon oxidl* sstem found ii the 9ER. pn,
prtu!$. nr,cdtuhr o|e?nr s Jd r2&d useof brhnuEB hi& b a $r ofbt.cn...
ir< hrslfqu{rcrd fr,,mlhe+'oolz'nn altoDLoq. wnh a dd.is in fi. dlfr6 oI rh. drur ind d. natl b
,,. {o/. fomrd trcmnbo,on! fft,4'on\ of rh. rc;h ur inci.rins dotrs.TIn:daphrion ddue to incRz*d
ER LRERrTh€lr.uok tu*5 wtrh y,o",-s b brm; eorun. th)p€tuophy)of $e sER ot h.Ddo.yr.! .nd
c,tdthasatya'an4 :nd rh. c. trl, .omlon.ns re in(osed P450 .n4m ( nr!trr. Ahh;ugh p.
di&*.d by lysdonll.nzyms. Auhphasyiinni:Ed by 4so-m.dftJ mod'filrnon6oh.n rhoi, r"f-jit-",
ifi.rtion,"manrcoDpounds 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. .nti-
b..ruit oI iDducaonol sFR r

Mi'qho.lrirl Atlnrimr. A!d.sb.d 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,Mhondfl:D.dk.conrd(tq 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
Ad4h|9(4h0andhd.|o'ba0!btR.dlrw| ..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 - .d hilrartu!! rd^&er6

rsri,rd wnh iicr..sed rumb.6 of u.urui y t2is. . Mnuhontrkl

rnchondn. conr.inilgebnorml trnb.. albatioas: Chsrgs in .
.umbri, si4, and sh,ts oI mirNhordii ar Fn in
Cy.o*eldalAbnondni.r.Th..yr.sl.l*onconsn6ol div.c ad{t iions rrd r.$on$ to chrcnic i4ury.
rctin rnd nlsrn ril,mha. nnrotubuks,a v.riour ' clioJtslsal clrd,.rbzr son. druss ,rd roxinr
d *..t iftlmldi.E 6lan.n6t svd,lorh.r nonpl,ly- :isnbly r.d lunaions ol
n.r;cdandronfiLmenrous fomsatonr,.ih Drorein5 cyt6k.l.bl fiLmens or rcsfi in .6nodal rau.
.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.,..tl
por,rirr,,lierinsunhiqup enddcsn)
. THnsmissionof rtll{.l| 2nd err<xnaallul,r

. Miinrtftn.. of mahanical $rtnsth tor i55u.

I rEctatttfls of cEr.L
r ruRy
Now thr s. h,!. dieu5*d rh. cau$sofRllinFry rd
narasis.nd .n no.pnotqic'nd tun(oni.orEtaks,
w. ie{ considerin norc d.r,il th. moreutar b.sn ot
cdl i,iury rnd lltd illun,ar rh. impoit nr prin.ipt.!
cdls ,nd rstr6 i..pond b .nvnonm€.tt sis.ts wiih r r.w krr,.d "xanpr6 orcommonryp.sofiriury
k.3.,she,rsca in bk,ody6skor iD.Fdtd prtsuc Th. bi&hrhicn mehanismslinkinemy sivm iniury
ii .l'!an) by con$antlyrtmad.linsdtir inrac.llular with ihe rcsukiq c.lltrlii rJ Gsu. mnife$.iions,ie
$:ffotdjns.Abnorm.tnmof rh. qbskd(on oaDr in, complex,ifueKonndEd..nd ishrly nrrwoytn wnh
vrri€ry oi pitholosic $1r!. Tij.e abnom.lri6 har 6.
mrny nhc.lluh! mdaboh. paih
mn1i.s.d s r .b.ormataDF3rrne 'nd lundi.n oI aft.n dil6.urt r pinroinr 3Deri6.mohculrr akd,
.d15(hrp.nophic cardiomyop,rhyt cl'.pEr l l), 3btr. rionscau$dby r pini.ular insuk.N€venh.lsi nlcral
:nelks.d.fdi!. ftll
ldonomn. dr inr..dlula ccuinuhiicn oI 61,!irh, s6d,r prin.ipl.s:r. rct.vrnr ro nai f.ros of cdl
nrnri2l ,s in ,coholic tiverdiksr (c[apE 16).p4.
o.h.rionsin th. ol8rnianonof,nrtubuLscane * . Th. eltulo ft:panr to i,i',h,' n'nuh d?p?n&oh
*erility by ,.hibnins .p.m honLty, s uell s d.fnaiy! the ,p? ol inj,4, it' dyn o\ and * rfu?7ifr. rhus,
mobirn'of!irr in,h. 15pnrory.ptrh.t,um,Kat ns,n low da*.aI!xi!5 ora bn.fdunrian.Inchlm; nav
!hronr nfld nn5d!. ro 'mFrr.d !qEnc oi rnhrLfd LrJ $ Beribl.ellniurx wl'e.:s lars*toxn dok;
6.ckia lkrtuseEt, or t\. idnotile dlir, stndrtdzr. sult n trrcv.sil'r.
Mtrrcrburs,i. rrn,.s$nnrt Ior kIL&rr m,4En,'n iniuq rnd e1ldeft.
,nd phrg,r)tosi5Drussrhr prc\.d m.i{ub!1. Fly. . rh. a,sq@ds ol dr k)u,ius n'autrs d?p?h!t
m{ft rron1e3...okh,!,ntr,r.d.fu " th. ttp.. iat"., ddnphhnt. cnd zdan tua.ap
€n' of mroph:g6 at th. inPnd .,r. rft en. ntq\ h's ! tr J ftqrnr
ro*ard ui,r.ftyi* unh subr'tue fru$srdd@pts ourona d.tsndins on th. c.1t 116 thun *tuEd
it ,h,*o+osis .nd inflanmrtion.sii.r hicrorubul.s sk.l.El muele in dr 1es"<omnodaks .onDltir
r.rm ih. mnoic spmdl.. dius. d'2r bild b microrubuhs i$hemir for 2 ro r hou6 ynhout rak6ibt. inlury.
(e.s..vincr rlk,lods) ,i. 21o .rtiDrotileHtive,nd m.y wh.r,s c,rdi2. muste dies rfrft onir 20 h t0
thercfor.b. u{Iul .s.Dtnumorr*.nB. nintrk.. Th. nunnio'rt (cr horhonat)naiu5ca, rlso
b. impon,nr.d.ir), ? sj.osen.rcptd. h.p,r{rk
w,[ ror.r,rcn(h.mn mrh bflkr rh,n "nr ${ h]!
run brm.d n! hrslu.or molRul..ccndcnty d.tcr
nin.d diy{siry i' mdrboli. p.r6way5can .Ls b.
Iru r,trr 'mpoftznr.For inr2n !. whenexpord rc rh. s1m.
dok or i raxin. individ$tswho lnh. yariancin
Slbclkl$ Ahdddr i. <.ll hl{E:
Elld ol r4udoBA!.it oi ds.;cl6.nd 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€
SoD. iorms ol ..n injury 'tu* prni.ut.r rot. ot Fnd. potlmclph',m\m (spon*. ro d,,uAi
olgimlr6 ,nd hay! uniqu. mrnilsbriotu. :nd rnh5:nd in dn.'( 5u{.otibitiF.Thr sudr oI
. ,4!rrra3'r In nurienr d.priv.d alh. olsanells 5uchinrmctio,r ir.dr.J Dh:;ase;omis.
. c.tl inqry ks\ns hon f,rctiorul dnd brrr.nnal
n. .nclosd in vicual8 thar fu$ with lKo.on6.
Th. are,nclI6 ar. digsrd bDt in .on.;as indi- cbhandhn' in ote ot rat o{ sr{al .seanat dqt
tat .onpo"nB \Fie. l-16). Th. Do$ mponrir
s.ii6l. pism.nt(..s. LNtusjn) rh.ins.
t l|.rntl'y of strli c.ll6.rEd to bnrs drt i:4dr or inird.us rimuli aG lt) mne[.ndria. rh.
rrcn.hboh?d,n,h.5tR 5howhy!.ndph, of (he sita of ATPs.r*arion! 12)rtllnchbBn ! on *hl.h
meh,ntrn h m.vm,z 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.
 Mr r - dr ntq .d M d^d4hc

-l tllnn
I
I
I I
B.Mlbdod.bribiE" nry kd b;;;bh;iryJ;-; i;;ii;;;;i#j

t Pr.rd8.d f {trfn,ns d+knon or aTp (ruer

ATP, ,h. .n.ry) 3rcr ot e s, ts ,rodlcd m,nn bv ,a. tun] dB,upran ot th. prct an s
a\id?,n. ph6phootrnon or adtro,ne dDhos;hri or ribo5"m6 fom th.
IADP) du,inc rlucion oI oirsen in d. d.d;on ;,ns rcDsh.ndopt,*icr.ricutumIRER).nddrri,ion of
por syirrm"r mndhondna.In rddr on. ,h. rtvcothc pdyen* nro honoen.q wnh a co6.oue rcdr
pflhv:,.rnE n.tur. crr '' rh.ik.rc.oroxv6 tion in prckin synrhsis. utrim.klx rh.. i; iftv.Bihl.
u;inr d,mis. b mn(hondi,atrnd teemrt mnbEn.s,
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
phosphr<rn rhr rom of AT? r
(qu,red far yinually ill syn$eac ind dcqriddvr
prr.s!{irhin,ht..l.''(tud,ism.mbmnr,;n5Fn.
S\e
n(6rry ror ohosDhot,Dd
nmov.t. D.ptehan a[ afP ta ter &ca t4c ta ]o9r ot
"mct t"Ek h^ vdnp2ad 4frd, u ia4 n.;t

