ROBBINS

ASrcPathology

tSAUNDERS

ELSE\]ER

KumorAbbosFo ustoMitche

Chapter 1

Cell Injury, Cell Death,and Adaptations

Introduction to PathologyOveaview ol Cellular Responses to Stress

and Noxious StimuliCellular Adaptations to StressHypertrophyHyperplasiaAtrophyMetaplasiaOverview of Cell lhiury and Cell DeathCauses of cell IniuryThe Morphology of Cell and Tisrue InturyReversible InjuryNecrosis

Patterns of Tissue NecrosisSubcellular Responser to InjuryMechanisns of Cell IniuryDepletion of ATPDamage to MitochondriaIntlux of CalciumAccumulation of Oxygen-Derived Free Radicals

(Oxidative Stress)Defects in Membrane PermeabilityDamage to DNA and Protein5

INTRODUCTION TO PATHOLOGY

Literaily translated, pdt olo6l is the study (/ogos) of suf-fering (pdrros). k is a discipline that bridses clinical prac-tice and basic science, and it involves the inv€stieation ofthe causes rcrraloeyr of diseare a. wel l rr rhe underly ingmechani\ms qatbogenesist rhar resuh in rhe pre.enring\ isn\ and (ymproms of rhe parienr. Parhologrsrs ure.rvariery of molecular, microbiologic, and immunologictechniques to understand the biochemical, structural, andfunctional changes that occur in cells, tissues, and organs.To render diagnoses and guide therapy, pathologists identify changes in the gross or rnicroscopic appearance (,rolpDology) ofcells and tissDes, and bioch€mical alt€rationsin body fluids (such as blood and urine). Traditionally,the discipline is divid€d into general pathology and sysremic parhologyi rhe former focuses on rhe fundarnenralcellular and tissue responses to patholosic stimuli, $hile

Examples of Cell Iniury and Necrosislschemic and Hypoxi( Injurylschemia-Reperfusion Injurychemical (Toxic) InjuryApoptosisCauses of AooDtosisMechanisms of AooDtosisExamples of ApoptosisIntlacellular AccumulationgPathologic Calcif icationCellular Aging

OVERVIEW OF CEttUtAR RESPONSES IOSTRESS At{D I{OX|OUS STtMUtl

Cells are active pa.ticipanrs in their environmenr, con-stanrly adjusting their structure and function to accommodate changing demands and extracellular stresses.Cells tend to maintain rheir inrracellular milieu wirhin afairly narrow range of physiologic parameters; thar is,rbey maintain notmal homeostasis. As cells encounrerphysiologic stresses or pathologic stimuli, they canuodergo adapiation, achieving a new steady state andp.esenins viability and function. The principal adaptive

the latter examines the parricular responses of specializedorgans. In this book we 6rst cover the broad principlesofgeneral pathology and then progress ro specific diseascprocesses in individual organs.

z CHAPIER 1 - Celltnjury CetlDeatl and rdaptatioB

hrpertrcpby, hfierpLasid, dtrophy, andnetdplasid.lf rtu adaptive capability rs exceeded or iftheext€rnal stress is inherendv harmful, r"1/ t',r,ry devetops(Fis. l-l). Wirhin cerrain limits injvy is reuersibte, andcells rerurn ro a stable baselin€; however, severe or per-sistent stress resuks in irrcuersibLe iniury ̂ nd dea,th oI rheaffected cells- Cell dcath is one of the most crucial evenrsr! rne cj i r rpuo l or dr\ea\e rn rn] t r \ \ueororqrn. l rTEit t is

cru\e\. Inctudrng r\hemra (h(k ot bloodfk)w), inf€ctions, roxins, and immune reactnrns. Celldeath is aho a normal and essential process in embryos.ner ' . rhe de'elupmenr of org;n' . rnd the mainrenance

The relationships between normal, adaprec, anoreversibly and irreversibly injured cells are well illustratedby the responses of the heart to different types of stress(Fig. l-2). Myocardium subjected to persistenr increasedload, as in hypertension or with a srenodc va,ve, aaaprsby undergoins hypettrophy-an increase in the size ofthe individual cells and ultimately the enrire heart-togenerate the required hisher contractile force. If rheincreased demand is not .elieved, or if rhe myocardiLrmis subjecred ro reduced bkxd ftow lrschenial t'ron anoccluded coronary arrery, the muscle cells may undergoinju.y. Myocardium may be reversibly injured ifthe stress

NORMALCELL

BEVEBSIBLECELLINUFY

NECBOSTS x

Figur€ l-l

SUBCELLULARALTEBATIONS

APOPIOSIS

Stages in the cellular response to st.ess and inju.ious stimuli,

x

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,1 r" tt" *i,pie.i.y.ca,riri"rhypertrophy {/ower /eit). the eftventricurarwal is rhickerthan 2cm dofiar, i_t.5.;) R;;;;tji;;;;;;;;;:;iilH;,iljffiffi-"I^"_*-yi'11,.:,:iy-sj:T grr,qht mi(o5<opk .hd nses. orreveribre cr,anseiIke ceir,t, ,i"'eiffiJiliLtty ;r,"nee Ghown he,;). rn th;;#lil'1i1il:".,*T:#::"i,:fli:il""j:::jl*ar rieht area in the posteroraterar reft ve;t.icre.represenis an acute myo.ardialcoro6 viabre myocadium masenta. Fairu,e 6 stain iill:f""""""#: i:::#i'i,::lihenvrtetraorium

chroide' an enzvme 'ubsiate that

CHAPTER I Ce l n l ! ry Ce lDeath , and Adapta lons 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 hercrr l r hr t i . r , r r m.r r unr icrgo r r rocrr lnc in turr L ia l . r r r, , 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 { ! ) .rh, r i \ r ( \ \ . ! r fJ ntur \ r i ic . r r r rx r r r l r t l t t r r rorpho ogth 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 s . T l r r ' .n r r r i h l r r r l u r t dr c s r m b l e r r o r r r r r l r r r r t r t t ' r n . r p h . L , g r c . r l l v r h ( , * f \ . f .r l , . \ . r r . . . r l . ' . I l . . , " , r ' r . r ' . . ' lnr lc l in ju, \ ! . r r h . r . t r lc th. r l c ,nL.r l ,nr j ) . r . r . \ \1h.rh. r rspc. f i r I rnrr , ) i \ t r$s r ( lL i . .s . r t l . rp t r r ,n r r eeusrsic \ . , \ l lJ l . , , r r r i , rc*rb lc Lr iLLrv r l r r .nr l ' n( , r ( ,n l \ ( ,n rh.i r . r turc . rn( l s( , \ f rLr ! oa rh. \ t r . \ \ bur r lsr ) on ' . \ . l , ) rh. lr . r r l . r l , lcs. ,nc l rLLJing .c l l r rL. , r n ,c t rbol , 'n , . l ,Ju,J srppl r .. r rd n! r r i rL()n. r l sr i ru\ .

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 , r r i )s t r t s c s r n d t h c , , r h r . i ! s r \ . , , , c t h . r , r i s r , ' . . t r r l r r n r rqU.nrc\ (n rh. \ xr ious k)r r ' o i . r ( ! t r . .L l ( i . rN.rg( . i fc r i ( li 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 . r l t . f . r i , ) , , \ . . r n d c ( lJorh. \Vc eorr i luJc r i r l r thr .c , , I1r r r t , , ) . ( ts f \ rh. r ( , r f i fcrcc l ls rnJ r*uer : i r r r r , rcc l lu l . r r . recrr r rLLl . r r rnr \ . f . r rh{ , logL.c i1ei t i . . r t l ,n . . r r r l ec l l . rg ,ng.

CEttutAR ADAPTATIONS TO 5TRE55

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 r r r t t L c n ! n r b o . \ , 7 c .p h r n r n i p c . r r e r . r b o l l e r . r r \ r r \ . . r l ! , r ! l i , ) n s ( ) r e ( l L s L ffu\ l ] l ) r r \ r t , , .h . r rg( \ i f rh . i f . . \Lronfr .nr . / ' r \v ,1, , ( r. r ,14,1, r / ' , r - r r \ ! . r l l \ r ( 'p , f ! n t ( \ tonn\ o i r . l ls to rornrr ll t l I r ! l r t i (nr b\ h, , rdrn( \ ( t r (n( l ,A, i ( , ' r rhemic. r l nr r l. r ( ( t r \ 1 f . i . . (hL hornrn rnthrrcLl or l . rgcnror t o i thcbt . r* . rnd LLtcrus Jur ing prcsnrno 1. / ' . r t r r l , , . !a rJr l , r . r1; , , r j . r r ' f .s t ) ( ! r i . \ k ' \ i r f$ rhr l , r l l (^ \ . . l ls n) nrod! l . r t .t h f r r \ r ( L . r L L f c r n . l h r n . r i ( , n i r d r h u \ . ' . r t c i n l u r r . S u r h,r rhpt . r t ions crr t r lc socrr l r l rs t rc t ior r r .

Hypertrophy| 1 \ l ) t l t l t ) t ) l : \ i \ .1) t 1r1.h\ t \ t1 t t l ) . : j : t t ) l , . l1s h ' r l t t I t t t l,1 .1. , t : . h t l r \ ! : . t l t1 , , , , , r ,1 .ur . I r rdr t r . rs t . hrprrphsrri r l l r c r r r r l r r i t , ' c h . r r , , r t t , , a r l h i . , r i n . r ' . r ' . , r r c l lr ) f i n l ) ( r : 5 r . r r { J r f , , r h . r \ . r \ . r p r r r c h r p r r t r , , p h r t h c r c

. . l l \ . i$r brgAir . f l l \ . . f l . r rs . r l hy r i rr n r r c r s i d . r r r r r r r r r i , 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 \ .l l \ t u t l . r \ r r i \ r r r . r J r p t l r r r c s p . r s t i r . r l L ' . . r I r l J e { ) lt 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 cnc. ,1. . , l r lc o i d , r , r lL , , r t1 \ t \ l t t , , t ) l ' \ , ,n l t / , \sr )1, , !k t ,

tn l r )L)sk r r l l r eru ' t t l L t Ic , i ) | r r . r ( . r \c ! i tur i r r i (nr . rJ o r r n l , , r b \ s p t . i l i e l r o r r r o r t , r L n r i L , r r r , r . l l \ t ) ( . r n )phr . r r r t l hrperp l . r r i r t . r r . r lso r t .ur n i r ( r l ] ( i : , r r r l , )h \ ,<,ush both rcru t i r r . r r r r rL, r r , * r l i / , \ ' / , , ,111,1, / , r , r ( i r ! . rn .l l r u : . r h t r , . , s n c p h r ' i r i I r g , r m l . , r g t n , m t , ) i r h . ' , r . f ' , \(1 ! i . i t r f i rn , r f . \ ( i . !LLf \ . rs . r . ( i r \ . { tL t r i r f ( ) f cdr( ig .n\ r i f ru l r t ( ( l \nr ( ! , th nrr rsc l t hrprr t fuphr . rn,1 \u(r i thr r r u ' t l c h r p t r p l . r s , r i l : r { . I l l . l n ! ( D r s t . r h . \ r f i . r l . Jn,u ' r l t ceLls in hrxh the skt ler . ,L n,usclc . ,nLl thc hcrn unrr r t l t rgo rn l r hrponophr i r ruston\ f nJ r roc. rs .Jr l tn , . , rJ bt rus i in thc rJul t ths hrrc L ln l tcd t rp. , r r lr , . 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 e r t . r r r l e v c J o p rr 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 . , l \ l . . l cn l , , ,uselc tc l l : r ,L luccd b\ . , , r l , , . , r l 'cd \1)r l l iu(1. l j \ . r , r l

l lcs ot p l rho|r , rL i rc l lu l . , r hrpcrr ropl r r r fe l r . lc r l ,ce r r J L r c r n l . r r g c r n c r t r h i r , t r . u ^ \ i r l r l r r l . r t c n r , r r , , r, r ( i r I r r \ . r l \c l i \ . . rs f 1 \ . r f rg. | - l r .

I I c r r e t h . r r i s r r r s l r i \ 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 r Ic . r \ t ( \ ( , r \ t ) (s , , i l i t , r . r l r : ar , , , / , . r r r r ' . r1 t r r rs l rs , su, :h . rs' 1 , . '

, / . . i : ,r r l r tn t rg ic rL 'cLptr rs . lhN' s t ,nrr : lL rL,nr ( )n $gf . r l l r , rnsJui r ror p. r rhs. r rs th. r t Lr . r r l ro th i rnr l r r , : r i ln o i . r nLrnrbcr' j ; , . . . r . l 'ic l lLLrr p i , t t , rns. i rc r r r l rng grNth a, r . r ( ) r \ . r f { l \ r l , ! l |Lr . r lp 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'-:--.. € - - ' . . . .

phF o loq i . hype( rophy o t the ! te ru5 d ! r nq p .eqna. .y A , Gross appeardn.e o l a .o rna ! te , ! t { / ,qh0 a .d a q ,av id u le , ! i ( /e / t ) th i twas r .movcd lo r ponp. . t lm b . .d ing B, lma l .p nd le 5hnped l te r ne rmoorh mus. . . . r l r .n r a norma l rc t r f comp. r . th s w i th (c )arge , p lmp hyper i roph ed smoo lh m! ( e .e s i ronr a q rav d u rerus (B .nd c , same magn n .ar on)

c

4 CHAPTER 1 - Cell Injury Cell Death, and Adaptation5

myofilaments per cell, which achieves improved perfor-mance and rhus a balance betwe€n rh€ demand and thecellt functional capacity. There may also be a switch ofcontracrile proteins from aduk ro fetal or neonaral rorms.For errmple. dur ing murcle hyperrrophy. rhe o-myo, inheavy chain is replaced by the p form ofthe myosin heawchain, which has a slower, more energerically economicalcontraction. Vhatever the exact mechanisms of hyper-trophl, a limit is reached beyond which rhe enlargementof muscle mass can no longer compensate for theincieased burden. When rhishappens;n rhe hearr, serer!1"degenerative" changes occur in the myocardial fibers, ofwhich the mosr important are fragmentation and loss ofmyofibrillar conrractile elemenrs. The variables that Iimitconrinued hlperrrophy and cau.e the regre*^e chrnge,are incomplerel) under,rood. There m,ry he f in,re hmrr,ot the vasrul i ture ro . :dequarel l suppL rhc enl j rged6ber, . of rhe m,torhondria i" ,uppl ' ; ieno. '* ' "pio,phate (ATP), or of the biosynthetic machinerv to providethe contractile proteins or other cyroskeletal elernenrs.The net result of these changes is venrricular dilarionand ulrimately cardiac failure, a sequence of events rharillustrates how a ada?tdtiaft to strcss .dn ptoxress K)fi,nctionally signifuaftt.ell inia^' if the stress is tlot

HyperplasiaAs discussed above, hyp€rplasia rakes place if rhe c€llpopulation is capable of replicarioni ir may occur wirhhypertrophy and often in response (o rhe same stimuli.

Hyperpla\ i r crn be ph!roloqrc or parholog,c.

. The two rypes of pbysiologic hypelpldsia zre tl)howonal l.ypprplasQ, erempl6ed hy rhe prohferrronof rhe slJndular epirhelum of rhe rema,r D'ca{ rrpuberty and during pregnancy; and l2) .ompensahryblpetpldsia, thar is, hyperplasia rhar occurs when aporrion of the rissue is .emoved or diseased. Forexample, when a liver is partially resected, mitoticactiviry in the remaining cells begins as early as 12hours later, eventually restoring the liver to its normal$eighr. The rr imul for hlperpla.ra In rhr( \et t inB rr(polypeptide growth facrors p.oduced by remnanthepatocytes as well as nonparenchymal cells in thel;ver. Afrer resro.ation of tbe liver mass, cett prolif-erarron is "rurned off ' by v:nou. growrh Inhrbrtoh(Chaprer l ) .. Most forms of pdtrolog,c hyperplasia are caused byercessive hormonal or growrh facor srimularion. Forexample. af ter a normal men,rrur l per iod rhere r . abur\ i of urenne epirhel i r l prol i feranon r har i r normattytightly regulated by stimulation through pituitary hor-mones and ovarian esrrogen and by inhibition throughprogesterone. However, if the balance between esrro-gen and progesterone is disturbed, endornerial byperplasia ensues, a common cause of abnormar mcnstruarbleeding. Hyperplasia is also an imporrant response ofconnective-tissue cells in wound healing, in which pro-liferating fibroblasts and blood vessels aid in re-pair

(Chapter 3). In this process, grofth factors are p.o-duced by white blood cells (leukocytes) responding tothe injury and by cells in the exrracellular matrix. Srim-ulation by growth factors is also involved in the hyper-plasia that is associated with cenain viral infecionsifor exarnple, papillomaviruses cause skin warts andmucosal lesions composed of masses of hyperplasticepithelium. Here rhe growrh facors may be producedby tbe virus or by infecred cells. It is important to noterhar rn r l l rhete -rruar ion!. rhe hlperplasr ic processremains conrolled: if hornron:1 or growth factor stim-ularion abrrrs. rhe h!perplasia disappears.lt is this sen-sirilitv to normrl regulator,v control mechanisms thatdisrinsuishes benign pathologic hyperplasias fromcancer, in lvhich rhe growrh control mechanismshecome drrregulared or ineffet tve r( hrprer 6t. Nev-erhele\\ . p ' t th ' r logic hyperpla\.r Lon,r ' rule\ a rerr i lesoil in which cancerous proliferation may eventuallyaris€. Thus, parienrs wirh hyperplasia of theendomerrium are ar increased risk of devetopingendometrial cancer, and cerrain papillomavirus i;fections p.edispose to cervical cancers (Chapter 19).

AtrophyShuakagp n the stze ol the cell bv the lcts, o7 rcll sub-ttancc is hn6wn as dttoprl U hen I .ufncrent number .fcells is involved, the entire tissue or orsan diminishes insize, becomins arrophic (Fis. l 4). Ir should be empha-sized that abhough dtlophi. cells nay haue diminishedfunction, they ale not dead.

Causes of atrophy include a decreased workload (e.g.,immobilization of a limb ro permit healins of a fractura),lo* of innerva"on. d 'mini \hed blood,uppt). in.rdequarenurr i r ion. lo$ of endo( f lne \ i imuld on. and rs,ns { ,en,teatrophy). Ahhoxgh some of these srimuli are physiologic(€€., the loss of ho.mone srimularion in menopause) andothers parhologic (e.g., denervation), rhe fu;damentalcellular changes are identical. They represenr a rerrearby the cell to a smaller size at whicli survival is stiltpossible; a new equilibrium is achieved between cetl sizeand dirninished blood supply, nutrition, or trophic

Arrophy results from decreased prorein synrhesis andinc.eased protein degradarion in cells. Protein synthesisdecreases because of reduced metabolic activity. Thedegradat ion of rel lu lar prorernr occun mainty by rheubiquitin prctcasome patbuay. Nr\ttie denciency anddr 'u\e mry rcr i !are ubiqui0n hgr\e\, \^hrch aFach mur-t ip le copre, of the ,mal l peprrde ubiquirrn ro cel lul . : r pro-rerns dnd rrrger the\e prorerns for degradarion rnproreaqJme\. Thi\ pdthway i \ r lso rhougl o be respon-ible ! . r lhe f fcelerr led proieolysi \ ,een in a var iery of.rraholc condi i ion., . rncluding <anrer crcheria.

In ma,y siruations, atrophy is also accompanied byincreased autopbagy, with resulting increasis in thinu.nhet ot autophasic uaruoles. Aurophagy r..retf-ear inB-l i ' the proce+ in which rhe srarved cel l eatr i r rown components in an arrempt to find nr:trients andsurvive. We will describe this process later.

Atrophy . A , Norma bra ino fayo !ng adu l t .B, Atfophy of the brain in an 82 yea.oldmale with atherosclerotic disea5e. Atrophyoi the brain is due to aging and .educedblood supply. Note that loss of brain sub-nance natrows the gyri and widens thesulci. The meninges have been strippedfrom the right half oi each specimen torevealthe surface of the brain.

MetaplasiaMetaplasia is a reversible change in which one adulr cel lt_vpe (epithelial or Dresenchymal) is replaccd b) anorheradult cell typc. In this tvpe of cellular adaprarion, cellssensitive to a particular srress rre replaccd bv other cellt l p e . b e r e r a h l e r o u r r h . r . r " d r h e . r d r r n e , n l n r r m e n rMeraplasia is thought to arise by genetic "rcprogramming" of stem cells rather than transdifferentiation ofalready differentiated cells.

Epithel ial metaplasia is exempli f ied bv thc sguarrouschange that occurs in rhe respi.arorv epirhelium in habit-ual cisarette stlokers (Fig. 1-5). The normal ciliatedcolurnnar epirhel ial cel ls of the nachea and bronchi arefocally or widely replaced by stratifed squamous epithe-l ia lcel ls. Vtamin A de6ciency may also inducc squanousmeraplasia in thr respirarory epithel ium. The "rugged'.rrrr i6eJ \quJr, 'd. eDrthelum mr) I-e . lb le ro srrnir .under circumstances thar the mo.e fragile specializedepirhelium would not t<rlente. Ahba gh the netdpldsti..q!n4out qtth.luh ha' rtuiutl ddua' dRc<. tnltut,tdtfn tet true nTl dntsus a'p / , 'st . .urh .r \ mucu\ n\ relr^nand ci l iary clearance of part iculrre marrer gpithel ialmetaplasia is therefore a double-edged sword; morcover,tbe influeft.es that indu.e metauldstic tra sfolmatlfi, ifpe/sistent, ndy predispose to ndligndnt trdnsfalnationol the e?ttheLium. ln fact, in a conmon forrn of Iungcancer, squamous meraplasia of the respirarorv epithc-lium olten coexists with cancers composed ot malignantsquamous cells. lt is thoughr thar cigarcrte smoking ini,r ia l lycauses squamous metaplasia, and cancers ar ise laterin some of rhese alrered foci. Meraplasia Deed not alwaysoccur in the direct ion of columnar to squamous epitheliumi in chronic gastric reflux, the normal stratified squa-mous epithel iurn of the lower esophagus may undergonrcraplasric rransformati()n to g:rstric or intcstinal rype

CHAPTER 1 Cellnjury CellDeath, and Adapta ons

columnar epithel ium. Metaplasia may also occur in mes-enchlmal cells but less clearly as an adaprive response.For exarnple, hone is occasionallr f(rmed in soft rissues,p:rrricularh in foci of iniury.

.*:la*-'--LFigure r-5

Metaplara of norma columnar (/eft)(rigrt) in a bronch!5. shown (A)

to 5quamous epithelium(hematkally and (B)

6 CHAPTER 1 - Cei ntury CeitDearh, andAdaptatons

SUMMARY

Cellular Adaptationi to Stress. Hypertrophy: hcreased cell and organ size, oftenIn re\pon\e r , , ,n.rer\ed $,,rk loadr induced b)mechJn,. .r l , f fe$ rnd by ero*rh facron;, ' .cun.ntissues incapable of cell division. Hypelplasia: increased cell numbers in re5ponsero hormone. rnd , , rher growrh {actor. i , ,crur. intissues whose cells are able to divide. Atlopb,: decreas€d cell and organ size, as a resultof decreased nutrient supply or disuser associaredwirh decreased synthesis and increased prot€olyricbreakdown of cellular organelles. Metdplasa: chrnse in phenotype of d,fferennarcJcel l \ . ohen a re\pon\e ro rhronit r-ntat ion rharmakes cells better able to withstand the stress;u,uJl l ) indu.ed b) Jl tered drf ferent iar ion prrhwrl ofr i*ue nem Lel l \ i mJy re.Lr lr in reduced frn.rrurrr orinc'er 'ed propen.I t for maLgnrnr rranrformatron.

OVERVIEW OF CELL INJURY ANDCELL DEATH

A . , r . r | , d , i r r h e h F g i r r n q ̂ t r h , . h J p r e r . . , j t n 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 r h r \ . r r e n , , t , - B e rable to aclapt or when cel ls are exposed ro inherenry oamagmg agen!s or suffrr f rom intr insic rbnormatir ies. Different injurious srimuli afiect rnany metabolic pathwavsa ' d . e l r u h r o r a J n e l h . . I n , u ' t n ' , 1 p . o q " r , , , , , " . . g n ,r e \ e r . r h e ' r J B e . ' n d , u l r r : r . r r e i n , e l l d e i r h , , e e F r g t - t . .

. Rercrsihle cel! oiutt.ln earll stages or mild fornso f . n i . , t r h e f u n . r r , , n r . r n d n , , , r f h o l n g t c h r n t r , , r er e v e ^ , h 1 . , r r h e d r m J t s , n s . ' , m , , 1 u . i . r ; , , , r e d A ' r \ , \srage, although there mav be siBDilicanr strucrurar andlunct ional abnormal i t ies. rhe injury has typical l l norprogressed to severe membrane dam.ge rnd nuctea.

. Cel l death. Wirh coDrinuin8 damage, the inlurvbecomes irreveBible, at lvhich tinre rhe cer carrnorrecove. and ir dies. There are two types of cett deathnetrcsis aftrl dpoptosis tuhich dif[er in tbeir mo4lhot

T.bre t-i Features of Ne( rosis and Apoptosis

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APOPIOStS

NORMAL

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NECROSTS

cellu ar features of necos s (/eft) and apoprosi5 (.bhO (Adaptedfrom Walker Nr, er al: Patterns of cet death. M;thods A;chvExp Pathol 13:18-32, 1988. with permission of S. Karger, Baset,

os!, ncdtdnnns, an.r robs n disease dnd physnk,sy( l i is. I 6 and Table 1- l) . \ (hen dam:ge t<, nrembranrls

c!toplasm, and digest the cell, resuiring in zerrosis. Cel-lular contenrs also lcak our through the darnagedplasma membrane and clicir a host reaction (inflam-matur). Necrosis is rhc major pathwav ofccl t death inmany comrnoDly encountered injuries, such as thoscresult iDg from ischemia, exposurc io roxins, vanousinlect ions, and rrauma. !(hen a cel l is depf ived ofqrolvrh lJrrol ' "r rhe ,el l \ DNA .,r prore.n, rred.rmrgcJ I 'eyond repJ,r, rhf cel l l , l l , , r ,etr t ' r ,nlrher

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Olrcn phriologr., merns.l ct,m'.anng un*,:niedcells: tr[r he f]thoL(aj( rft.r y,fre nrnj! ol.eLl rDrur!. c\peor lr D\A dinrtrsc

typc of death, callcd dpoplo$r, which is characrerizedby nuclear dissolution without complete kxs ormernbrane inregrirl. Apoptosis is an acrivc! r,,crsydependenr, rightly regulared type of cell death that is'een in . ,me .pe. i f i , \ lurr ion,. $rc,cds l r . , / ,^^ r5alwav' .a fath"] .u, t 'h\ 'et t . ap,,p! .^t t tctuc, f tanynuthal lu't, tn n' dnd E h"r neccssanly a':,riaral utthpdtholoei. ell Mftry.The rnorphologic fearures, mech-anisms, and rignificance of these two dcarh pathwaysare discussed in more derail larer in the chapter.