.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 I I
rio.o$di. eir oI qn(. a6ms @ .41/,s {j
! Th.r. k : ompdn6q, dare in ,tudobn
sty
I
..'r5r In r .lhpr to n.'nhin rht et|n .n.rcv I
e!ft, A5r.onr,tu.nc,,nr3e !h, gtv.ar.n(o;
rft Bprd\ d.ptd.d, .nd tidr .fld ;d;Eu|JA
r.idins to dri.lid inr'c.llutar DH md d.crikj
activityol @ny cdlul,r .nzvmc.
. F.ilrn olth. C., p'-nte2dstoiniuxolc.l.wnh
dim"cins dftr6 on nun.mu. c uhr conmrn6.
 cyro$li. t ..i.iuh n nom:lly n,inbintd 6y AT?
I 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
.ffrnslFl8.l-19).Th.r.n?ynsindud.phGpholipird
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
e IAII:*5, rh(.b) hrn€ninBATP depl.'ion Incer.d
,p.prcsn,by dnN z.iv,bon of.spsa ind 6y ind.i!
oe ins nno.londri:lpqhc,biliry.Th. inpon.nccoI ci.
I in c.ll inlun wasesablish.,lbv rh. firdin! rhr,l.Dle!
ingexna;eliul,rG' d.hys cdi de,rhilitr_hypoxi,,nd
I
I
t 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 .b.ni.n r.t s ar
.*Emdy un*abk rrd rcr'lilynctutrh inoqrnic,nd
ddhb,i(ldBo|rFdsAreeeigietipigptnl'

D.rag. to ilito.hondria
Mnahondi. aE rhe cdlt supplicdoI lif. s!$rinins
.n.Ey in the fom of ATP,btrtrh.y in i.o.riri.i phy.^
in e injuryandde,rh.Mnehondnl .an b. d.mas.dby
incr.{a of .yroeri. ca-, E.div. oryen sF .s ld$
cu$.d bdowl.nd oxys.ndepi!,!on. d so rl'ty r.
snsnivero vntu'lly rll rypA ol injuiousnihuli. irclud
No maior otr+

l?
qu.nc* 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 kn-
sid.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 I
. 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 l.al.s. 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..
 t . *
E-@s@ HF@
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
:b&r{ddid|}'@nod|giaol

oren in! hn tu.rodo,444! b |n d

hllr tu rojor r4roidn liryna d!

n (etk 4 aldty ! Th€ .bicauuo d rud,inro{cy le.s.,ut,Erot.r

rnr(I nucl.,ca!id5 n well* a \:n.D of! ut.r Dro rcnr, \ ny(). lonirns Edir'ion !rn hrdrotya ur.r
teins,nd ripids.In rddiinni fR bdn.L intrirt .i!t,. ii'a hldro\rlLoHl andhrdrcc.niHl fre hdioL
cdrrync r..ciioE motlcuks rh,r r..r vnn tft adicri . TXr.n4mii( n{,b.1'rm oir.oFno,s.h.o,.rts
,ir n tqrnmiv.d(d nto ne Dd'cn5.rhui D&D.crunr (..s.,crrbonGr.chtoidq * tai.n
rh. (hrn or damas..r.,Ju. orys., "p-,;, tio.-,,; . I.tl,naation, bft,u* t.e mdic,k rE Drcducd bv
r iyp. ar oxysendoiyld fR hdigt whosercI. in crtl l.ulcytes dit or.r tisstrB he Cn:oF lr
'niuo k"ell6b6lsh.d Tho r( rrc.lu!.d normalvm . Nitriccridc lNO),rn inponant. tirni.rt -.db ro.
!.lk dunnsnr,{hondnr rts"ahin rnd -{E c;r normlly rnthB'kd byr,;nety orcttbD6rlhrDrcr
rion. bu' rr n. d.sEdd rnd rcn"\ld bi ; un 2), crn rfl 13r fk cdi(Jt or !,n b. .onrert.d;b
dd.dn srtem' wh.i $. produd,vnofRos,na..*5 highly rcadrv. nnnt sFls
ai rh. saveryins rn ms $. in.#ctiv.. rl1t 6uh n,n
.xa$ of rhd. fc ndisls, l.adim to a .ondnion.al.a Gll, hilrdr(lop.d naq zer,,n,,h, h, tno!. h2.
rEitltE ti.s_ Cjll iniuq in maiy circumsD(A rddral and 'h.i.by hnm,. ,nrury Fre nd k rE
'nvalv* drmrsr by fc rrdrcd.: d.s snu'dons irctude inh.cnrr urirbl. md dery sponrnsudy. Th.rc ,i.
1dieu5*d b.lou). .h.mist inJ are ev.r,r ion.nzyn i. and .nz',n.ric sysrDs rh,r
Ed':i,on mED. roxl$ .onr,b,r. b inad'v'doo of fft ri/i.at r.ediom {*.
ellulirrs,ns,m(rcb:t rilrnsbipf]sqr^ rttG:,nd
itrjtr.flury!'ujdh'ln['mn:|o0d|5'
Th.,eunularion of nr adicds r d.unin.,l bv ih.; . Th. hrc of iFnmn.ou! d(ay or suDrord.6,c
Earorpddu.tionrndEmolallF€. r-20J \r!.p r.n. n'66n'ly n(i.&d bl rh. :cucn af,uFordr d;
non!,F Espon'bt.r.rrhe8da,rn4 d h4 tdd@k. 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.
r Th. rcdudion.oxidaiionl.doxl r.rd6ns thatBur . cruEdiunelcsH) p4o\rdee il
dufln8 no.mi mnmhondnrl fr.hbotisn. Du.iru 'niuo br crrltnnr fEe+rdor bft;tido"n, roH.+
(!r eumol(, ssk \hr .*ks is 1CSll - lHlo + CSsr ls\uD,n,on. hmud,m(r .th.
Fqrnri,lrrrd(ed nniGhondnibr'h..ddrionaf inrlelluh, ntio of aiidi-d duhthion. ICSS(jlro
th. Drcss. m1ll rtd(.d sluiathioft(CSH)i5r rtfl(tion of ih. ondr
,m"uns otro.r ntem.d':k 5rE,e5ri p.!saE,l bv !y. shk of d. ..ll an'l rn ihrotunt rsr.n ol r!. .e r
p.dsl rcdufinn or oxy*!n,d;f rn.tud;rFrcrd: ab i$ m..tabolir t. r.dicats.
ndn,L loir, hvdia3d p.fid. lHror). rid oH.
, dc6 the dtE .
dationof iydr.Fn pdoxd.l2H:Or + o, + 2HrO).
vr do,r. fE dfr'rcil dunns .(D n mriedrut;r
readlons2nd ihercby.:i.tyk Ift rudi.atformition. miff E, A, ald C. .nd Fc.locnel mr lithq bick rh.
sf,h. F.nto' ftdnr lt.!+H,o, j Fcr + oH.+ romdo! of fF adicrs d s*ds. themd.. ih.y
 t7
. As m$tior.d,bov., toz .nd .oppd ei.arzlrt . Dut.Lan ph.sOhobA ,nthe'k The ,rcdmioo
rh. rjormrion of Ros. The l.vds of d.* rcrive of ph6pLolipidsin €]ts m,v b. rJulrd urr.D.vs
mdrl. .r Edued by bindine oI rh. bns ro *o$se rh.( n a Gll in ATPlevels,Lidjng to d6rc&d enersy.
andtnnsDodFrat ins(..*..Ensf.rin. ferinn.l.do d.p.nd.nr .nzym1ft ,c.iyni.s. Th. rcdued phasplo
f€rn, /nd ftrulopsm,nr, rhsebr d(ls'nc rh. roF .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 . I|.t%.d
b.en inplicd.d in &.ivaion of cdls by i vri.B ol phy' phosphnlip'd bt akdoan. s.!n .tll
idlogic rimuli. Hq.v.4 rhirt €dioff arc tsnicDlidy miuy r "$Gnted wiih mcrc1*d /.gr.d:non of
cwlnr 6 .an ntw! h,llidkA la h.e adi.ck tk Fi*. n mb.an.phGphalipidr,p66.bly duero ectivrtion
of.ndos.noxsphspLolipas by rncrc.sd LveL of
. Lipi.tt roriddtiaa af nmbft, .Do.bl 6ondsi^ . ros. Oxyc.r t* rrdftt sue injuryto cellmem
n.hbG!. pol)unsruEr.d lipids .E vulnd,bl. ro br.n.s by tipidtsroxiddon.di$u$€d.rrtff
.ftack by oxys.nddi!.d ,r4 ndic,ts_Th. lipid, . clb:ldtul db,omlitEs. cytoskeld2l 6lh.nb
ndicrr intfurions yi.rd Froxides, *hict' '. them. sfl. iMncho6 connetinsrh. Dt,sm,n.mbnn. ro
nlvaunsabl..nd rcad,v.,"rd,. rurG:hlyticciar d. ..ll lnErioi Adrvrion oI proEa$s by incrcakd
cllosl,c car. n1/ cau$ d:m8e io dend6 01 th.
. (ns hnrt4 ol p'nt.ur
5ultydivt mrdEEdprckL' *6, Lntrn& Guhrns,n . Lipid btahdoa ptod"*. T\.r! inclu,l. unaren
lild hE h'ry icd!. nrlarnr'nr, rnd \,aphoiph"
Fc{:diel rcrctionmy.hodnetly suk p.lyFp. lLpids,.r,bolk orcducB rh,, rrt Lrou ro
r..umut?k in,nrqrt:dalsfi aut! !f Dho5DholDd
. DNA t ace,hror. Fi.ebdiel edions sri dcsEdnion Tr.y hiv. : ddlrsld .fh:cr oir man
rhyoin. in nucl.ar rnd niu*ondrial DNA produc. br.,d.Th.):re rrhtr inqtrinro 'h. hpd h GFr ot
nnsl..nruid br,l.5 su.h DNA din:s. hn b(n ,h. mdbEn. or.:.hrns. wrt' mrmbtsn€pho5Dhc
mprlrkd in <i d€rh, isms. ?nd mat€n:nrrrii lipidr,p.knirll) .,ueng .hans6 Lnp.rm.rb'ltry,nd
.lg'ophFiolo*'..lrdarions.
Tht m,&,mpofttrersar h.mbrrft drmsedur ns
ttelect In il.nbrane P.me.bility crr,niuq ei. . ni,*hnnd'i.t n.nbdn., 'hr pG5Dl
t.rlr 165 of *i.h{ ftmbnnr p.trob,tir katlns m.mbmn,,nd n.obnnes oI tysosonn.
. Mnothandnat nmb E l,es,, As di$uscd
ratuE vr m6r fomr ol <ll nruD k:ftphFptuys) 2bov.,d,masrb mn&hond t meDbrr.s 6utu ii
The ph,Di mrm6En. .,n b. d.mia.d by ,rh.nB. ds.rsrd piodudjon of ATq cuhin2tins in nEosiq
v.riour n,cbbi:r bxilr, tyticconpLm.ntcomronens, did trkJft llf prcre'Bfi,' r'es.r rFprotr. deerh.
rid , !eri<4 of phFut ,nd (h.mraLrFnL. s.vrBt . Ptdsd' 4erbrale 4,44. r,hrmr nehbEnr
h*h.m..l mtrh:ntrm! m4 .onr'bureio m.mbEm dama$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
. thir4 to lt$etul flnb ..s 6!ksii lerlact.t
rhu .nzymB inro rh. .ytoDl.sm 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