CAUSES OF CELI. INJURY

The causes of cell injLrry ranse from the gross physicalrrauma ot a moror vehiclr accident to the single gcnedefecr that resuhs ir a defecr;ve enzyme underlying aipc-ci6c merabol ic dise:se. Mosr injur ious st imul i ian-begrouped into the following caregories.

Orlgen Deprirar ion. HV,,r t t . o. , , r1gen deri , i rncy.rFrertere\ $irh derobrc n\rJdr ire re,prrrrron ,rnd r , rn!xrremely imporranr and common cause of cel l in iury andd,JrL. HlpovJ rh,,uld be Jr,nnguirheJ l r , ,n rd..nta.$ h , . h , \ - , l o $ n f h l , , u d \ u p p l 1 n a r r s . u e d u c r o r m p e d e darterial flow or reduced venous drainage. n0hile ischerniais the most comrnon cause of hypoxia, oxysen defici€ncycan also resuh from inadequatc <ixvgen atn,n- o I rhe blooj,r . i r p n e u r . o n i i . , , r r e d u . r r o n r n r h e o $ g r n - a r r y i n gc r p J . f l ) , , f r h e b l o n d , J , I n b l . o J l , ^ . a n e m , r , r c r r b o nmonoxide (CO) poisoniDs. (CO ftrms a stable complexwirh hemoglobin that p.events oxygen binding.)Chemical Asents. An eDormous number ofchernicat sub-srances!an injurecel ls; even innocuous substances such asglucosc or sah, ifsufficiendv concentrated, can so derangethe osnnric environmenr rhat cel l in jury or dcarh results.Oxygen at sufficiendv high p:rtial pressures is also roxic.Agerts commonly known as poisons cause severe damageat the cellular level by altering mernbrane permcabitiinosmotic hofteosrasis, or rhe inregrity of an enzyme orcotacror! and exposure to these poisons can culrninate inthe death of the whole organism. Other porent ial ly roxicagenrs are encountered daily in our cnvironment; rheseinclude air pol luranrs, inscct ic ides, CO, asbestos, andsocial sr imul i" such as ethanol. Even therapeut ic drugsL . r n , , r u \ c , e l l o r r i , ! r c i n i u r y r n r s u s c e p r r h l r p a r r e n r n r r fu,ed er(( \ \ i \e lr or inJnfropri : rr l1 rr h.rpre- 8 ' .Infcclour Agenr\ . fhe.e rrnge trom .ubmi.r , , ,ot icvrruscs to meter'loDg tapeworms; in betwcen are rhe rickettsiar, bacreria, fungi, and pmrozoans. The diverse waysby nhich infectious pathogens cause injury are d;scussidin Chapter 9.

Immunologic Reactions. Although rhe imnrunr sysremdefends rhe L,ody againsr pathogenic microocs, rnnrunereact ions can also resulr in ccl l and t issue iniury. Examples include autoimmune rcacr ions asainst ones owntissues and al lergic reacr ions against envi .onmental substances in generical ly suscepriblc indjviduals (Chapter.s).

Genetic Defects. ceneric defects can result in pathologicchanges as conspicuous as the conseniral malfbmmr;onsassociared with Down svndronre or as subtle as the single

Ce I Injury Ce I Dearh, andAdaplations

arino acid,rh,rrutun in hemoglubrn \ grung n.e ro\ i . k l c . e l l r n e r i J . a , e n e t i i d e f e , r \ r r a y i . r L l e r r l l r r r l u r rbecause of de6c;ency of functional p'oteins, s'ch aienzymes in inborn errors of metabol ism, or accurnulat ionof damased DNA or misfolded pnrteins, both of whichtrigger cell de:rh when rhev are beyond rep:ir. Variati{'rsin the genet ic makeup can also inf luencc the suscepribi l -i ry ofcelh to iniur l - by chcmicals and othcr envrronmen-ra1 insults.

Nurritional Imbalances. Even in thc current era of burgeoning global affluenle, nurritional deliciencres rrmarna major cause of cell injury. Proiein-calorie insuffciencyamong underpr iv i leged popular ions is only the rnostohviour cr l rple: ,pe., i i . \ , r rmin drf i r ,e,rre, arc n,r

in devek)ped countries with high stan-dards of l iv ing (Ch:rpter 8). l ronical ly, excesses of nutr i -ron are also important causes of morbidity andDrortality; f(r example, obesiry markedly increases thcrisk lor iype 2 diaberes mellitus. Moreover. diers rich inrn mrl f . rr ; re,rr ,rrgly impl,(Jred In rhe Jev,. topmenr orarh(-u\clero!. a ' wel l ar n rn.rer,ed r .r lncrrhi l r t t rornany disorders, includins canccr.

Physical Agents. Trauma, extremes of tcrrpcrarures,radiarion, electric shock, and sudden changes rn armos-pheric pressure all have wide ranging efficrs on cells(Clhapter 8).

Aging. Cellular senescence leads to altcrarions in replica-r ive and repair abi l i t ies of individualcel ls and t issues. Al1of rhe,e . hange. rc,uh ,n a drmrni,h, J rhr l rry ro , e,1,,ndr o d J m r g e J n L l . e r e n r u a l l l . r h e d e r r h , , f L e l l . r n d o f r h e,trgJI i ,m. Tl- , me.hJni,nr urderlv ing . , ) lubr ,rging rr, l iscussed ar rhc end of rhrr rh,rprer.

THE MORPHOTOGY OF CELL A]{DTISSUE INJURY

lr is useful to describe rhe basic alrerations that occur indamaged ccl ls before wc discuss ihe biochemical mechanisms that briDg abour rhese changes. All strcssesaDd noxiou! intluences exerr rheir effecrs first ar rhemole.ul l , ' r hlochemi.al le\el . Lpl luldr lunctton nay belosr lons b, l , . re ccl l dearh "ccuts. and the nuryna,,st .chances of ce iniury lot dedth) lds fdr behind bo,b tFiE.1-7). For examplc, myocardial cel ls becomc nonconrrac-' r le r frer I ro 2 rr l rute. ot \ hemu. Jlrhnutsh rnel oo n. ldie un r i l 20 to l0 nr nure' of i* her ia hrve (rJp.ed. Ihe.(myocytes do not appear dead by electron rnicroscopy for2 ro 3 hours, and by l ighr microscopy for 6 to 12 hours.

The cellular derangements of reversible injury can berepaired and, i f the injur ious st imulus abates, the cel lwi l lr 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 .cJu,e\ cel l ' ro pa.. rhe nrbulour "p,rnr ur no rerunr" rnronrcuersible iniury ^nd rell drarb. The events that derermine when reversible injury becomes irreversible and progresses to cell death remain poorly understood. Thecl inical relevance of this quesrion is obviousi i f we canan'wer i t rr mav be ahl( ro devi,e ,rrJregre\ Inr t re\e t;ng.el l in lury from harrng perm.rnenr deleterrou, r , ,n,equerces. Although rhere arc no definitivc morphologic orbiochemical co.relares of ifferers;bility, xuo phenomena

CHAPTTR 1 - Cell Injury Cell Death, and Adaprations

The rclationship between cellular function, cell death, and themoryhologic changes of cell injury Note that cetk may rapidtyberome nonfu nctional after the o$er of injurv atthougtfthey ar;ttill viable, with potent'ally reversible dam;9;; a tong durarionor In,ury may evenludlly lead to irreve4'ble Iniurv and cett de.th.Note also that cell death typkally precede5 uttranructural, tightmi<roscoPic and grsrly visible mo.pholoqi. danqes.

consistefltly cbaracterize it/eyercibilitf: the inabili, torcu erse mito.hondlial dystlr.r'b, (lack of oxidarive phos-phorylation and ATP generarion)even afrer resolurion ofrhe original injury. and profound drsnrbances n mem.brane functio . Ls mentioned earlier, injury to rysosomarmembranes results in the enzyrnatic dissolution of theinjured cell rhat is characreristic ofnecrosis.

Differ€nt intudous stimuli may induce death by necro-srs or apoptosis (see Fis. l-6 and Table 1-1). As men-tioned above and detailed larea severe deDlerion of ATpand lo* of membrane rnregnry rr€ typicilly assocratedwjth necrosi5. Apoprosrs r . an ,c !e and reeularedprocesr nor assocrated urrh ATP depletron and n harmany unique fearure\. whrch we wrl l descr ibe.eparatelvlarer rn the chaprer.

Reversible IniuryThe two main morphologic correlates of reversible celliniuty arc ce ulat swelling and fatty thange. Cellutarrwel l ing is rhe result of fai lure of enirgy-deprnu.nr ronpump\ in rhe plasma membrane. leading ro an inabi lny romaintain ionic and fluid homeosrasis. Fatty change occursin hypoxic injury and various forms of roxic or merabolicintury. and i ! manife*ed br rhe apperrrnce ot \mal l orlarge l ip id racuoles in rhe cyroplasm. Ir occurs mainly incel ls involved 'n and dependenr on fat merabohsm, suchas hepatocytes and myocardial cells. The mechanisms offatty change are discussed later in rhe chapter.

Morphologlt

C.llul.r 3w.lllnt (Fig. 1-€B). th6 first manitostation ofalmost all forms ot injury to cells, is dif{icult to appre-ciste with the light microscope; it may b€ more app6r-snt at the lsvel of the whol€ organ. Whsn h affectsmanycells in an organ it causes some pallor, increasedturgor. and incraase in weig ht of the organ. Microscopicexamination may rsveal small, clsar vacuolos withinlhe cytoplasm; these ropresent dist€ndsd and pinchsd,off segm€nts otthe ER. This pattern oI nontethal injuryis sometimes called hydropic ch€ngc or vacuol.ldog.n.ration. Swelling of cells is r€versibte. F tlYchrng. is manifested by th€ appearancs of tipid vac-uolss in the cytoplasm. lt is principatty encounrsred incells participating in fat metabotism (e.9., hopetocytesand myocardial c6lls) and is also reversibl€. Iniuredcells may also show increased eosinophitic ateihing,which bocom€s much more pfonouncsd with progres-6ion to necrosis {describ€d bslow).

The ultrastructursl changss of reversible cell injuryers illustratod schematically in Figure 1-9 and inctude (1,plasma membran€ alterations such as blobbing, btunt-ingordistortionotmicrovilli,and tooseningof intorcet-lular attachments; l2l mitochondriat changes such asswelling and the app6arance ofphosphotipid-rich amoFphous densitiss; {3) dilation otthe ER with detachmontot ribosom6s and dissociation of polysomss; and (4)nuclsar alterations, with clumping of chromatin.

E

Figurt l-7

Figurc 1-€

Morphologk (hdnges in t€veBible .nd nreveBible (ell injury {ne(oris), A Noftat tidney tubutes wrth v'able eo'theti.t (e r. a. Eartvrrelenrore, 6oem( Inlury 3howrng surtace brebr, increaeed eotnophilia of q/topl.sm, and twelling ol o(csionat (eth, C, Neooria {nre'-vereore, InJury or eprthelral cerk, with ross of nu.leiand fragmentation ofcelk and leakage ol(ontenti. The uttr dttructurat fearu,s oftherestage or.ell injurv de ehown in F'9. l-9. (courtery of Dis. Neal Pin(kard and M.a. v;nkatadatam. univel'iry ot Texas Heatth Sdences

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CHAPTER I - Cel lnju44 Cel Death. and Adaptal ons

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Clumping

A normal .el and the.hange5 in revereible and i.reversible cell injury (ne<roris)

NecrosisThe term narrosls was first used by morphologisrs to referto a series of changes that a.companl cell death, largelyresulting from rhe degradative action of enzymes onl, i hJl l ) Inrured cel l , . \ecronL tel l . r re unable r , , mrrnra nmembranc inregrity, and theircontents often leak out. Thcenzymes responsible for digestion of the cell are derivedeither from thc lysosomes of the dying cells rhemselves orfrorn the lysosomes of lcukocytes that are recruited as partof the inflammatory rcaction to the de:d cells.