Dan.ge !o Dl|A andP.ot.in.

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 inrid ns
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
hjury redi{ i3trtEdKri s'n!eA6.nrhrr'3mid(n;lu4 rjp
4ei s4
er ry au* rpopro3lj 'h!y n. d'*u,qd hEr n rh.
 la

Th. tund1on,l .on*quen.s niy b. $v.F ar ihij

I 'Uflf iV
n.s.. Forin*rnc., h.:d musL ea
L<n-kfr of cdl niury 60 smnds ot corcmry(tueion. Hou.!.q to$ of6.
,.djrry dc nor n€i cdtd.rth. rt lyFxia co,tintrs.
. 4,P J4J|ry' btLg. , !!Iw J.+Yd- n9l6iE,{D&Pk!!guxtl.q
wnh bsolmicrovirri rnd th. formitianot "bt.bs"ce
. Mibchoa&id arws. AIP dqlLrtd : i.i,tt€ Fis. r-9r. Ar rhi5ime, Jh€cnrf.tll and ns [email protected].!
oI se4yrl.pad.ni e['nrr tusions + Dlti inrehondria, tR) ,ir n,i<.dty s*o en, wtrl iniE.sd
Drery, nd6'q und.r lm. .ondnioq t..t4. ot ..n.mnations or srEr. sodiun. ,rd .hloride,nd :
d(rcr{d lonrhrEion oI Nir$run. , 6?., r
. I'nlB of aLir,: riwnt oi 6zyr' d^r E orta,alt Ltth-. dLtuia;atak kAt;bt.'
drm,e. allul.r comporcnts.nd n.y 'ts Eiss.r II inhnn t 'sk,q nEr-rble nitt dna neoa'i:
.e. krcv.slbr. ioiury r ssi2i.a wnh sv,.
. Acdr.t'tid 6l urw axwd $?e'.s. .ovl. smll,n8 at inchond'i,, .rmjv. dmrc. ro Dlimr
r.n, hodjri.ni.i of.. uhr pmru5j Lp,d5,nu!t.r m.mbBn6. ind 3*ell,naor |lsom3 i!4. h!. !9r
MassiE,nnuroro ! u;'nro ihe !t[ hr Go; D€5rh
. tnd.@a tmabiltt .l e.lqtat nmbrr"6: n n:inly by mrtEit blt iF rs,..lrc;ndbu6: 16.
my affet pl,sm n.mbnn., ly$sn.t m.n- b$ty by d.a$ ot
br.n6, mitchandial ftmbrrnst rypiglly .Dlmi prcrpdproric moleul.r fioh t..kv mirehondnl The
(rlr5 compomii, ,ft |rosrcstrel' d.scd.d, and .r.
. ^affiahtiot af &tuE d DNA and hllotdd n wrde.prt:dkaL;s ote u[r.n4me5,nto itr..sa
elurf !p{e. Iinally, rh. d..,1 elk my b.sm.
rcpr,lcdhr ha n,,!6 (,mNfd or ohosDhohDd5 ,n
rh. rom orm'dm riBd.5 rh.,t rR rh.neilhd;hrco
.,rordb) kur.(y'e, ord.srJJ?diqnh.r ohryn;5
EI fPrI5 0f Clu |l|{rtY
At|DrEqosls
l*ieni..8.perft,rion Injury
To illusEar tll..volu o! an'l biel'tiic.t neh,nnh!
orcdliniury,w..oDdudeihiss(n'n by di$usings.me It cells ,rc rtvd5ibty iur.d, th. E*orrtion ot blodd
comndry 6n{nised d"nd6 of rcv.slbt. c.1tinjury flow.r r.$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 Liif lh. lo$ of els ;z r'ddl,o, ,o tr.p thd M nrc
k.h.mi,,ordimi'ish.dbtaodfloy ro. tissu4n th. mo* w6ih, d'aed dt th. dtt oj th. t\h.nL @Lod.. rhb
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
rnaeDbl 3ry!ur15n an.on'nu. lalbcr t6! cl6..ndv d2naF in myEfdiit and erebr,t hfdions.
tnrn by okjdanv.prd*1yt, isch.ni,,hd comDromie: s.vaal D{Mnnns nav ,rou{ ao' rhc .xrctrb2iion
rlr d.livery oI strhnEi.s for sly..trsis. Consiquonr of cdl miury rcsultins fr;h EFrlusicn ino irhmrc

!su6 ,Frd poFnii,l subsrars ,r. .rhaun.tl or . Ns dr mcc tul b€'ntrri'.dd!

rl'i6iEd by th. ,ccumubbn 01 b! 'nr.iid *rn.n'ion or RoJ rromNr.nchrdn rld
mchhvrn6rhr Eoltd normith k (mor€J b\ bttld .ndorh.li.l ..lls andtan inFlintinc titrlcy;. Wh.n
Ha' rh.rt'orc. E ^da tnp6 n,e4 jasq i,n do6 rhl supplr of arys.n is increakd, tl.E mri b€ r cor
b?dir. The bici.nic.l :nd nruc0r,t ch3D!6 rn r.5pondi4inaq* in . produdon of Ros, 6F
oxys.nJ.piived .e s -.rc discursd in d.tait .anii ind lirny b.our mtrdhanJnn drmrft had5 rc
rh! aquene or.v.nr s ft,pnubrd b€lo* tu.mpt.re rcdud.n ui oxlsen,,nd beru* or ,h.
Ihe rundan.nhlbnh.micat lbnormtis i, hymi. :don or o\jdr*5 in ku!&}16,.n,lorh€tu kk. or
elh th,i rea&to cdl iriury n rdurtd i"r.;€[ut;; k, prrc.chynll cdh. Cdlul,r.nioxidr d.f.n* hEh.
mn,{ of ATr, r I .onrqu.nc uf rdKd sooh of ,nnns mar,:ts b€conpomi-d by ishrhia. hvor
,nrr A! d.sr bed rbo!.. t!$ of Arp krd5 ; the ina tb. :ccunuliti.n of fF. mdidL.
hrlua ol qdy ddsyd+e4d.at a,] st.ns, . rsheff iiiuD is isri.rd yith ,r&,e'1o,,
ta.hdta? ltl tM punps lerdhs tu crt 5w.t'ne.rnd whrh mr inr$( w(h r.Frfuion b<:ur or
mlEs.d innu\ olhut()re5rid pL!tu erokrG.rllt
rcn, hn,6Leicr , by prcducbof2dvaFd l.uldyr! frav..u; rddnlonal
r.duld 5hLn'nsror drbohrdnns 1.ts. by 'he p.nodc tissr inrury lch2 d 2). Aaiv.tion ol t6. thrtn.at
rnd thir'rn), wtrhr(murnit{ ofhcn! rud, rhu5 qs., may 3ko coniribur b ish.mi, co.6sion
!'Er'ry th. inrac.lluhr pH\ .nd tJt flau4io. in r!ry 9om.in' boJ,6hrrr prornjryrc;.6trm
i(h.m,. r,iu6 t,{ unt'owi rt:!n::nd *hei btdd
 flos r rtsumtd,..mplciot prori$ bin'l ro thr rh,, ih. rtl1 rd n! 6asm.n6 b.come avid blgds for
d+osn d antihodn!..!eactiv.kd.' nd .x,arbik 'r phes€,16.Th.deadellnrap,dlycle,i.dbelo*jB.on
elliriuryand i!flrmndrn. 116 hav. kal.d ou+nd ih.rttort .rll &.rh by rhis
lrthury des nor tlnn an indam4roq rcactionm rh.
(heni@l (loxi.) Iniury ho*. Thu\ .poprcis diffe^ fron ndosn, which n .hf
.ddized by los of ne,nbrdr inteln( dzymdi! drs.'
[email protected] indua atl inify by ont of No s.q.ral 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.(
. sone .h.dkrk rtt di4tly b .o,binnE uith r .n lpoptosisandnercsn enetin(.mxnr, ind rF,pn\ir
nd nob.qlat !'nporent at eelhht otpn L. F.l induce,l by en prdolosic *inuti m1y proeGs ro
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,
r.oplastic.h€nodd"pt'tic ,s.ni! ar{ indue cdl siiuenons, dk a
d.magtby dnR cyron;. eff($. In suchrn*,nes, b dimin.t poEninllyh.rmfulcdlsrnd..lls rhr hrlc
rft srtdb4 d'dar. is ssi.'nen b! th. t lk tlint 'n, ou ived lhdr ukIuln s. k tr ,te, a paihotosic .v.nt
obsoft, exoek, at bndnncte th, a,nt,aunds. *h.n rtft 1r dflased b.yond reprq 6p..nllv wh.n
nt4,.a t bblast $c damac..ffec ih. cdlt DNA or prorin! iD rlsc
att cdn . bqt 4u! b. fi,.t ,o4v.nedta 4'.hu to'n situarions.rhetrrcprmblydime.J d1 k.liminai.,l.
-.tdhotits ehch thea.d an tuts.r ./i I1)n mtd, Apoprsc in PhFiokgi.sirurioB
ificaionis usm kdompli.h.d ty rh. p 150 mix€tl-
ru,ction cxi&*s in d. smoothendopt.smrcrcticutuf D"oth bt tpopto3i' t a noffil ph.notutur that s.e6
or rht rild,nd ods oB!s. Ahhou*nd. mhbdna to .li,uak elk ttat . rc kns- 4..ta1 and to nain.
miehrcrur mrmbiine dim,s. rnJ \.ll niuq bt bha,.d4 ",hh{ ofwno$ett pop a,ons intsu?s.
n,l lipi&,,he m6r ItG iEpotunrin rh€follo*ns physio los,.lnu*iq s:
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]!,.
lhich -as ukd widelyn ih. d4 dcaDins irduf) bur ss,,$. indrding inpraninion, ors.n4eneri delel
opndnrrl indution. md mdanoDhasis.ftr itrn
is m* binn.d) ,nd $. anate.sic aetuntnott.n "prcsnnm€d Rll d.,,1" *r! lrieinily
oined to
hdong in rhn c.Esory. cct , lor .xrnph, is .ony.n d tl.roit d.dh oI 3ptci6(cll 9p.s .i defin.drnes
t, rh. hxn frceHdielccl, pincipnly in the livei dunnerhddcllropD. of3n os
The fre radlcrlsc,u$ ,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 plor.in 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$h as
h.p,rNyt q i.2 r5uh of lhcn Ln,bil1ty io synllaia
rp.p!.t in b tom .onptex6 *nh ristyc.nd.s 3n,l
th.icbr fa.ilr,k lipoproitid s(Eion; th. rcsult is ih. . D.ad of alls th$ hrv. *i.d $c; urrul purp.r,
"Iatq liv.r" .l ccl
F,ierins. MnEhonddil iniury
rcllo{s,rdsubs4u.ndydininnhedA]}io6 Esult lnd r)mph&y6 d th..nd otan in
'ndrfK € 'on n;nrp.n ind prcgrc$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\n-
pro.r't J, .nher b.forc cfufie '!y hay! .ompl.ted
ih.n matunaonj in od{ io preven
on \ ovn dsu.s (chaptn 5)
I |'oPlosrs . arl d.oth 'd4.a1 by .ttob'n T |tntho.rts. a
,{potrdk n 2 pnhy.y oI cdl d.rtfi rh ninJu..dbya d.f.n$ m(h nm r*iini yirues and &mo6 ihar
iishny rceulartl suicd. pm*sn in which alls d6tin.d s Bto kdind dihi!& ynulinf€d.d rnd n oplis
ro die ,ctiv.rc .n2yda c.pabh of 'l.gidns tl'..1115.
ownnu.r.ft DNA andnud..r:ndcybDt,smicp.orirs.
rhg!.ds of lh. apoproticrtl1srld b!.ak oft. sivins fi. Apopb* in Prd'ologkConditms
.pp€amnc. rhd r rsponlihl. for rhe.rme l,r"rrdsti Anotbrs.linut?s ..lk that dre !.r.r.allt alt red ol
"fllhs olf). Thcprasm.m.nbnne oI rh. lDoForic
dl '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 .
 20

D!.th by apopiosn n rcsp.nrbl. lo! to$ ot cdG h :

YrEry or prtholoqic iaks I
. DNI /,zqs. Rrdi, r,cytoioxicrndcanardruss,

DNA.etrh-d,Ed ) or \D pru.lu(reird h{ -d sl,.

vDvla!,rdrnae€
I
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 .
lnlh.rsiiudions,clioinanonof 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. $;i*i.uli --h h
i(uclrll Jqrh liduuo!rpoFo,rof .:n..i clr 6
r d6 Ed rffn of.h.mdhsiDtur
!h,rh B!,k br d,hrsrs DNA IT
. A.,un,tatua ut ar{otlta! ,D,.,,J. loDroDertv
roldedpuEns m4 rnr h..rur oi h,Er;,;
s.na o.odins ih.!d pror.ins oI h&1u* of exrtinsn
rh; F
r&ro6i sNh * drnaBecaukd6y rEemdists.rra,
ste..cumul,iion oI ther prt,Einsn rheER t.adsb
rmndnnrsll.d ERrres, whichcutnin:6 in rDo,
. a niury in eia'a '{..th,as, DaiticuLny vnal
inf.dio's, in whi.h lcs of irleted caltlii t.rc;h dF cdnranns in riy.tior of nu.Lr56 th.r d.snd. DNA
ro,poproticd.rth r[rD:y b. indu.d byrh. !rs 1.5 and orh- d.ms 'hr prtam.btt dnror nld.oDro
in ad.no\trr rnd humrn ,Fmunodfi.,hq \,ru, k ,, rnJ crol.t.rit pruEins Th.idrdddusD,*j
Dk(non,)or br rhehoe,mmurcrc drFndr or z fine1viu!.d bahnc. b.
ipoproiic mol(ular pathwiys. Two dis;.t plrt$ys
..rdth losnatbphn pa2t.h\wtv'san,.tk dur conve4. dn .:sDdr .ctiv:inn ctled rk -ro.han*bt
n rh. DJG . Dro!,1 prthwd lrd thc dzdh re..pta, patru,l Ahhough ,hE
8rand,:ndttidnq .r.tb ,ndu!.d und.i
n!ot!. d /tircn, motKut$. rnd
r|ethanismrol ADoptorii id.dnrirctrctcsinphFiotosyrnddi*:s.lFi*. I nt),
Apopro,sn 2Dadiv. en,vh.ti. pr€ss in whichnuctco rh. Mi,udond;.t (tnbiosn) rrtl*ry of [email protected]_
pDreinsaE brclcr du-! d dd the cdt r fBg, Mroth,ndflrcono n nlerrlprcr.,n5 rhl n.!i;bror
m.nrd. 8€for disrusinsd. notrcutarDdrisms.it 'nducins.p.pmliri th* pmrins inctud. ctr4tirome.
i5u*tulrD rc\r$ ,hemoroh!r,arofrhr orhwry orlrtl ,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 ro
|nHlE&imdrhsdid.,.poldic6|t.nly nut,r uia.ceorabt.
,mounE of ni+otd.d proE tr,; snpaf $rio6 B1d
asim9hlb cnQhrm (Fio,1-22).Nat.r rhd rdou; ;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,m.nr. ru.n
,n,o ih. mir(hondfl:t m.nbmn., rnd form !h:in<t5
cld pi*6'. rh. 6n. .rpidrv IrnnL iom doobmic ,holsh sh(h r/chDft . :nd orhtr mrehondm
bud!. lnd r[gftnr im .r.crdc bod- 6in.id .r pror'ff elF inro rht labsot. o6tr iJ.t d $nsos
,nh,btrrhl ad'.rpop'ou. mo (! s 3.t2 rnd B.t \ L!rt
h.. Frs r-a). B*a@ tu. rEo bdowr, rirh 'h. hn. .nd rcru[
.,1'd.ndphlgocylo..dgiihoti . t.rtcc oI mib.
dondial prckin5. Cytahroht a i%edtr;th som€
coiados, rclvaks cr$&.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
Tl. tund,nt!.al .v.n in aDoDror tI .dt5 'i. .\Dord ro so;h
of €D2ynescarhd 6p,s5 Go n J b43uk ihey aE ric,o( and dh.. $ntrn nstut\ rho ,n,hc; ; r.
ih,r cteeve pr.r.ins rfiu 6r.ftjc lpoploti. n.Db.G oath. Bcl 2 f,Eit{ rh. rso nai ona
i.sidtral, Adiv,rd .asprsesct..Y orwhich,it D.L2 ndt,rd &lxL.Thd.poEinsanb*
 .ll^mr - d n4crM,ddi{ah 2l