Morphology

In one common pattern ofcel ldeath result ing from lackof oxygen, the necrotic cells show increasedeosinophilia 1i.e., pink staining from the eosin dye, the"E" in "H&E"). This is attr ibutable in p6( to increasedbinding of€osin to denatured cl toplasmic proteinsandin panto loss ofthe basophi l ia that is normal ly impartedby the r ibonucleic acid (RNA) in the ct loplasm(basophi l ia is the blue staining from the hematoxyl indye, the "H" in "H&E"). The cel l may have a more glassy

homogeneous appearance than viable cel ls, most lybecause of the loss of glycogen particles. Whenenzymes have digested the cytoplasmic organeiles, thecytoplasm becomes vacuolated and appears motheaten. Dead cells may be replaced by l6rge, whorledphospholipid masses, called myelin figuret that arederived from damaged cellular membranes. They arethought to result from dissociation of lipoproteins withunmasking of phosphatide groups, promoting theuptake and intercalation ofwater between the lamellarstacks of membranes. These phospholipid precipitatesare then either phagocytosed by other cells or funherdegraded into fatty acids; c6lcification ofsuch fatty acidresiduas results in the generation of calcium soaps.Thus, the dead cells may ultimately become calcilied.By electron microscopy (see Fig. 1-g), necrotic cells arecharacterized bv discontinuiti€s in Dlasma andorganel le memb16nes, marked di lat ion of mitochondriawith the appearance of large amorphous densities, disrupt ion of lysosomes, intrac), toplasmic myel in f igures,and profound nuclear changes culminat ing in nuclear

Nuclear changes assume one of three patterns, al ldue to breakdown of DNA and chromatin. The

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l 0 CNAPTER I aell niury cellDeath andAdaprarons

basophi l ia of the chromat in may fade (karyolys is) , pre-sumably secondary to deoxyr ibonuclease (DNase)activity. A second pattern is pyknosis, characterized bynu€lear shr inkage and in€reased basophi l ia ; ihe DNAcondenses into a sol id shrunken mass. In the th i rdpattern, karyorrhexis, the pyknotic nucleus undergoesfragmentat ion. In 1 to 2 days, the nucleus in a dead cel lcomp ete ly d isappears.

SUMMARY

Morphologia Alterations in Injured Cells. Rcrcrcible cell iniury: cell swcllins, fetry chansc,plasma membr.rne blebbing and l(xs of mic(,v i l l i , mnochondri : r l s$cl l ins. di lar ion of dre Elt ,eosinophi l ia (due to decreascd cl toplasmic RNA). Nerrosa' increased eosinophi l iar nuclear shr ink'age, fragment: t ion, :nd dissolut ion; breakdown ofplasma membrrne .rnd orgrnel lar membranes;mycl in l igures; leakage and enzvmatic digest ion ofccl lular conrcnts. Ar(rn)s's: nuclcar chnrnrnnn condensation; formation of apoprot ic bodies ( frrgments of ruclei . r d

Patterns of Tissue Necrosis

\ , . - . , . r ' , ' f r . , ' l e . , , , i . e l l . r . r r r * r r c , , , , i , B , , . r i rinsran.c !n rhf ,schcnr lc mrrr . r r t l iunr . rcr rhs in r lcr rh ofrhe enr i r . nssue ind vr l ret i r es . r l r c l r t i re organ. Thcrc aresr lc f . l nr ( t r thologic l l l r drs lncr p: r t tcnrs of t rssuc nccrrs is , \ !h ich nuI pro! idc ! lnes . rbr i r t the u lder l r i r rs erusr .Al though rhe tcr rns rhr t dcscf lbe rhese prr rerr rs do norref lect undcr ly iDs ncthanisms. rhe terms.r re used o i rc lr ld thej f i lD l j . !n(nrs r rc unr lcrst r r rd bv borb p: thologrsts

Moryhology

Coasulativenecrosis is a form oftissue necrosis in which. the component cel ls are dead but lhe basic t issue architecture is preseNed for at east several days (Fig. 'l 10).The affected tissues take on a firm texture. Presumablythe in jury denatures not only s t ructura l prote ins but a lsoenzymes and so b locks the proteolys is of the dead cel ls ;as a resul t , eosinophi l ic , anucleale cel ls may pers is t fordavs orweeks. Ul t imate l r the necrot iccel lsare removedby phagocytos is of the ce lu lar debr is by in f i l t ra t ingleukocl tes and by d igest ion of the dead cel ls by theaction of lysosomal enzymes olthe leukoc},tes. Coagulative necrosis is characteristic of infarcrs {areas ofischemic necrosis) in a l l so l id organs except the bra in.

Liquelactive necrosis is seen in focal bacterial or,occasional ly , fungal in fect ions, because microbes stamulate the accumulat ion of in f lammatory cel ls and theenzymes of leukocytes d igest ( " l iquefy") the t issue. Forobscure reasons, hvooxic death of cells within thecenrra l nervous systern of ten evoles l iquefac l ive nFc 'o-s is(Fis . 1 11) .Whatever thepathogenesis, l iquefact ioncomplete ly d igests the dead cel ls , resul t ing in t ransfoFmat ion of the t issue into a l iqu id v iscous mass. l f theprocess was in i t ia ted by acute in f lammat ion, the mater ia l is f requent ly creamy yel low and is ca l led pus(Chapter 2) .

Although gangrenous necrosis is not a distinctivepat tern of ce l l death, the term is s t i l l commonly used inc l in ica l prac l ice. l l is usual ly appl ied to a l imb, gener-a l ly the lower leg, that has lost i ts b lood supply and hasundersone coasulat ive necrosis involv ing mul t ip letissue layers. When bacterial infection is super:mposed,coagulat ive necrosis is modi f ied by th€ l iquefact iveaction of the bacteria and the attracted leukoc!,tes (socalled wet gangrene).

Caseous necrosis is encountered most often in fociof tuberculous in fec l ion. The term "caseous" {cheese-l ike) is der ived f .om the f r iab le yel low whi te appearance o l Ihe ared of aeLrosis {T ig. ' l 12) . On miLroscopicexaminat ion, the necrot ic focus apDears as a col lect ionof f ragmented or lysed cel ls wi th an amorphous granu

Coaqu la tve ne . ros i i A ,Awedqeshaped k id .ey n fa rd(ye low)wth prererva t ion o f theout lnes . B , Mr<ro tcop . v iew o t the edge o ithe 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 loss ol nuclei, andan inf ammatory lnf ltraie I prete.t (difiicult ro d s.ern at th s maqn f.ai on)

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6ibl. initrs ind 6tldeed in ih.n isues rrt rtne(d in incm*d 5!runlelels ol !u.h pror.'ns, ind m.asurcmcnr oI erum twekn uedclini.ally rc s!.$ damrs. b .* issues.

S||br.llubr rerponr.s ro Inl||r!rhus f2rv. h:ve mrnt fo.ued on ihewh.teissur orlh. ..ll as , u.n. HolBer! .eit in z*.nb znd jr..*s

ntt,l!ns ony sub.dtuhrol8,n.rh!. Ar+oleh em. ot 'hG;tk ron, (cur,rrd . rdha r in ruq ,o .EJE( rn ,nLh ron t r ru ,mor rd liniurn and ,ill.orl'ds arc id,pl1y

n :nd 'ntr.nine o'ther rtnion! arc d\o^w.lauropbaSr. Aubptisy EG6 ro tvsos.nal disenion .frh. c.ll\ osn .onponenr rnd is .onm$.dtnh ,grefopr,431, nwh,chrcdlsuberi.o hom rh€ cdriJc for i,riicd/uta! dsruqioilFis.l-15). Aurcph,sy n rhousir b L. a suryi!,tm.th-.rrn n nm.s or nuri.nr d.privarion, su.h rbar thrfiflrd cll liy6 br sms ib own .oftns, tn ll1rprtu!$. nr,cdtuhr o|e?nr s Jdir< hrsl fqu{rcrd fr,,m lhe+'oolz'nn altoDLoq.,,. {o/. fomrd trcm nbo,on! fft,4'on\ of rh. rc;hER LRERr Th€ lr.uok tu*5 wtrh y,o",-s b brm;c,tdthasatya'an4 :nd rh. c. trl, .omlon.ns redi&*.d by lysdonll.nzyms. Auhphasy iinni:Ed by

ev.Er prckrsihr$nsenrntntd.pnv,.on. tf nis nor(o arcd,aroph:8) m4 resisnrt.d drnh h) rpop

hn.d ellrh,r Lr lrnn,, ions.imp. br Inins on B"$n or6ndL!.

Thr.i4n6 n lr5o,on6.an brcrl do\n msr Dorii!,nd crbohydrua, at'housl sohr tiD& rcrfu,nuidicdEd tF6on6 wrh und&{.d d.bi,s mr *.n{ wtrhLn alL a! E &,16,,&., o' m! b. -;ud.d.Liort..i, prr44 3hnul6 r.prckft md,s6nbL€ n,i.rur rt5drnB hom frc. Dd,c,t_m.dDEd hDd Ddo",d,ion. cddn indisKnbtc pisnrn( 5uch ,s i,rhonp3rti.rs hhd.d fom rh. .rmosphei. .r incul.ted

,i pL2sotrsosom6 ofmr.ophases rar d.sd.s (disus.d tarrr.

L)sosones,r.akorepariroi.! whercr etls*qu6Ermdribr\rhrc;nno'b..,,mpftbd.q,drd HeEdrrr

.Dzymes rh,r dtsade v,irous n.cromoh.ut*. Rsult in:bnorm.l 6l1.dons of int @.diar n.kh.tn6 iQ a.Irsoson6 of als, .v.r fi. b.dyd2nr :us.ptibl. rt, l.thaL Lriua lrcm such dhuta.

Indtroion (H}}.drop[y) of Smoarl' ER. Th. smoorh Et(SER) is'.volnd in thend,h.lnm otvaria!.ch.miak.and c.lk qFrd to rh6. ch.mi.ab show hyrrt.onh!of rh. ER a! .' ldipiv! Esp..s. r[n oa], h;v. idorr

n$nc€, b$birur.tesarc nerabolized ir tllr llve by the crehrcme p-1J0m,xed fundon oxidl* sstem found ii the 9ER. pn,r2&d use of brhnuEB hi& b a $r ofbt.cn...wnh a dd.is in fi. dlfr6 oI rh. drur ind d. natl bur inci.rins dotrs. TIn:daphrion ddue to incRz*deorun. th)p€tuophy) of $e sER ot h.Ddo.yr.! .ndin(osed P450 .n4m ( nr!trr. Ahh;ugh p.4so-m.d ftJ mod'filrnon 6oh.n rhoi, r"f-jit-",ifi.rtion," manrcoDpounds ai€ rcnd.d,o/. inMi.6by rhn prE q on! exanpk n.rboo ter'ch torid.. dis..usd l,r.i In addnion, d! p.oduc6 forn.d by thisoxidrtiv. f.tabotism in tud. recrvr oxyeln !;f!rRosr, qhrh cin r!ft rh. ([ .rrs adji'ed ri, om

. r rbo t r , {he r ! onpounds hrndl.d hy th. sE. syn.n. Thu5. if DdmEhkins ph.nobarbnd Iq.Dit.Dsr rncrt1s rhff ;Loholrblc, rh.y m.' hrv. subiherip.ud. tev.h ct th. .nti-

b..ruit oI iDducaon ol sFR r

Mi'qho.lrirl Atlnrimr. A!d.sb.d t,kr, mrGhondier drrrundon Fhy. :n ,mpon,inrury and d€aih. ln en. ronldh.t Dnholmic d,!diiion!, hou.v.l rhG n,y b.,h&aioi,s n iha lumb.isi-. shrF, 1nd presumrbly lundion oI nirrhondni.ro r$ rnpk , i ne uL rh rFnophin 'hr fumbn oI m,Mhondfl: D.dk.conrd(tq miro.lhondnr d..rtas. 'n nunb.r dunnr cdlutar irioDhrrrob,bb !E arcphisr. MtrEho;d.r m4,,s;-;elftmlr' ri'3f ,nd ;hnomrt lha

,ous,dri,t,r, drti..noa,nd i.ohotic tivd dk..5emer:bolic di**6 0I strtdal nusb. thc nno.hohdtidlnlotdltE', d.ks in mirEhondn.t mdrbotjf n€

Ad4h|9(4h0andhd.|o'ba0!btR.dlrw|

rsri,rd wnh iicr..sed rumb.6 of u.urui y t2is.rnchondn. conr.inilg ebnorml trnb..Cy.o*eldal Abnondni.r.Th..yr.sl.l*onconsn6olrctin rnd nlsrn ril,mha. nnrotubuks, a v.riourd *..t iftlmldi.E 6lan.n6t svd,lorh.r nonpl,ly-n.r;cdandronfiLmenrous fomsatonr,.ih Drorein5.ko cornibuk ro rh. cdluhr siffolJ. Th. .rlosLddonis impoit ni for n,ny c.llula! Iundions. inctudns

. lnfec.llulrr hnsDort 01 .@ndl.r .nd nokcuhs

. Mirhli.i oI 4.5i. cdt;rchn durc 1r.g., ..tlpor,rirr, ,lierinsunhiq up end dcsn). THnsmission of rtll{.l| 2nd err<xnaallul,r

. Miinrtftn.. of mahanical $rtnsth tor i55u.

cdls ,nd rstr6 i..pond b .nvnonm€.t t sis.tsk.3., she,r sca in bk,od y6skor iD.Fdtd prtsucii .l'!an) by con$antly rtmad.lins dtir inrac.llular$:ffotdjns. Abnorm.tnm of rh. qbskd(on oaDr in,vrri€ry oi pitholosic $1r!. Tij.e abnom.lri6 har 6.mn1i.s.d s r .b.ormat aDF3rrne 'nd lundi.n oI.d15 (hrp.nophic cardiomyop,rhyt cl'.pEr l l), 3btr.

:nelks. d.fdi!. ftllldonomn. dr inr..dlula ccuinuhiicn oI 61,!irh,nrnri2l ,s in ,coholic tiver diksr (c[apE 16). p4.o.h.rions in th. ol8rnianon of,nrtubuLscane **erility by ,.hibnins .p.m honLty, s uell s d.fnaiy!mobirn' of!irr in,h. 15pnrory.ptrh.t,um, Kat ns,n!hronr nfld nn5 d!. ro 'mFrr.d !qEnc oi rnhrLfd6.ckia lkrtuseEt, or t\. idnotile dlir, stndrtdzr.Mtrrcrburs,i. rrn,.s$nnrt Ior kIL&rr m,4En,'n,nd phrg,r)tosi5 Druss rhr prc\.d m.i{ub!1. Fly.m{ft rron 1e3...okh,!,ntr,r. d.fu

€n' of mroph:g6ro*ard ui,r.ftyi* unh subr'tue fru$srdd@ptsit ,h,*o+osis .nd inflanmrtion. sii.r hicrorubul.sr.rm ih. mnoic spmdl.. dius. d'2r bild b microrubuhs(e.s.. vincr rlk,lods) ,i. 21o .rtiDrotileHtive ,nd m.ythercfor. b. u{Iul .s.Dtnumor r*.nB.

Iru r,t rrSlbclkl$ Ahdddr i. <.ll hl{E:Elld ol r4udoBA!.it oi ds.;cl6.nd

SoD. iorms ol ..n injury 'tu* prni.ut.rolgimlr6 ,nd hay! uniqu. mrnilsbriotu.. ,4!rrra3'r In nurienr d.priv.d alh. olsanellsn. .nclosd in vicual8 thar fu$ with lKo.on6.Th. are,nclI6 ar. digsrd bDt in .on.;as indi-s.ii6l. pism.nt (..s. LNtusjn) rh.ins.t l|.rntl'y of strli c.ll6.rEd to bnrs drtrrcn.hboh?d,n,h.5tR 5how hy!.ndph, of (he

meh,ntrn h m.vm,z

oAdnr - .d hilrartu!! rd^&er6

. Mnuhontrkl albatioas: Chsrgs in .

.umbri, si4, and sh,ts oI mirNhordii ar Fn indiv.c ad{t iions rrd r.$on$ to chrcnic i4ury.' clioJtslsal clrd,.rbzr son. druss ,rd roxinr

:isnbly r.d lunaions olcyt6k.l.bl fiLmens or rcsfi in .6nodal rau.

I rEctatttfls of cEr.L r ruRyNow thr s. h,!. dieu5*d rh. cau$s ofRllinFry rdnarasis.nd .n no.pnotqic'nd tun(oni.orEtaks,w. ie{ consider in norc d.r,il th. moreutar b.sn otcdl i,iury rnd lltd illun,ar rh. impoit nr prin.ipt.!wiih r r.w krr,.d "xanpr6 orcommon ryp.sofiriuryTh. bi&hrhicn mehanisms linkine my sivm iniurywith ihe rcsukiq c.lltrlii rJ Gsu. mnife$.iions,iecomplex, ifueKonndEd. .nd ishrly nrrwoytn wnhmrny nhc.lluh! mdaboh. paihaft.n dil6.urt r pinroinr 3Deri6. mohculrr akd,rionscau$d by r pini.ular insuk. N€venh.lsi nlcrals6d,r prin.ipl.s :r. rct.vrnr ro nai f.ros of cdl

. Th. eltulo ft:panr to i,i',h,' n'nuh d?p?n& ohthe ,p? ol inj,4, it' dyn o\ and * rfu?7ifr. rhus,low da*.aI!xi!5 ora bn.fdunrian.Inchlm; navLrJ $ Beribl.ellniurx wl'e.:s lars*toxn dok;

sult n trrcv.sil'r.iniuq rnd e1ldeft.. rh. a,sq@ds ol dr k)u,ius n'autrs d?p?h!t" th. ttp.. iat"., ddnphhnt. cnd zdan tua.ap

at th. inPnd .,r. rft en. ntq\ h's ! tr J ftqrnrourona d.tsndins on th. c.1t 116 thun *tuEdsk.l.El muele in dr 1es "<omnodaks .onDltiri$hemir for 2 ro r hou6 ynhout rak6ibt. inlury.wh.r,s c,rdi2. muste dies rfrft onir 20 h t0nintrk.. Th. nunnio'rt (cr horhonat) naiu5 ca, rlsob. impon,nr. d.ir), ? sj.osen.rcptd. h.p,r{rkw,[ ror.r,rc n(h.mn mrh bflkr rh,n "nr ${ h]!run brm.d n! hrslu.or molRul.. ccndcnty d.tcrnin.d diy{siry i' mdrboli. p.r6way5 can .Ls b.'mpoftznr. For inr2n !. when expord rc rh. s1m.dok or i raxin. individ$ts who lnh. yarianc ins.n s .n.odrs crtchrcn P 450 n.r crabotiz the'oin ai differcnr fira,l..diir b diff.rcnrourons.Mu.h.ffofl is now dir(kd tosrrd und.d.ndircth€rot. ot Fnd. potlmclph',m\ m (spon*. ro d,,uAi:nd rnh5:nd in dn.'( 5u{.otibitiF. Thr sudr oI5uch inrmctio,r ir.dr.J Dh:;ase;omis.. c.tl inqry ks\ns hon f,rctiorul dnd brrr.nnalcbhandhn' in ote ot rat o{ sr{al .seanat dqttat .onpo"nB \Fie. l-16). Th. Do$ mponriri:4dr or inird.us rimuli aG lt) mne[.ndria. rh.sita of ATP s.r*arion! 12)rtllnchbBn ! on *hl.hrh. ionic and ormdn hoi(Ebsnolg.n.llcs dtptndi 1rl prorin s)nrhsiq i4) rhecyt6keleroir ind (t) ihe sndic app,i B oI th€ cdl.

Mr r - dr ntq .d M d^d4hc

tllnnI

- l II I

B. Mlbdod.br ibiE" nry kd b;;;bh;iryJ;-; i;;ii;;;;i#j

ATP, ,h. .n.ry) 3rcr ot e s, ts ,rodlcd m,nn bva\id?,n. ph6phootrnon or adtro,ne dDhos;hriIADP) du,inc rlucion oI oirsen in d. d.d;on ;,nspor syirrm "r mndhondna. In rddr on. ,h. rtvcothcpflhv:,.rnE n.tur. crr '' rh.ik.rc.oroxv6 u;inrslu.,* dtrtred drh.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.,odn5 ks . qand . ) t i sG $ rh , s r t : k r e t y .o tF ..rprcfy i..e.. rh. hs) r. rbk ro 5urvilr to$ of oxv!.!ind dni.r*d ord . phosphoqh on b€nd,hr;_arc

phosphr< rn rhr rom of AT? r(qu,red far yinually ill syn$eac ind dcqriddvrp r r . s ! { i r h in ,h t . . l . ' ' ( t ud , i sm.mbmnr , ;n5Fn .

n(6rry ror ohosDhot,Ddnmov.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\ orpor.s'uD. Th. nd s'in oI5otur. is,.comDanird 6vrio.o$di. eir oI qn(. a6ms @ .41/,s {j

! Th.r. k : ompdn6q, dare in ,tudobn sty..'r5r In r .lhpr to n.'nhin rht et|n .n.rcve!ft, A5r.onr,tu.nc,,nr3e !h, gtv.ar.n(o;rft Bprd\ d.ptd.d, .nd tidr .fld ;d;Eu|JAr.idins to dri.lid inr'c.llutar DH md d.crikjactivity ol @ny cdlul,r .nzvmc.. F.ilrn olth. C., p'-nte2dstoiniuxolc.l.wnhdim"cins dftr6 on nun.mu. c uhr conmrn6.

t Pr.rd8.d f {trfn,ns d+knon or aTp (ruer,a. tu n] d B, upran ot th. prct an s

or ribo5"m6 fom th.rcDsh.ndopt,*ic r.ricutum IRER).nd drri,ion ofpdyen* nro honoen.q wnh a co6.oue rcdrtion in prckin synrhsis. utrim.klx rh.. i; iftv.Bihl.d,mis. b mn(hondi,at rnd teemrt mnbEn.s,

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cyro$li. t ..i.iuh n nom:lly n,inbintd 6y AT?depsd.d ca lcium r: nspoftr ar .orc.r r onsfiar3rc,s nu.h rs l0,000rnes lower tia. d..onc.nt,,Dn of.ft,cdltrh.rLiun orol*quaErtd inrlrllubr dnochondill .nd tR sLium. latumia .nd ..nain !,in5cau$ a! increa* h cyGolic qlcium .orc.rnnion. iniarlly b.c,Ds of rcl.rk af Crr' trom ihe intrftllul,rioi.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$ potenmllr ddd{ious allular.ffrnslFl8. l-19).Th.r.n?ynsindud.phGpholipirdlvhi.hclu! m.obr.ne d.m.$), prctes* {-hich bEaLdown borh nembran€ and qroskd(t porins),cndonucle*s lwhrch.i. rtspo$ibl. Icr DNA rnd.hrenrin tisndbrionr. rnd ,Jdo!in. riph.sph:m!6IAII:*5, rh(.b) hrn€ninB ATP depl.'ion Incer.d

,p.prcsn, by dnN z.iv,bon of.spsa ind 6y ind.i!ins nno.londri:lpqhc,biliry. Th. inpon.ncc oI ci.in c.ll inlun was esablish.,l bv rh. firdin! rhr,l.Dle!ingexna;eliul,r G' d.hys cdi de,rh ilitr_hypoxi,,nd

A.armllatlon ol Ory9.r.oe.ived FEeR:di.ab {Oridative 5t|6)Frc. r:d,c.ts,i. ch.mi.,tsp.da wrt , sinstt unpiirtd.L.r.n in rn ouE orbnal. Su.h .b.ni.n r.t s ar.*Emdy un*abk rrd rcr'lily nctutrh inoqrnic,nd

ddhb,i(ldBo|rFdsAreeeigietipigptnl'

D.rag. to ilito.hondriaMnahondi. aE rhe cdlt supplicd oI lif. s!$rinins.n.Ey in the fom of ATP, btrt rh.y in i.o.riri.i phy.^in e injury and de,rh. Mnehondnl .an b. d.mas.d byincr.{a of .yroeri. ca-, E.div. oryen sF .s ld$cu$.d bdowl.nd oxys.n depi!,!on. d so rl'ty r.snsnive ro vntu'lly rll rypA ol injuious nihuli. irclud

No maior otr+qu.nc* of hnchondlial damse lFig. I-13)l

. Mndhondfil drmrs. often iauk in rh lom1nonof e hlgl.onducrinc. chinn.l in ,h. mircho.di.lm.nbhne, ..lhd rhe nnrthondrhl Fm..biliry kn-sid.n por, Th. op.nins of ihn ch$ncl l.ds io rh.bs of mnEhondi,t membran. pordii,t and pHcnaas.s, rtstrtnnq n [ritn 6l diddti. prosphotyh.toa cnd prsn,,i datdaz d ATP (qtm'nrnns n

. Th. m(chondri, ilso .onDin 5&r.l Drcteinsrh,r ,ir c,p,bh at 2diy.nrg apoFoti. p3ihw2r,includins ./khtuh. . khe m.jor prckr invclv.din d<.rcn r:nstsn). lncrs.d tsin ibi|nr of ih.mirchondrirl n mbbnt nry r.sult in l.al.s. ol rh.*p6t ins inro rh. .rrcor .od de,i, &r, "toprosi Thus,.yi(hrt,h! . play! . k.y ,lu2l ol. ,n cdl ruiviv2l 2ndd..thr in i6 norml lc,mn insid. nnchdndn., ft k6snti,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..