BE nEcfti (ffirerc)

tr

I3D
€,0
pe.d,.Fp'otr p.;nr rlinh,br n(ab.

onia Bar .nd B.k, .n,l thur Lmn $....2p. oI mno- i* calle,lFLlr,b|ck
chond,ial prc.rpopion. pbi.in5. Cdl5 deprived of rctiv,lon ot osp*$ down*rcan of d.rth re.pm..
growth, 06 io' on|Jadiqc |h lnrc nslr em. viruks pbdurt homolosu.soI FLIP,
i . . n r b d J r ! , 5 h o qr . d u ( e dk f L o f & t 2 , n d & t \ , :nd ii is su*ned rh lh6 is r m.cha.isnth.r vnu$
ihur tunhq tihiry fi. b,lrn.. ro!,/ d.lrh, The mno- c.lls .liv.. Th. &rth Geptor
chon,lrial prftw,y kms o h{ th. p3rh*ay th* is pdw,y is irvohed in d'minaiion of alt rt2lriy. lyh
rtspomiblr ror md mrDm of rpopt6n, 's w. !I.11 phcytd d i. killns ol blgr <ll5 by em. cybrxic

Tl. D..rh Ra.pror lExh.n.r Prrlwry of Apop'on, cld.n r or ,^poplotic C.lls, Apaprctic cdls unJqso
s,c:lled'lsA Grp nvqal chans.sin tnar m.nbnn* rh promoEth.;
tcr, ih,i riss.r aFpbsn. Mo* of th.r ,rt ndGc ol ph.sE)tusn. h nom,r .dl5 phcphatidylsine ts
rhl runor nercsn hcto' ITNF) r.Plor tamil) rhrt prtrt,t on d. inn.r band of th. phsm m.nbi,nt. hur
s: con$fled"d.rth in ipoptori. alls fiis phospholipld"nip." oui .nd is
dom,i,." so nin.d b.qu$ it ned .xpced on the out r Ly.r oI d! D.mbrane, *h.r I
od.r proEins. Th. prctorypic drlth r.ptoc arc th. is ftor,rtd by nacroph.s*. Glls lh ft dring by
typ.l INF K.!br hd F.5(CD95).Fzsliprd lF*Lln apoflo5n.l9 ss.tc solDbl.fuo6 thr Edun ph.eo.
e meDbiin. ptukin .xpr.sd m'i.t) on ,c v2rd T cn6. Thn f..ilitrr6 pronF.Lrnn. ot th. d.rd cdls
rynph&yi.r. vLc! lh6. T cdts rc.qniz F,s*xpr.sins b.forcrhe' und.€o *."ndaa m.mbcn. drn,se ind
DBdsj F:s moLcuLs rrc crcs linl.d by rh. F:sL ,nd rcr. . .nlrlurarconk'6iwhrhsnrsutr,n,nnrm
lh.y binddrpri pid.insrwhichin tum bmd.,sp,* 3. manunl \om. rpop,d( bod'.!.,p65 adhFnr sllco.
chsring or iany c:sp:s.moL.ul* t.ds to $d .cti. Rsed b phrs&rrs, ,nd
y2iioAlhusinitiatinsih. ssp,*.,$rd.. In m mrophlsa rhrmells mr prcduRFrodns,l'n h,nd
] all
np.5.rlpJq 3 m,y !|aE:nd adi roepiiptutic.dhlburno' 'ol,!.(lltaid hrB(th.d€rd
m.mbdar,h. Bd 2 frm'ty.rl.d B'd,as Gdrsrb c[. for .$uLfmmi. Num(us mraophrs. R.p'cs
th. nn(hordi:l paih%y.Dr canbin.d.dvarion of t u h r n r o l Y € 'dn ' h . b ' n d n e , n d
6orbprhq.ys delivns1 ldhil 6|0- b thecdl.Cdlul,r .nsulrm. or apoproti. cells.Ih[ pu.s oI phae{q,
 $ .firdc,t lhr dradrttL Jn dF,$q inrluding
rla. and Lnfl,nnddi i5*. Alzhdm.(Huniingron. ard prrkinsondinass, ald los
iiblr aF IId rb.re5Depn!r.n,,l g ucor rnd o:ysri,
ahMushw. hiy. .mphisird lhr dktindionsb€Nen rnd s($ suchA ht,r.?ry, Esuk in proHn nlt"tdms,
n<rels :nd :pop'un!,'h!\r Nv fomsafklld.rh mry culmmtinain.rllinlury andderh.
!(!trrr,d & rthkLrmchJn nrr t). Fof,nshn(. DNA
drnasr rftn ,n 4)ptosi5) ad'v,r6 :. .nuym€c.ll.d ap.ptnir oI s.lf-R..div. Lynpiocyk, Lymphqi.s
polr ADPkibos) polym&,*, which depl.G .dlula! .rpabl. of Goxn,zng ltf rn B.n
5upph6or n'corimnjdrad.!ined irucl.od., l..dins io d4rd ii rll ndiyidurlslf rh.k l' nph&r4 .n.ounkr
i hllnATPl.yrls anduh'm:kly ndosn. h h.i&n nft riris<n5,rh. e 5 d'e by ,r,pi4k 8olh ,h. nro
i,,.onnoo siE.tiors suchas ikhcmi.. ir hd bc.r suc !h,{dr;tprhrr} ind 'h. Fa,dorh reRplorpnh4?r
psEd thar .any cdl d.,il can b€ panly rftbcd ; hav.ben impli.,Edid thn prE s lch.pir.J). Fitu(
apopbrnirnd drnEn n rhedomimnNprolcelldsth ar rloposn of rtf.rcr.ii!. lynpL(yt s is on. of lhe
hr., wtrh,.*nine i$hemir
clrbxic T LFp[cn-Mdi{d ap.poen. cyto-
Ennple. ot Apoptcij ror.I hmphoqls lr-rln h,B
cdLd.ith in m,nr liruarionsr lnown m h..auFd bv nE*nEd on ,heinr< , f nri(ed han c r rnd tumor
rpopions.inJ the $t.d.d ex'mpt.sli*.d bdow i[!r' (lh l(hiprrsr up,{ r.n,rron,cT
hftrhr rc|. ofthid.rth p' wry in nomat physiolos, c i [ . d 3 , , . r ] z . . . n E r r h f r i r s d < l 5 . c r a n z r m . , . k r .
pnrons.t asFrt,r. rtndua andai. ablero,tiyri...l
run cnprs. rn,hn 4:r, Ihe (TL L' ! hrts{ (t5 by
cronh Fdor D.p,ivarion,Hcrhon.snsniye alls d,R'ry Lndu!inB ft rff{ror phi!. ufap,,r'ons.wtrhour
depiredofrh. claart homon.,llfiphan6 th:i rr en8lsig midhondflr or dtrh
nor i'huhEd by rnra.ff ,nd qtokines. rnd n.u.ons (.p65 tr3r an ,hdr artr(
rnd mrr l, hrts{( 5by
del)r ed of ne r ero-d lador d1. by ipop.6is. In 3tl
rJ by th€ mtrcllon
d r pr,h4!r rnd r irflbfahr 'ii rflnr,on oI prf
rp,,phtr( m€mh.6 or 'hr 8.1.2frn'ly rnd d(r.5.d
synihelsoI B.l 2 rnd B.!x. I surrurY
ol .dlls r' cdirtio' or
.henoih.Ep.uti. i3.n6 indu<s DNA dam4e, dd it . R.srlat d mrh"nio otc.ll d.rtl' ri{,F.s b
brp,,prtr,cdrarh. ehf,h.it unlrnEd ard trramblt d.m.Ed elk.
when DNA ! drm:e.d,'h. pst prukr:(unutft! n wtrhd. kd Ns,bl. ho{ ;.Kio;
cdh. h rid f.$s th. R .r.|l kr rh.c, phrk)ro2llow ' ChrnRi,r.d 6y, m7yruh. d.sird,honorprc.
ntu n' r.pan lchrpE 6r. Howvei n rh. damag.N kins rnd DN{, inniaFdby !.stsqt rnd t@r
id B(r' ro br npincd su(c.sfutl don :nd Enonl of ddd ftll! br ph:sr)rs
r urrimr.tl irrr.
Bi\ JnJ Brr. ind by j,mubrns an,h6D 'n Dro. . Mto.'.rlr;al nrhB.) pcthM, B he$ red
1poftrrc n,e,nbss!f d. 8ct-t t 'nni vh.n p5r is by rx or rurivil rdniL, DNA drmra. ind
nuhted ofub* (ar n k in cdrn gn..6l. r ia ind :(unul,i,mor mist6ld?d prokinr(ERfts,,
p,bl.afindu.ins rp.ltosn, !, thar.etk *iih d.m.s.d rsrnnd rnh |e|('s. oI !6:poptonc pG
DNA arc allow.d m $ryiv.. tn suchrtlh rh. DNA
I iEnnc.io.s drr troprnm. sh.rt 'hq insEa ctrp:k mq.
re,d to nedprdn ..ndonnltun (ch.ptn 6). tion: inhibn.dby anii..Doprod!mrm&r5 of
A.cuddlrion of Misfotd.d prd.inr. Dtrri.g nomal ,hr B.r f.nitr whi.[ ,i. ,nducd bt 5uvrvrl
.h1Fror.! in th. ER .onnol thr ,isMk imludir. *ro*d hdoR.
. Ddh n.pptor t4mas4 pcthwt . r.teoni-
nrop.i Iad,ns "t n.prr 5)n'hs,4Llprok,r, rid nD
rordrdplrrncoridFrrc ubquhnaEd :nd 6Qdrd for bl. for rtLninn'onof *lf !ffia tDoh;qs
pn,k, )ns lf, hoestq unfoldrdor m',rot,lJprckn! iid d.ms. by cybbxi. r tmptuir;t n iii
aamuhr f lh. ER be'u! of in trrFd by .4as(m.n' oI d.:'[ E.oro6
lm.mb.d of rh. TNF i.c.Pbr hnity) by
.ork rt, at.d r rny' /r?/ 1'3m&on adirc.nt..lls.
pnr.t '.,porn.Ih! 6ponn r!"vrs 'en'nBFrh
of .hrp*oia rnd
rcbrdDbt r r.rdrticn.lhusredu.in!rh. ltvclsotmn. rhn d<ripnon ot ,p.ptulk .nnctu
folJcdprote'nsi', ih..dl. How.v.i I rhn Eeotr. r "r ([ iniu4 ind (tdo(h. A5B. hrr {.n, rh.r
u!:bk io copt wnh th€a.cunut,riono! misfodrdoro
idni rhr 6uh is rhe:dlv,iiq ofcaspNe rhr t.a,lto .d rhn .h4E wirh bIi.I .oi sid.rarionscf r[ft oih.r
ipoprtxn. Irri..llul,r a.cumulanonoI ahDom:ttv pd6!s: inr,ellJr ac.umul.tio.sot v2iou5 sub.
6ld.d pbkL's,ciukd by nuhtionr, rsiis or unknow; n{c.s:nd exucllul., deDosnion ot.2lcium.bothof
.d .s: t iitrr. ol whi.h .i. oft.n sfiard wirh ..ll iniury,and rsra.
 .21