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@

t . *E-@s@

HF@

ft..o. or rcrdEorye.i 'Bi6 (R6) har m!ry or n @iEdd ro {tsrdid. loj)

3,o, b1 drndn d md ikft! ro d.r rh!c,rc orrzd Fldd ddai Bi, B: b & r { d d i d | } ' @ n o d | g i a o l

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

hllr tu rojor r4roidn liryna d!

n (etk 4 aldtyrnr(I nucl.,c a!id5 n well* a \:n.D of! ut.r Droteins,nd ripids. In rddiinni fR bdn.L intrirt .i!t,.cdrrync r..ciioE motlcuks rh,r r..r vnn tft adicri,ir n tqrnmiv.d(d nto ne Dd'cn5.rhui D&D.crunrrh. (hrn or damas.. r.,Ju. orys., "p-,;, tio.-,,;r iyp. ar oxysen doiyld fR hdigt whose rcI. in crtl'niuo k"ell6b6lsh.d Tho r( rrc.lu!.d normalv m!.lk dunnsnr,{hondnr rts"ahin rnd -{E c;rrion. bu' rr n. d.sEdd rnd rcn"\ld bi ; undd.dn srtem' wh.i $. produd,vn ofRos,na..*5ai rh. saveryins rn ms $. in.#ctiv.. rl1t 6uh n,n.xa$ of rhd. fc ndisls, l.adim to a .ondnion .al.arEitltE ti.s_ Cjll iniuq in maiy circumsD(A'nvalv* drmrsr by fc rrdrcd.: d.s snu'dons irctude

1dieu5*d b.lou). .h.mist inJEd':i,on mED. roxl$ellulirrs,ns, m(rcb:t rilrnsbipf]sqr^ rttG:,ndi t r j t r . f l u r y ! ' u j d h ' l n [ ' m n : | o 0 d | 5 '

Th.,eunularion of nr adicds r d.unin.,l bv ih.;Earorpddu.tionrndEmolallF€. r-20J \r!.p r.n.non!,F Espon'bt. r.rrhe8da,rn4 d h4 tdd@k.

r Th. rcdudion.oxidaiion l.doxl r.rd6ns that Burdufln8 no.mi mnmhondnrl fr.hbotisn. Du.iru

(!r eumol(, ssk \hr .*ks isFqrnri,lrrrd(ed nniGhondnibr'h..ddrionaf

th. Drcss. m1ll,m"uns otro.r ntem.d':k 5rE,e5 ri p.!saE,l bvp.dsl rcdufinn or oxy*!n, d;f rn.tud; rFrcrd:ndn,L loir, hvdia3d p.fid. lHror). rid oH.

vr do,r. fE dfr'rcil dunns .(D n mriedrut;rreadlons 2nd ihercby.:i.tyk Ift rudi.at formition.sf,h. F.nto' ftdnr lt.!+H,o, j Fcr + oH.+

! Th€ .bicauuo d rud,inr o{cy le.s., ut,Erot.rrcnr, \ ny(). lonirns Edir'ion !rn hrdrotya ur.rii'a hldro\rlLoHl and hrdrcc.n iHl fre hdioL. TXr.n4mii( n{,b.1'rm oir.oFno,s.h.o,.rts(..s., crrbon Gr.chtoidq * tai.n. I.tl,naation, bft,u* t.e mdic,k rE Drcducd bvl.ulcytes dit or.r tisstrB he Cn:oF lr. Nitric cridc lNO),rn inpo nant . tirni.rt -.db ro.normlly rnthB'kd by r,;nety orcttbD6rlhrDrcr2), crn rfl 13 r fk cdi(Jt or !,n b. .onrert.d;bhighly rcadrv. nnnt sFls

Gll, hilrdr(lop.d naq zer,,n,,h, h, tno!. h2.rddral and 'h.i.by hnm,. ,nrury Fre nd k rEinh.cnrr urirbl. md dery sponrnsudy. Th.rc ,i.are ev.r,r ion.nzyn i. and .nz',n.ric sysrDs rh,r.onr,b,r. b inad'v'doo of fft ri/i.at r.ediom {*.

. Th. hrc of iFnmn.ou! d(ay or suDrord.6,cn'66n'ly n(i.&d bl rh. :cucn af,uFordr d;muh*51 toDrL tuund m n iny < qp ; l 6h t , . nqrh . K rdo i ro ;2H - H ,o r+ O , l .. cruEdiune lcsH) p4o\rdee il'niuo br crrltnnr fEe+rdor bft;tido"n, roH.+1CSll - lHlo + CSsr ls\uD,n,on. hmud,m(r .th.inrlelluh, ntio of aiidi-d duhthion. ICSS(jl rortd(.d sluiathioft (CSH)i5 r rtfl(tion of ih. ondr!y. shk of d. ..ll an'l rn ihrotunt rsr.n ol r!. .e rab i$ m..tabolir t. r.dicats.

, dc6 the dtE .dation of iydr.Fn pdoxd.l2H:Or + o, + 2HrO).

miff E, A, ald C. .nd Fc.locnel mr lithq bick rh.romdo! of fF adicrs d s*ds. them d.. ih.y

. As m$tior.d,bov., toz .nd .oppd ei.arzlrtrh. rjormrion of Ros. The l.vds of d.* rcrivemdrl. .r Edued by bindine oI rh. bns ro *o$seand tnnsDod Frat ins (..*.. Ensf.rin. ferinn.l.dof€rn, /nd ftrulopsm,nr, rhsebr d(ls'nc rh. roF

ROS have mny dlves..ft b on c€Is lnd hiv. a.nb.en inplicd.d in &.ivaion of cdls by i vri.B ol phy'idlogic rimuli. Hq.v.4 rhirt €dioff arc tsnicDlidycwlnr 6 .an ntw! h,llidkA la h.e adi.ck tk Fi*.

. Lipi.tt roriddtiaa af nmbft, .Do.bl 6ondsi^n.hbG!. pol)unsruEr.d lipids .E vulnd,bl. ro.ftack by oxys.nddi!.d ,r4 ndic,ts_ Th. lipid,ndicrr intfurions yi.rd Froxides, *hict' '. them.nlvaunsabl..nd rcad,v.,"rd,. rurG:hlyticciar

. (ns hnrt4 ol p'nt.ur5ultydivt mrdEEd prckL' *6, Lntrn& Guhrns,n

Fc{:diel rcrction my.hodnetly suk p.lyFp.

. DNA t ace,hror. Fi.ebdiel edions srirhyoin. in nucl.ar rnd niu*ondrial DNA produc.nnsl..nruid br,l.5 su.h DNA din:s. hn b(nmprlrkd in <i d€rh, isms. ?nd mat€n:nr rrii

ttelect In il.nbrane P.me.bilityt.rlr 165 of *i.h{ ftmbnnr p.trob,tir katlns

ratuE vr m6r fomr ol <ll nruD k:ftphFptuys)The ph,Di mrm6En. .,n b. d.mia.d by ,rh.nB.v.riour n,cbbi:r bxilr, tyticconpLm.ntcomronens,rid , !eri<4 of phFut ,nd (h.mraL rFnL. s.vrBth*h.m..l mtrh:ntrm! m4 .onr'bure io m.mbEm

t 7

. Dut.Lan ph.sOhobA ,nthe'k The ,rcdmiooof ph6pLolipids in €]ts m,v b. rJulrd urr.D.vsrh.( n a Gll in ATP levels, Lidjng to d6rc&d enersy.d.p.nd.nr .nzym1ft ,c.iyni.s. Th. rcdued phasplo

.ff€d '[ a JI n.hbr.!.sindudi4 lh. mn€hodiii ih.n*lv.!, rhus .x.ft.

. I|.t%.d phosphnlip'd bt akdoan. s.!n .tllmiuy r "$Gnted wiih mcrc1*d /.gr.d:non ofn mb.an. phGphalipidr, p66.bly due ro ectivrtionof.ndos.noxs phspLolipas by rncrc.sd LveL of

. ros. Oxyc.r t* rrdftt sue injury to cell membr.n.s by tipid tsroxiddon. di$u$€d.rrtff. clb:ldtul db,omlitEs. cytoskeld2l 6lh.nbsfl. iMncho6 connetins rh. Dt,sm, n.mbnn. rod. ..ll lnErioi Adrvrion oI proEa$s by incrcakdcllosl,c car. n1/ cau$ d:m8e io dend6 01 th.

. Lipid btahdoa ptod"*. T\.r! inclu,l. unarenlild hE h'ry icd!. nrlarnr'nr, rnd \,aphoiph"lLpids, .r,bolk orcducB rh,, rrt Lrou ror..umut?k in,nrqrt:d alsfi aut! !f Dho5DholDddcsEdnion Tr.y hiv. : ddlrsld .fh:cr oir manbr.,d.Th.):re rrhtr inqtrinro 'h. hpd h GFr ot,h. mdbEn. or.:.hrns. wrt' mrmbtsn€ pho5Dhclipidr, p.knirll) .,ueng .hans6 Ln p.rm.rb'ltry,nd.lg'ophFiolo*'..lrdarions.

Tht m,&,mpofttrersar h.mbrrft drmsedur nscrr,niuq ei. . ni,*hnnd'i.t n.nbdn., 'hr pG5Dlm.mbmn ,,nd n.obnnes oI tysosonn.

. Mnothandnat nmb E l,es,, As di$uscd2bov., d,masr b mn&hond t meDbrr.s 6utu iids.rsrd piodudjon of ATq cuhin2tins in nEosiqdid trkJft llf prcre'B fi,' r'es.r rFprotr. deerh.. Ptdsd' 4erbrale 4,44. r,hrmr nehbEnrdama$ Lrds b 16. oI osnoic b,l!r..rdinflux oflluids rnd ionq sEll rs los ot cdlular conrns. 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.trhu .nzymB inro rh. .ytoDl.sm rnd ..tivlrioi oI the&'d h,drclij6 n ft n'd'c nr,!.lul?r pH of rheinrurcd ks. i*h.m(l e . Lrs,{,,ms conn,nnNr6. DNrr! prorcraj stuc6dai,, ind o,hs

m6 t .ad r n , .na .mn. dis6tion of cdl compordb, .nd lh. alls die by

Dan.ge !o Dl|A and P.ot.in.c.ll\ ha( m(hrn6ns 'fr KFirdil ihk drmrg. r 'oo 5-{. ro br lofthd ke, rhnmdi,non intury or oxitlative $6.t.h.cdl inrid nslunid. prnsDn Jd d,.! b, rp{'ok ris{.d by 'momFny loll.,lmo,.'ns.*hrchnar b€Ih. rcsuk of,nh-,Ed nuurcii or.r.nn r'*er 3u!hi 3 t r t E d K r i s ' n ! e A 6 . n r h r r ' 3 m i d ( n ; l u 4 r j per ry au* rpopro3lj 'h!y n. d'*u,qd hEr n rh.

hjury redi{ 4ei s4

la

I 'Uflf iV

L<n-kfr of cdl niury. 4,P J4J|ry' btLg. , !!Iw J.+Yd-

. Mibchoa&id arws. AIP dqlLrtd : i.i,tt€oI se4yrl.pad.ni e['nrr tusions + DltiDrery, nd6'q und.r lm. .ondnioq t..t4. ot

. I'nlB of aLir,: riwnt oi 6zyr' d^rdrm,e. allul.r comporcnts .nd n.y 'ts Eiss.r

. Acdr.t'tid 6l urw axwd $?e'.s. .ovl.r.n, hodjri.ni.i of.. uhr pmru5j Lp,d5, nu!t.r

. tnd.@a tmabiltt .l e.lqtat nmbrr"6:my affet pl,sm n.mbnn., ly$sn.t m.n-br.n6, mitchandial ftmbrrnst rypiglly .Dlmi

. ^affiahtiot af &tuE d DNA and hllotdd

EI fPrI5 0f Clu |l|{rtYAt|D rEqosls

Th. tund1on,l .on*quen.s niy b. $v.F ar ihijn.s.. For in*rnc., h.:d musL ea60 smnds ot corcmry (tueion. Hou.!.q to$ of6.,.djrry dc nor n€i cdtd.rth. rt lyFxia co,tintrs.n 9 l 6 i E , { D & P k ! ! g u x t l . qwnh bsolmicrovirri rnd th. formitian ot "bt.bs" ceFis. r-9r. Ar rhi5 ime, Jh€ cnrf.tll and ns o@.dl.!inrehondria, tR) ,ir n,i<.dty s*o en, wtrl iniE.sd..n.mnations or srEr. sodiun. ,rd .hloride ,nd :d(rcr{d lonrhrEion oI Nir$run. , 6?., rE orta,alt Ltth-. dLtuia;atak kAt;bt.'

II inhnn t 'sk,q nEr-rble nitt dna neoa'i:.e. krcv.slbr. ioiury r ssi2i.a wnh sv,.smll,n8 at inchond'i,, .rmjv. dmrc. ro Dlimrm.mbBn6. ind 3*ell,na or |lsom3 i!4. h!. !9rMassiE,nnur oro ! u;'nro ihe !t[ hr Go; D€5rhn n:inly by mrtEit blt iF rs,..lrc;ndbu6: 16.

b$ty by d.a$ otprcrpdproric moleul.r fioh t..kv mirehondnl The(rlr5 compomii, ,ft |rosrcstrel' d.scd.d, and .r.n wrde.prt:d kaL;s ote u[r.n4me5,nto itr..saelurf !p{e. Iinally, rh. d..,1 elk my b.sm.rcpr,lcd hr ha n,,!6 (,mNfd or ohosDhohDd5 ,nrh. rom orm'dm riBd.5 rh.,t rR rh.neilhd;hrco.,rordb) kur.(y'e, ord.srJJ?d iqnh.r ohryn;5

l*ieni..8.perft,rion InjuryIt cells ,rc rtvd5ibty iur.d, th. E*orrtion ot bloddflow.r r.$rt in ft i..ov.a. How.v.i und.r etuin

.unenrc.q ih. rtsbGion oI blmd flav to ishenrbur orh.fl ( L rbt. ri5su6 rtluE, prrudou.,ly, r.\4*bakd rrd r.etehd riuDLiif lh. lo$ of els ;z r'ddl,o, ,o tr.p thd M nrcw6ih, d'aed dt th. dtt oj th. t\h.nL @Lod.. rhb\o.el| d r.h.dur.pnratoh nBry 6r.t,i,i,tt,,mpoFt.t prees ftr m,y .ondbute si8. i.,nrly b issued2naF in myEfdiit and erebr,t hfdions.

s.vaal D{Mnnns nav ,rou{ ao' rhc .xrctrb2iionof cdl miury rcsultins fr;h EFrlusicn ino irhmrc