IIITRACEIIULAR
ACCUMUTATIOIIS

m i f t i { r d f n \ ' \ { ) r r n . L l n h , ii s N l $ r(,pl
(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 rrt]( 6p d

a?)
or rqtr r.J J.f.G
r n)l,lfs. Nrhri,,s.
-x-
d t;
. An nrofmi .\olr.tu$ nnnndr . Ll.N!r.d iJ

mr!h,ns, n, JL8nJ. rhr n,hn.D.. rr rh.:bt'n ri

qoi {,a q

o
sli.i fJ.r$.ifu.r r L $ ! r r 1 n 5n p ( d i l r ( . r ! D
a3) a

Di o, org.n, rrLrnr h(nr(.i[i,tr .h(r tr dr.ir it!]

46.p".;.
. a11nht,11''r,hl
nrtd* J$,trirnl,r, ,lL!^ ,r( t|\ qd 4nubl
d'r' 'l l,rtr tt\Dx( or th,: L'4 |

ltuc hr\ r ! f!n iJiNsr hs!

.ft $r(ri(J x) hsr,.sJ$. !r\.tr J ro.Msren,l

or,rdri k, tddr( t,!Jn5 rri,s.

N . \ l i J i . t r ! . , b 1 !r l

r,!r\!{,J$ D.,, burr f0n !rcfc

. .hus r..qini,lg nr d
oldrnr; (.(.t. trrJ

Th! nantlinq or fn$.h.rise dqitrrn o lk !!$(

ri {\tr{\ oi rtl r.druir on. \\

rdr. [trr un-! !, (

, t i r r i r . i r l J L (s . D
 i

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

wnho('Enili.:nr nn:clLular
rit l.r micrc$opi i(umulanon. How.v( phisNyri. ftlk mi) b-om.
orerlo.dedwnh Llpidlr.elrindA,.hdl.i.rol,,nd.ho
rh. o4.iic $ v.i6 tpi€ny 63d i lsiql6'qt in lrwn Jirrqo, p
srh ft Lrpiddebnsof
idonc .elk o' ,brcn,l te.e.,ordtrd) Iorh. of
ndioqlhal.'klh.nid.n'iff.dbyal
lipiJ. Thcr manorhag6 mar b. 6lled !trh mrruk.
Dembcn€.bouidvicuotesot tipLd,rnpairL,si formr
F odic Eid-s.hin d.in lfiich d rpperrr.. ro ih.n qlopl,$ lrrn .,1k\ h\ atr?.)
viord).Ivlcuola donord:in tor.it !LnM, \moothmu5dcccrkrnd rusophasesarerirL€d
Fdych.ng.i.froncommon]Y$3ninlh.|iwl:nd wnh Lipidya.uol.\omposd or .hole$nolij,d .hol.r
'hohaan,Mldrdychdng.inth.I ie4Le$r5;ihen sNer$erorkrorr phqus rhtn.[]r
trrtdsn. ytllo! colord'l $nn,6utun,ihr rrhoBcn$^
or thc l.si{D lchaprr r0l. h hredtrry ind a.qutr.d
gh3'o6rgll'n3 hyp(hp,de'nL.srndrams. n,.rophtrsn,.rnulr.
iN .elluhr .hole$(.li 'htn rr$rnt ,n thr \ubrDnhr
5n:.ndgro8r€,dvlfiychan'.b.eenbvlohi tentloDs.du(6 or
]nlhe.ylop|8m rhN f,nm,\mr{.rhi3s ntrnrmrf s.rtkd a.d,.,,,s.
rrot ins.MonhaLoFtrll! ri6lr pnr.in ituhuGhis
rorha6rl Fiph.ry lFiq.r-2531.oe$ionrllv6dieu
olt6|hruplucandth3sE|osd o<urh.c.usex.ses r. prernkd (o$e.elko' beciur
$e.ells slndstrerr..*r. rnounB.ln thd!]ddq, nr
hv pncnGn h.he
I)nxjmal(nduted n'bul.s.Ho*.!ei Lrdsodenwrh
h.r$ pror.ir 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 dnb.re5melll
ttrs.rh. prio. txrnpk ofrbncrhil glu.o* n.,6.1nn,
a!.pnhdium..ardia.
mrcyks. end9cdls orrh. il.$ of Lrnserhrns. rjly.o-
s.n ako a..unula6 wnhin ftlk in r sroup clokly
ol
relakds.n tic disord.6.olldiv.lv rtt ii.d tu i\ d.o
s., tnhs. dk nss, o, xr.os.nos lchapkr 7). In
rh.s dk..ses,.nzyma.c ,LIe6 m d. srnih.ns cr
brcrkdow, of sty.4.n rtsuk f n$,. edtpitiis,
wirh$.ond,v riurr :nd c.ll &nh.
Pign.nc.Pi8qenisarecolocd submancarhiarcenh..
.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' M6Bducfu ) 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 pisr.fi bl.cktn ihe dn,nins llhph
f u*wiih ry$om6, r.surn!Fin thehisiotosic app€annR nod(,trdp monanp1ftnchrfre{dnthaatisl.Heavr
of pinl, hyalin.crrplasmi. ,lrople6lFia. r 26). Th. .Da ora fibrcbhr
prc.s is revtrnbl.tifrh. proreimn2,b1E rhcpnn.jn i. Eadlon rhat can rcn'[ 'r a s€rioDs luns dn.i!.
dropla!1r ndlb.ltcd anddisaDFa i Anoihqexanple elled corl worldr pn.undonidij (Chapr.rr3).
n fi. m.rk.d a(umulaiion Df fltwl) sytuiai?d r Endogd.ur pismlns indudeliNfu$in, mrlanln,
immunoslobulins rh m.y uur in rllt RtR .f a,m. and enain deivrivs of hemoslohn. Lipofutk, ot
pl,sm. .elh, fohing roundtd, <Einophirn R!$', "q..r:nd{.rr pdmtni," s ,n inn,lu6l. hrcwnnl
yellawsrin ' fr,..11urar m.teri.trhn a(mut.Gs
Aaumuhtionsof intraRllulf prot ins ir,l$ *n in. v .ry or n$ueslpanlcuh ) rheh.rd,l1v.i,rid
'n c.drin ryp* of..ll niur For.xinplq ih. Mrllory bnin)as a fundionof.Be ofurophl. L'pofurin rp
bonn or -,lco6.li. hyalii," k.n.osinoDhili. qropler rcsenis.anphxaollipi,ldd pn,.in lhr d.,iv. frcm
micinclusion in liverelkrhr is hisll).nr cdistic ol ihe rr.. ndicalra&lyud peroxitlation of poljur$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 pism.nr 1ri3. t-17),
n,fibrillaryinslefound 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 lch"pr.r2l). trd,ron dcn{ BEnuks1Fi8.t-2-Br
 hrcwn-bh.t pisnhr s($ivc ac.umuh.on.p,i.n.hrn,l.(11!,hrcushoui
follow'rs rh. rrtr,fu{ rh. bodylburprin.p,ll! rh.liys. ranc.:s. heiit.and
c alyTedo\id ioi of twonn. b dihyduyph€ny. end(rift ore,n, bdoh. "hronrd" sidr.ctrnut,r
lihirre. k n lmrhdkd Lxdusiv.lyby mdindvrs ingpishcnr.H.nosidero$s o.cu6 in rh. rninsol lr)
ro.1r,r in ,hc cridsmn ard ads a; ";.* "g;" inq.a5€d:b5o4'rioi of di.hr! ;on, l2) impan.dui.
hlrhfur u|fa{ord cdHtioi. Akhouahf.trn,trcs rtsionof non.1r)hen.LFi.1ioias,.Dd t4)r:nstu
JR ihe onlr eurce of mdrnin. 2di,.r hasr rcr sionsld. u,nrlu{d cd cdk coni
irndrsr $. skr on a..umuhEthr pism.nt{..e., bidornonr, ln mo*'nn:neof svi.ni. &ooidero.
,i r.&kr.t,15!?n dermatnacroph4a. eciherarenchyn.l
. H.a,,,/.,i is r h"moctobm d. .ells or mpff orgii fundiond6pn an 'mr6rivr
m.n, rhr EAotd.i !. a$ ,,, tr,,En rnd i(!mutrrcr r.ctrmul,ion (Fis. r-23). Howve( nor. .-dsiyc
Li rsues *h.n *.( n a tFat or ssrenN rxrts! of a.cunulaiionsof non,i.ei h r,tulitan hno.hto.
;on. rroni5 nomnty nortd wtrhiicdtr Li js!)or!!r q,,cD 1(hipkr rb,, {rh n$u.,nFn m! ud'nah!.r
wnh lhe proreinapol.rrl,, Idn,ns f{nin nicdles. 6bb, i. ht,d b,r.rc.rnd dBh.r* ne tu!
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 I P l||olo6K c tctf,c^no||

tF,s. r 23r. Akho+h h.mosjdnn:(unuhnotr n
Lhir pichdr a.. Prholosrc.aLdici .n ,\ i .ommonprc6s rn r wid.
n,nmalh rh. monofucle,iph,sorrk! or .he bone v,itrry or dn.ri nr6: n impl'( ihe,bnorhrlJoo5i
marow.sph.i,rid 1!!.r,wh(E.h{. n.xGn'v. Rd rioi oI.alc'um $16, bserhtr wrh !hnF!.noun6 of
15.vho th. d€pDn
t ld! cx.fi*5 0l ;on, and .ons.quendy of h.mo. n is.altd4rtupri.
siderir,rcsultnom h.noiihrs(. The b.$ examplets akti.atn 4 it 0(6 h th. absen . ol cdLiun n tabott.
rh. commonbrun.. afi{ rysnot thr {}drc.yB 1r um kYrlsofcilc'um).
rhr nr of hcno ase,rh. Ed c.I d.brn n ph2sGy- In conMn, rhe d.pniq of c.tcrumshs in noffirl
'.!cd hy @.'ophases: thr hem.slohn.ofttu n ihen rsuer n rnawi as ,.iar,r. .,L,lnaiDr ana otna,
.rabolird br lysgona {ith a..unutanonof thr dtudf '.l.ds saft .le ,24n2nt i, tdla\n a.tabol'st
y ol.cLonrhroush lhfi.rcakma). tt st lld h. natd rh{ rhrl. hyptr il
wh,.hdr bruis F$6 l.ll(h rhn. r,nsforh{ions. .em,r isnou prtrcqunn€n'd)*roph(.,td6oi.n. n
Thc orisinalrc,l.blue.olor oI h.moslobinis rane
fomedro v:ning3hdaols(n-btu. by$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 rh.ie 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 ,ro- he,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

d.snb.dindvnbphicca|c|f.di.n
c|ini.a|dv:rundion,.n.Giw

Eoinr. Dvnrorhi. .al.i6.aron of rhr hnL. !116 n d6po.rr in rh. kidnry l4r'.ahhdr.) 6n 6u$
of ioni. {.nai n ihc cueny

tufu tY
dft6nth.3srirt Ahnoml htEellul.r D.rodtioB
3ymp6hd.n
. Abno.m:l deposiisoI mi.rirls in (ll5 ud
s[yc'|.|ficdio..'F!6.6inn!6||uhl.nd/ol.n'a
tissnaar.rh. rt k of.i!!*iy! irtal. or 'Lfetiv€

. tiit .r,,ce ,c.umtrliiio. oI lr.c riclyeid.s

r|1t prrl,.gd$ir of dErophic ..Ld6crioi i'rvohs rrom ex.esiv. mhke or
;,r!,roz i,r nud.anon):nd prop,t ro,. hdd ofwhich d.r.{iv. ranspod lohr. be,trk at d.t 16 in
may be €,iheri.riftlluhr or cnhtclluhrjhe uhrmrk lynd.sis of hn5pon prorinti h.nif6tarion
{aline dLun oh.s
,r,r.. InnDhn iD cxna.ettuhr sG drm r ii(m . Aohtdol deto'tion: resuk ol delfrarr
h4n€ bourd vsi.le5 abor]00nm in dianftr: in casbolism r.d .xc.sik mDL.i jn maqo.
pMsesrnd snotrh iufl. ..[s of y.sd qilts
.r.r. ,nd Li p,rhok4j. .aL.licatioi rhry tldve lrofr
d.gdq,ir3 crk. rt is ihouahr rh:r c,tcim n ,nnBly t D.poinion .f t'oe,t! rcibsorbed pbRins in
lDcnrited 'n rh&vsicler hl n! rfiiDiryIqm€mbnre kidn.) tubtrl.s! nDuncslobulitu in plasmaalh
phospholipidr.*hi[ pholph.cs a.cumuhk rs i rtsuh . Deednioi or srlrosd, i! meroph,ses ot
or ibr nio! of Dcmbrao..boundpho'phrri\6. rnnB pIi.na wiih der.G in ly$sml .nzym.s 'ai
,n oI iDra.dlubr .aL.'ficrtioi o. b(ak dorn sly.orn l*ly.caen *o!,k dneast
d,ir old.rd or dlng.r1l\ { hale ron then rbiLft ro . D€poltio. ol pis,e,aj typically indise*ibk pis
r.*uhk inratclurrr .ncium. Ah. menr, such .s carbon, tlPotusr l6rt2lJow!
r{ariq, prcpagrDn otqst fom p.oductor lipidp€roxid:rion), non Gsuallydu. b
d+rnd€ni on rh. coiftnrrrian ol(:r rnd PO. 'n ihe ovgroad,asr h€nordebrn)
exricdluhr sprrts, rhr p(vn.( or nineHt rnh bnoq
rid rhd dqtu !l .orbsenmtioi, w[i.h .nhrn.s $c I Dt*n,pLn .ak'li.aho,: deposni.n.1 .2t i\o
* snc oI ftll iniuryinJ ne!trn
r Md,r,rr ar./,rdrnr d.pcnion of ekiun
Mdsh...:L.L6.rrio..rn in ndm,l fisu6, eued by hrptftl..nir
qer iD BrmaL issu6 shen.ver d.rt nlrrqel(nn. lusuallva con$,tuencoI pf,rh rrcid hormone
The n)ur maiorc es or hrp.r.lrlcm; nc l |l 2 re"s1
'.-4tar.f pa thrtuil haMD.. nu. o siher pi'mrr
 lrl^ru r - dr 44 Gr M dadFds

'3i I I

I
I

qi 'o 4h. n h!hd! Ei| i;