. Ns dr mcc tul b€ 'ntrri'.d d!b! 'nr.iid *rn.n'ion or R oJ rrom Nr.nchr dn rld.ndorh.li.l ..lls and tan inFlintinc titrlcy;. Wh.nrhl supplr of arys.n is increakd, tl.E mri b€ r corr.5pondi4 inaq* in . produd on of Ros, 6Flirny b.our mtrdhanJnn drmrft had5 rctu.mpt.re rcdud.n ui oxlsen, ,nd beru* or ,h.:don or o\jdr*5 in ku!&}16,.n,lorh€tu kk. orprrc.chynll cdh. Cdlul,r.nioxidr d.f.n* hEh.,nnns mar,:ts b€conpomi-d by ishrhia. hvorina tb. :ccunuliti.n of fF. mdidL.. rsheff iiiuD is isri.rd yith ,r&,e'1o,,whrh mr inr$( w(h r.Frfuion b<:ur ormlEs.d innu\ olhut()re5rid pL!tu erokrG. rlltprcducb of2dvaFd l.uldyr! frav..u; rddnlonaltissr inrury lch2 d 2). Aaiv.tion ol t6. thrtn.atqs., may 3ko coniribur b ish.mi, co.6sionr!ry 9om. in' boJ,6hrrr prornjryrc;.6trmi(h.m,. r,iu6 t,{ unt'owi rt:!n::nd *hei btdd

To illusEar tll..volu o! an'l biel'tiic.t neh,nnh!orcdliniury, w..oDdude ihis s(n'n by di$using s.mecomndry 6n{nised d"nd6 of rcv.slbt. c.1t injury

lt hemi. and tlypoi. tniuryk.h.mi,,ordimi'ish.d btaod floy ro. tissu4 n th. mo*olm.n q6. ai en iniury in ctini..l medici,t. rn.onFa{ ro h}p.!a. m whtrh oq$ senehnon byrnaeDbl 3ry!ur15n an.on'nu. lalbcr t6! cl6..ndvtnrn by okjdanv. prd*1yt, isch.ni,,hd comDromie:rlr d.livery oI strhnEi.s for sly..trsis. Consiquonr

!su6 ,Frd poFnii,l subsrars ,r. .rhaun.tl orrl'i6iEd by th. ,ccumubbn 01

mchhvrn6 rhr Eoltd normith k (mor€J b\ bttldHa' rh.rt'orc. E ^da tnp6 n,e4 jasq i,n do6b?dir. The bici.nic.l :nd nruc0r,t ch3D!6 rnoxys.nJ.piived .e s -.rc discursd in d.tait .anii indrh! aquene or.v.nr s ft,pnubrd b€lo*

Ihe rundan.nhl bnh.micat lbnormtis i, hymi.elh th,i rea& to cdl iriury n rdurtd i"r.;€[ut;; k,mn,{ of ATr, r I .onrqu.nc uf rdKd sooh of,nrr A! d.sr bed rbo!.. t!$ of Arp krd5 ; thehrlua ol qdy ddsyd+e4d.at a,] st.ns,ta.hdta? ltl tM punps lerdhs tu crt 5w.t'ne. rnd

rcn, hn,6Leicr , byr.duld 5hLn'ns ror drbohrdnns 1. ts. by 'he p.nod crnd thir'rn), wtrh r(murnit{ ofhcn! rud, rhu5!'Er'ry th. inrac.lluhr pH\ .nd tJt flau4io. in

flos r rtsumtd, ..mplciot prori$ bin'l ro thrd+osn d antihodn!..!e activ.kd. ' nd .x,arbik 'relliriuryand i!flrmndrn.

(heni@l (loxi.) Iniurych@ic.ls indua atl inify by ont of No s.q.ral

. sone .h.dkrk rtt di4tly b .o,binnE uith r .nnd nob.qlat !'nporent at eelhht otpn L. F.lex.n p h. in m.rcu ic chtoridt poison,ns, h.(u ry bi.d sorhe,utnrydry sroup!ot,r,ff crl m.nbnne pcknr. lasin! inhihirion of ATt.d.tsnden kanspunud in(.ed m.nbmne p.mei5it,rr. Mdy .!ti,r.oplastic .h€nodd"pt'tic ,s.ni! ar{ indue cdld.magt by dnR cyron;. eff($. In such rn*,nes,rft srtdb4 d'dar. is ssi.'nen b! th. t lk tlint 'n,obsoft, exoek, at bndnncte th, a,nt,aunds.

nt4,.a t bblastatt cdn . bqt 4u! b. fi,.t ,o4v.ned ta 4'.hu to'n-.tdhotits ehch thea .d an tuts.r ./i I1)n mtd,ificaion is usm kdompli.h.d ty rh. p 150 mix€tl-ru,ction cxi&*s in d. smooth endopt.smrc rcticutufor rht rild,nd ods oB!s. Ahhou*n d. mhbdnamiehr crur mrmbiine dim,s. rnJ \.ll niuq bt

n,l lipi&,,he m6rinpon,ft mahannm of cdl ,nitrry invoh.s rh. torhnion of fc r.di.ak. t /ro, ,rrd.bLniL taa]!,.lhich -as ukd widely n ih. d4 dcaDins irduf) buris m* binn.d) ,nd $. anate.sic aetuntnott.nhdong in rhn c.Esory. cct , lor .xrnph, is .ony.n dt, rh. hxn frce Hdielccl, pincipnly in the liveiThe fre radlcrls c,u$ ,uidararytic membnn phcsphotipid p.roxi!,ion. wnh cpi bekdown of rL.ER. ln 165 rhrn l0 mnuies rhd .xFsur. to CCL,lheE is a ddft in Ldpltic plor.in q,nth6r of€nzyn.!rid prr3hr Fftinr wnhin2 houu,3k ,ngor,ht lntu,h m,r,ph5mi. rcKutum rnd da!*Do.nor ihleo* lion tn. smoorh tndoDlIEi. diculumh:ve NurrJ Th.r n r.duc.d lipid expon from rh.h.p,rNyt q i.2 r5uh of lhcn Ln,bil1ty io synllaiarp.p!.t in b tom .onptex6 *nh ristyc.nd.s 3n,lth.icbr fa.ilr,k lipoproitid s(Eion; th. rcsult is ih."Iatq liv.r" .l ccl F,ierins. MnEhonddil iniuryrcllo{s,rdsubs4u.ndydininnhed A]}io6 Esult'ndrfK € 'on n;nrp.n ind prcgrc$ry! (ll 5rell'rsr

,JrmaFd by Lrt,rd.hyd.! pddu(rJ hy rip'd Fjo d*,on n 't( ERTh.tnd6uhqn b..alciDn nfl ux2nJ dlniuallyell

I |'oPlosrs,{potrdk n 2 pnhy.y oI cdl d.rtfi rh ninJu..dbyaiishny rceulartl suicd. pm*sn in which alls d6tin.dro die ,ctiv.rc .n2yda c.pabh of 'l.gidns tl'..1115.own nu.r.ft DNA and nud..r:ndcybDt,smic p.orirs.rhg!.ds of lh. apoprotic rtl1s rld b!.ak oft. sivins fi..pp€amnc. rhd r rsponlihl. for rhe.rme l,r"rrdsti"fllhs olf). Thc prasm. m.nbnne oI rh. lDoForic dlrmiins inbd. bui ft. m.nbnne r rk.r.,l io luch a qay

rh,, ih. rtl1 rd n! 6asm.n6 b.come avid blgds forphes€,16.Th.deadell nrap,dlycle,i.dbelo* jB.on116 hav. kal.d ou+nd ih.rttort .rll &.rh by rhislrthury des nor tlnn an indam4roq rcaction m rh.ho*. Thu\ .poprcis diffe^ fron ndosn, which n .hf.ddized by los of ne,nbrdr inteln( dzymdi! drs.'aon ot aLtr. hit,3e ct.r utrr !frn15. rnd tr.quen, yr hoe rtFon Ge Fiq 1i rnd l:bte t-1. Howd.(lpoptosis and nercsn enetin(.mxnr, ind rF,pn\irinduce,l by en prdolosic *inuti m1y proeGs ro

siiuenons, dk ab dimin.t poEninlly h.rmfulcdls rnd..lls rhr hrlcou ived lhdr ukIuln s. k tr ,te, a paihotosic .v.nt*h.n rtft 1r dflased b.yond reprq 6p..nllv wh.n$c damac..ffec ih. cdlt DNA or prorin! iD rlscsituarions. rhe trrcprmbly dime.J d1 k.liminai.,l.

Apoprsc in PhFiokgi. sirurioBD"oth bt tpopto3i' t a noffil ph.notutur that s.e6to .li,uak elk ttat . rc kns- 4..ta1 and to nain.bha,.d4 ",hh{ ofwno$ett pop a,ons intsu?s.ItG iEpotunr in rh€ follo*ns physio los,. lnu*iq s:

. fh. ptovann?d tuatudn,n ol..tts d,inE nbno.ss,,$. indrding inpraninion, ors.n4eneri delelopndnrrl indution. md mdanoDhasis. ftr itrn"prcsnnm€d Rll d.,,1" *r! lrieinily oined totl.roit d.dh oI 3ptci6( cll 9p.s .i defin.d rnesdunne rhd dcllropD. of3n os1 B"n.ric G'n for rhis panem ol d1l dtrh. rcs.dl.$ofth€conkxr, br r i!.ft.D used inkrch..s.rb! wnh-prarinhld..ll d.arh.". ku,tqho4 of tanotu d,t."d.,t tissr.s utanh,,one d.ptildnn, sn h x d,tt nnnr atl b'eak.dow. during rht nd$ruar.ycte. ud rcsirsDn ol rh.

. Czll lo$ in ptoli[doinc a topubhn' s$h as

. D.ad of alls th$ hrv. *i.d $c; urrul purp.r,

lnd r)mph&y6 d th..nd otan ind.* snu{ions,.ells undnso.pcptosn h&:us thryaE d.priv€d of n(a3zry luiiyar sisnak. such is

. Etinituti.r at natdtnb h.,,ful ltttzddive 1\n-pro.r't J, .nher b.forc cfufie '!y hay! .ompl.tedih.n matunaonj in od{ io prevenon \ ovn dsu.s (chaptn 5). arl d.oth 'd4.a1 by .ttob'n T |tntho.rts. ad.f.n$ m(h nm r*iini yirues and &mo6 ihars Bto kdind dihi!& ynulinf€d.d rnd n oplis

Apopb* in Prd'ologk Cond itmsAnotbrs.linut?s ..lk that dre !.r.r.allt alt red ol'aiuted be|ond q.n urhout ctrnns a 3.8re ha! rta.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

. DNI /,zqs. Rrdi, r,cytoioxicrndcanardruss,vDvla!,rdrnae€

DNA. etrh-d,Ed ) or \D pru.lu(reir d h{ -d sl,.rh ,h< mNri 'h.

r I r& r^n f t i n !nmdhrn i5m5,h i nduc . :N ! ,6b .lnlh.rsiiudions,clioinanonof ihecett mav biilxft ralrmaive rhr risk'ns nddois r ih. danaFdDN^. trhnh mn poeE$ rc mit'sDni FaFbl'iiI on. I hN 'nrunou!,nmuti .run rtuDrci5 if rhr f3u/ri! mild, bur l,R! dons or rh. $;i*i.uli --h hi(uclrll Jqrh liduuo!rpoFo,rof .:n..i clr 6r d6 Ed rffn of.h.mdhsiDtur!h,rh B!,k br d,hrsrs DNA. A.,un,tatua ut ar{otlta! ,D,.,,J. loDroDertvrolded puEns m4 rnr h..rur oi h,Er;,; rh;s.na o.odins ih.!d pror.ins oI h&1u* of exrtinsnr&ro6i sNh * drnaBe caukd 6y rEe mdists. rra,ste..cumul,iion oI ther prt,Einsn rhe ER t.ads brmndnnrsll.d ER rres, whichcutnin:6 in rDo,

. a niury in eia'a '{..th,as, DaiticuLny vnalinf.dio's, in whi.h lcs of irleted caltl ii t.rc;h dFro,poprotic d.rth r[rD:y b. indu.d by rh. !rs 1.5in ad.no\trr rnd humrn ,Fmunodfi.,hq \,ru,Dk(non,)or br rhe hoe,mmurc rc

..rdth losn atbphn pa2t.h\wtv'san,.tk durn rh. DJG . Dro!,1

8rand,:nd ttidnq

r|ethanismr ol ADoptoriiApopro,s n 2D adiv. en,vh.ti. pr€ss in which nuctcopDreins aE brclcr du-! d dd the cdt r fBg,m.nrd. 8€for disrusins d. notrcutar Ddrisms.iti5 u*tulrD rc\r$ ,he moroh!r,ar ofrhr orhwry orlrtl

| nH lE& imdrhsd id . , . po ld i c6 | t . n l y

asim9hlb cnQhrm (Fio, 1-22). Nat.r rhd rdou;

cld pi*6'. rh. 6n. .rpidrv IrnnL iom doobmicbud!. lnd r[gftnr im .r.crdc bod- 6in.id .r

h.. Frs r-a). B*a@ tu. rEo.,1'd.ndphlgocylo..dgiihoti

Tl. tund,nt!.al .v.n in aDoDrorof €D2ynes carhd 6p,s5 Go n J b43uk ihey aE

ih,r cteeve pr.r.ins rfiu 6r.ftjci.sidtral, Adiv,rd .asprses ct..Y

cdnranns in riy.tior of nu.Lr56 th.r d.snd. DNAand orh- d.ms 'hr prtam.btt dnror nld.oDrok ,, rnJ crol.t.rit pruEins Th.idrdddusD,*jdrFndr or z fine1v iu!.d bahnc. b.ipoproiic mol(ular pathwiys. Two dis;.t plrt$ysconve4. dn .:sDdr .ctiv:inn ctled rk -ro.han*btprthwd lrd thc dzdh re..pta, patru,l Ahhough ,hE