I Glruuf, AG G ri.an(of (lli. cn i lron.h, drtn haveih.cip{

,\ ro und.Bo ni{. Dund! of (!ti.ruon,h:n docdlr
t2nukt 'snq i5 th. rc,,h ol a ptat.4,v. dkh4. t4 th. kon ord.rFopte.In lodEr,c.l! fton Drkm wrh
p'atile tiv. @po!^ '4d t'l? \pan at atk r4.t th. 4kd3 \ymr st dtm.. ^ a,. dn tk.!5ld4iz,l bv De
ot,odtr,lqs.rpdra tt *oseta6 t'd,6 thatdue n,ruE .sin& h,v. . mrkrdly r.dued m vitrc lili
c<y4rro|on .t .. uht ann d.hdl.t ip.n. ln htrn.n celk, rh. n(hannm of crlicrtiv.
d,hdp. tle
l-r0r. Thi prf65 or rs'ng R.onrn.d fromten ; rn.knlr hvoh.i tn(ompt.re rcpt,.r,on ,nd qm
humin!,rnd<r krs n,motemod. 3rs!. shon.niig or Flom.r6, wh'ch 'tinrEty
'o b. rcsurnedb,, , 'mtr.d'umbrr ofiens. rh. d€r E5u 6 in (lrrcl. nftr. LLz*.r *.,hon r.Fned
'hr r8inBb.on,rcl.d b' prn'cutrrsm6 rrr55puftd equenG.r DNA r@nr ar the tin.,r.,ds oi chro
n6om6 thr ft imtsdr,,Ior(n5unnc a. lonol.rc
k.!trFfiw !rnd
ir d.vi.inswarsto hriplhte, pr6.s ihrt w,a onc. Epr auon of.hron6om..nd5 and lor;!oE(r;,h.
.an.id.Gd inexcbbl. S.v.r,l m<hanism ft tnon or .ndrrom run,,n:ndd.sredn'onvhd!,mrtr.; s
3uspd.d rc b. rsponsibt.Iorce ulft ising, Ep,cft, a 5m' R'i!n of ih. rcto
6'.d, and rcloh&s b€oft pros(snet, !h,d.n.d.
. DNA dam|.. ctltllr as'nE is assjned with a5 rb.,dotuG beom. lhotr rrh..n&ut(hlomD
n{.s ns DNA d:m:8., sh'.h roy hipFn dunm $Ds crnnoi b. p'ord.d and ft sn ar bbkh
nomrlDNA (ph.rion rnd (rn b.dh:nc.d bv t.; DNA, whi.h5l3n,Lcettcych,r6t.Tt. tenqhsotrh.
Ddi.rrs.Alrhou8hm6t DNA drmas tr rF;d bv t lon.Es ir nomall, miinnin.d by nuc[;nd. rddj
r rid rt;umrh,; tion n di.rd by in h,yi. cald r.lou.r6e T.toh
.s alls5s.. sonea$n8syndrom4,rci.*iak,l wiih .rak r. sp€bti*d RNA.prctin .om!l.x rh,r u$s
dehcBin DNA repff n&hannms.'nd th. tift .brn n! uw' RNA r a EmDhk for addmeiddrid-."
or mod.r:nimrkc'n !t incrtistnif rslonms o DNA 'h. endi of chomastu5 Tdom.;s rchv& tr
drmrserrc.nhrrc.d or prok,ns,hr j:b u. DNA .xpr6..d in sem c.115.!dis Drtknr.t tou Lvii3 iD
Ie inroducd ln t r, 'h. nFru.nhonrhr h,5 moil $tn .dlr but n n usurlly,b* in nsr 3.maric
conls.nrb, potons.d tire sp,' in mo* sFi.s G Gsu.s(Fi& l lrL lh.ftfor,.5 ce[si*r th.n ktom
r[,nf '.!rkrror. Renrln i hn b..n pbp,{.d rhrt .6 eon. shonerrd th.y .xn ll). e rycL. i6uh.
cron. rcnr(on iDts*5 a te\.t of *($ rh,r:rt ing in an mib't,D ro s.n.,k n.w e ! ro fetra
v*s proEi[ of ih. situin fimitn 5uchr sr2, rh.t drmrsedon6. (o'\.et', r 'mnoit:t qncs idlj.
tunfton as hrron. d.aeotik.. TrEe DroriB mav rdomd,n n rcad'vded 2nd cton
d.r.ryhte rnd dseby ictiv,c DNA rt;r mln ; .n.d. sgs6ring 'hn Etomftetongnio, mrsh,& ai
{hB jrb,ttr4 rh€DNAi n rh.,ben!.oftn.; dp
,eins,DNA n Fmn.In drmr. non.Thr D d,xus,ednor. t!l[ d
. D.leued 1lhb aphatan A nom:tc ! h,v. 5uchiIunnsobk r,otr,howav.r,rh€;trflffih,;"i
a limtredlrpaciry for trptnrtron,:nd :ft.r r n*d rron{rr rd\ir and relatuE tmg'h ro as,ne
numbdor divnion.c.1k beoni,r6ted in . (mi. _ rnd
€nar h,3)d 'o h€fultr 6Db|Bhed.
nilly nondividns n.te, kna*n .5 r.rliart Ja.J . R?,1"4.1'q.nefttik @nad, at ti$,. t.n 1r..
..'.. Ag'ns i.1$mi!rd wnh progGriv. rptic,nve R(.nt studies susg.n thai *nh ase, iI. pt6
 I slfrI||I
! Rdul6 tmm .onbiution oi rccumrtati'r
ell'Jrr do.e (.e, by fc 6diciL), rcdx.a
€Paciry b divid. {rcplic,riv. b*rnc.), :nd
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!
,

$ . A.pa@iw 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

r6n.6 preqEiwt ibnli w rh i(eiR en dr ft; udi rr $ourd bQppr@ h. hev.rio$ torm ot cdlu
and adlphiians d.siibed ii rhi5
insnom:daphhons
'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' Reflr.ne 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
lcDKN2Al pocin .ccumuhi.rm snn c.lk, andrh.y
prusr6i v.ll loF rhnr cip,ur, r, elf ff.q pt6 B i
phrs,otas,cit mh,bbr "f..[.rk prcB($ron!i, p.
di{s5 n chrpkrb, dctcuon ort6i ot Iuid,ln muE.
rioli or Dr6 r. rsiar.d with.1
. a.t,uktia" al n4.boln dn-q.. c.llilar tle
spanr rlsc dd.rminrd by a b:l:ne b.*en dim,e.
rtsurinefrom m.rahohc.v.i,5Nlrflng wlhm (he )61 Fb, 4u4 enbd k. bai,. al
!!ll rnd (olnEncnng molduLr rop,{$ th.r c,n irbt 64t'iRtu' at khd4. tu4!q.1
(p:n rhedrm8.. on. eroup,,I pohnrlly ror. pro Dii! N/ r4qaq t
16 zas. zaal re.ht thl rttu E tq,r ot4qt6'
duci or nonirnd:bornm n Hc @rb Qtu's o, ttt 3d. h6ttt ot Piota j
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!.
idr n olei tuL rd oxd{r a
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 !n|N.oLfrENjcddtr.lytsnl4r':(*pd.'*ei.'dd.
dani d.f.6. mah, hs. D.msed (llul,r olgm.ll..
,.ctrnul.r * <llr ae. ThisDry,ls b. th.6uhof 6t&"e4,,t1A.L *tudt rt, ,,ryhhdd6i.bIrm t
d(linins tundion of d. prai.1ofr., th. prot olrlc
qqqw ot $. rch ot 4o&&ra r .d turtp, qd d{@t.t
n. Fd4t'd4t r ni4rdin 6r
. srtrdi8 i! modet osnsns, titc th. ,om 4n[ !<8. !J 6e. ,B' /o,!fu.! '
Genorhabdrs .l.eaE. h,( 5hown thrr soqh
hcro6.5uch,s iniuln 11,.8rc{h frdo(:nd nft D4,11\ 16s tc@41 @<a' ot q4 ad b@ 4LD.@td.
anubr signllins tsrhweF r.inrr.d 6y $!* IDF
nunlr knd b Edtrft tLt .prn. Th€ undstyms
mEhan',mir. noi illlr und{rmd,bur,hreEroMh r6a A 4ens d oe@ at e,. tu
rFou n,r anrnun tn2 rceon(i 'o rtllGr !F.s
,nd du. Educ. th€ $rbiliry ct rh. DNA.
 r@z tD!lr6@ 4 ltu Nt@ 4 tuftt ns,6 le.dtu w ot tk @ t@@ ol
kel(l:ftknq xu6ud@ Rlq&d&K"rcueaiFqrl"fu
.* Fd.d e* rq ,ttu Fm, d rw &;'
1 6 [ D .s L d ] M e ' c u . e B r e r ! [

ry.tu, d tbvd@ "t4ottu^t d4 ot h4rtut rn d qad htub.,]

zl4D'9l!ry|r&[e'|M'h!cM.M..L--.
Eo.Ic-. ,6t rk au ot DN^ atqx n au ry,j
M Mddr q[i0u dilrk
z4LlU'cE!i[PfioFM|Gjb

rfr d qtrd4 ttutw al.a h6. 14 qtu tu &@4 @M. aL I

& h4hnna d &nr an | | r:.r r. ,@r