.r.tb ,ndu!.d und.in!ot!. d /tircn, motKut$. rnd

id.dnrirctrctcsinphFiotosyrnddi*:s.lFi*. I nt),rh. Mi,udond;.t (tnbiosn) rrtl*ry of A@.6tr_Mroth,ndflrcono n nlerrlprcr.,n5 rhl n.!i;bror'nducins.p.pmliri th* pmrins inctud. ctr4tirome.,ntl enHsrnk oI .idogrriu5 o'oetc ,nhrbro6 otepop,oJ! Th€.hoK b.sRn.r lu^natrnd d.nh 6dtismin.d by rh. Dgm€:b nr of mnchcndri.. whichis conirohn by : frmity of moE th" l0 ,rorins. drprora*p( of !h!h ! B.l.!. vh.n.c , nadeDnkd otstu$rh fa!'Durnd rophtr hahi{.5, orrr..\p"(d ro

nut,r uia.ceorabt.,mounE of ni+otd.d proE tr,; snpaf $rio6 B1d

;r. memb.6 0t rh€Blr 2 hm, n m rum anvirc N" pro.aDodoucn.rb€r,,frhe fim,b !rled B.] ind Bar;whih it,m.nr. ru.n,n,o ih. mir(hondfl:t m.nbmn., rnd form !h:in<t5,holsh sh(h r/chDft . :nd orhtr mrehondmpror'ff elF inro rht labsot. o6tr iJ.t d $nsos,nh,btrrhl ad'.rpop'ou. mo (! s 3.t2 rnd B.t \ L!rtbdowr, rirh 'h. hn. .nd rcru[ . t.rtcc oI mib.dondial prckin5. Cytahroht a i%edtr;th som€coiados, rclvaks cr$&.9, whnr othn D.otcins btelrhr i(ni,i.r or 6+re .,esaiDh rh:i funft,un 5phFero8ic inhrbituF ofrpoprd5 Th€ nd 6utr , rh.a(iva'ion of 'h. .npr( !*ad., ulnh,Ety k.drm o

tI .dt5 'i. .\Dord ro so;hric,o( and dh.. $ntrn nstut\ rho ,n,hc; ; r.lpoploti. n.Db.G oa th. Bcl 2 f,Eit{ rh. rso nai onaorwhich,it D.L2 ndt,rd &lxL.Thd.poEinsanb*

II

ITF

.ll^mr - d n4crM,ddi{ah

BE nEcfti (ffirerc)

2 l

tr

pe.d,.Fp'otr p.;nr rl inh,br n(ab.

onia Bar .nd B.k, .n,l thur Lmn $....2p. oI mno-chond,ial prc.rpopion. pbi.in5. Cdl5 deprived ofgrowth , 06 io' on|J adiqc |hi . . n r bd J r ! , 5hoq r .du (ed k fL o f & t2 ,nd & t \ ,ihur tunhq tihiry fi. b,lrn.. ro!,/ d.lrh, The mno-chon,lrial prftw,y kms o h{ th. p3rh*ay th* isrtspomiblr ror md mrDm of rpopt6n, 's w. !I.11

Tl. D..rh Ra.pror lExh.n.r Prrlwry of Apop'on,s, c:lled 'lsA Grp

tcr, ih,i riss.r aFpbsn. Mo* of th.r ,rt ndGc olrhl runor nercsn hcto' ITNF) r.Plor tamil) rhrt

s: con$fled "d.rthdom,i,." so nin.d b.qu$ it nedod.r proEins. Th. prctorypic drlth r.ptoc arc th.typ.l INF K.!br hd F.5(CD95). Fzsliprd lF*Llne meDbiin. ptukin .xpr.sd m'i.t) on ,c v2rd Trynph&yi.r. vLc! lh6. T cdts rc.qniz F,s*xpr.sinsDBdsj F:s moLcuLs rrc crcs linl.d by rh. F:sL ,ndlh.y bind drpri pid.insr which in tum bmd.,sp,* 3.chsring or iany c:sp:s. moL.ul* t.ds to $d .cti.y2iioA lhus initiatins ih. ssp,*.,$rd.. In m ] allnp.5.rlpJq 3 m,y !|aE:nd adim.mbdar,h. Bd 2 frm'ty.rl.d B'd, as Gdrsrbth. nn(hordi:l paih%y. Dr canbin.d.dvarion of6orb prhq.ys delivns 1 ldhil 6|0- b thecdl. Cdlul,r

i* calle,l FLlr, b|ckrctiv,lon ot osp*$ down*rcan of d.rth re.pm..lnrc nslr em. viruks pbdurt homolosu.s oI FLIP,:nd ii is su*ned rh lh6 is r m.cha.isn th.r vnu$

c.lls .liv.. Th. &rth Geptorpdw,y is irvohed in d'minaiion of alt rt2lriy. lyhphcytd d i. killns ol blgr <ll5 by em. cybrxic

cld.n r or ,^poplotic C.lls, Apaprctic cdls unJqsonvqal chans.s in tnar m.nbnn* rh promoE th.;ph.sE)tusn. h nom,r .dl5 phcphatidylsine tsprtrt,t on d. inn.r band of th. phsm m.nbi,nt. hurin ipoptori. alls fiis phospholipld "nip." oui .nd is.xpced on the out r Ly.r oI d! D.mbrane, *h.r Iis ftor,rtd by nacroph.s*. Glls lh ft dring byapoflo5n.l9 ss.tc solDbl. fuo6 thr Edun ph.eo.cn6. Thn f..ilitrr6 pronF.Lrnn. ot th. d.rd cdlsb.forc rhe' und.€o *."ndaa m.mbcn. drn,se indrc r . . . n l r l u ra rconk '6 iwhrhsn rsu t r ,n ,nn rmmanunl \om. rpop,d( bod'.!.,p65 adhFnr sllco.

Rsed b phrs&rrs, ,ndmrophlsa rhrmells mr prcduRFrodns,l'n h,ndro epi iptutic.dh lbur no' 'ol,!.(lltaid hrB(th.d€rdc[. for .$uLfmmi. Num(us mraophrs. R.p'cs

tu h r n ro lY€d ' n ' h . b ' ndne ,nd.nsulrm. or apoproti. cells. Ih[ pu.s oI phae{q,

I3D

€,0

$ .firdc,t lhr drad rttL Jnrla. and Lnfl,nnddi i5*.

ahMush w. hiy. .mphisird lhr dktindions b€Nenn<rels :nd :pop'un!, 'h!\r Nv fomsafklld.rh mry!(!trrr,d & rthkLr mchJn nrr t). Fof,nshn(. DNAdrnasr rftn ,n 4)ptosi5) ad'v,r6 :. .nuym€ c.ll.dpolr ADPkibos) polym&,*, which depl.G .dlula!5upph6 or n'corimnjdr ad.!ine d irucl.od., l..dins ioi hllnATPl.yrls and uh'm:kly ndosn. h h.i&ni,,.onnoo siE.tiors such as ikhcmi.. ir hd bc.r sucpsEd thar .any cdl d.,il can b€ panly rftbcd ;apopbrni rnd drnEn n rhedomimn Nprolcelldsthhr., wtrh,.*nine i$hemir

Ennple. ot ApoptcijcdLd.ith in m,nr liruarions r lnown m h..auFd bvrpopions. inJ the $t.d.d ex'mpt.s li*.d bdow i[!r'hftrhr rc|. ofthid.rth p' wry in nomat physiolos,

cronh Fdor D.p,ivarion, Hcrhon.snsniye allsdepired ofrh. claart homon.,llfiphan6 th:i rrnor i'huhEd by rnra.ff ,nd qtokines. rnd n.u.onsdel)r ed of ne r ero-d lador d1. by ipop.6is. In 3tl

rJ by th€ mtrcllond r pr,h4!r rnd r irf lbfahr ' i i rf lnr,on oI prfrp,,phtr( m€mh.6 or 'hr 8.1.2 frn'ly rnd d(r.5.dsynihels oI B.l 2 rnd B.!x.

ol .dlls r' cdirtio' or.henoih.Ep.uti. i3.n6 indu<s DNA dam4e, dd it

brp,,prtr,cdrarh.when DNA ! drm:e.d, 'h. pst prukr:(unutft! ncdh. h rid f.$s th. R .r.|l kr rh.c, phrk)ro2llowntu n' r.pan lchrpE 6r. Howvei n rh. damag. Nid B(r' ro br npincd su(c.sfutl

r urrimr.tl irrr.Bi\ JnJ Brr. ind by j,mubrns an,h6D 'n Dro.1poftrrc n,e,nbss !f d. 8ct-t t 'nni vh.n p5r isnuhted ofub* (ar n k in cdrn gn..6l. r ia indp,bl.afindu.ins rp.ltosn, !, thar.etk *iih d.m.s.dDNA arc allow.d m $ryiv.. tn such rtlh rh. DNA

I iEnnc.io.s drrre,d to nedprdn ..ndonnltun (ch.ptn 6).A.cuddlrion of Misfotd.d prd.inr. Dtrri.g nomal

.h1Fror.! in th. ER .onnol thrnrop.i Iad,ns "t n.prr 5)n'hs,4Ll prok,r, rid nDrordrd plrrncoridF rrc ubquhnaEd :nd 6Qdrd forpn,k, )ns lf, hoestq unfoldrd or m',rot,lJprckn!aamuhr f lh. ER be'u! of in

.ork rt, at.d r rny' /r?/pnr.t '.,porn.Ih! 6ponn r!"vrs 'en'nBFrh

of .hrp*oia rndrcbrdDbt r r.rdrticn.lhusredu.in!rh. ltvclsotmn.folJcd prote'ns i', ih..dl. How.v.i I rhn Eeotr. ru!:bk io copt wnh th€ a.cunut,rion o! misfodrd oroidni rhr 6uh is rhe:dlv,iiq ofcaspNe rhr t.a,l toipoprtxn. Irri..llul,r a.cumulanon oI ahDom:ttv6ld.d pbkL's,ciukd by nuhtionr, rsiis or unknow;

.d .s: t iitrr. ol

dF,$q inrludingAlzhdm.( Huniingron. ard prrkinson dinass, ald losiiblr aF IId rb.re5 Depn!r.n,,l g ucor rnd o:ysri,rnd s($ such A ht,r.?ry, Esuk in proHn nlt"tdms,culmmtina in.rllinlury and derh.

ap.ptnir oI s.lf-R..div. Lynpiocyk, Lymphqi.s.rpabl. of Goxn,zng ltf rn B.nd4rd ii rll ndiyidurls lf rh.k l' nph&r4 .n.ounkrnft riris<n5, rh. e 5 d'e by ,r,pi4k 8olh ,h. nro!h,{dr;tprhrr} ind 'h. Fa, dorh reRplor pnh4?rhav. ben impli.,Ed id thn prE s lch.pir.J). Fitu(ar rloposn of rtf.rcr.ii!. lynpL(yt s is on. of lhe

clrbxic T LFp[cn-Mdi{d ap.poen. cyto-ror.I hmphoqls lr-rln h,BnE*nEd on ,he inr< , f nri(ed han c r rnd tumor(lh l(hiprrsr up,{ r.n,rron,cTc i [ . d3 , , . r ] z . . . nEr rh f r i r sd< l5 . c ranz rm. , . k r .pnrons.t asFrt,r. rtndua and ai. able ro,tiyri...lrun cnprs. rn,hn 4:r, Ihe (TL L' ! hrts{ (t5 byd,R'ry Lndu!inB ft rff{ror phi!. ufap,,r'ons. wtrhouren8lsig midhondflr or dtrh(.p65 tr3r an ,hdr artr( rnd mrr l, hrts{( 5by

I surrurY

. R.srlat d mrh"nio otc.ll d.rtl' ri{,F.s behf,h.it unlrnEd ard trramblt d.m.Ed elk.wtrh d. kd Ns,bl. ho{ ;.Kio;' ChrnRi,r.d 6y, m7yruh. d.sird,hon orprc.kins rnd DN{, inniaFd by !.stsqt rnd t@rdon :nd Enonl of ddd ftll! br ph:sr)rs

. Mto.'.rlr;al nrhB.) pcthM, B he$ redby rx or rurivil rdniL, DNA drmra. ind:(unul,i,mor mist6ld?d prokinr (ER fts,,rsrnnd rnh |e|('s. oI !6:poptonc pG

troprnm. sh.rt 'hq insEa ctrp:k mq.tion: inhibn.d by anii..Doprod! mrm&r5 of,hr B.r f.nitr whi.[ ,i. ,nducd bt 5uvrvrl,isMk imludir. *ro*d hdoR.

. Ddh n.pptor t4mas4 pcthwt . r.teoni-bl. for rtLninn'on of *lf !ffia tDoh;qsiid d.ms. by cybbxi. r tmptuir;t n iiitrrFd by .4as(m.n' oI d.:'[ E.oro6lm.mb.d of rh. TNF i.c.Pbr hnity) by1'3m& on adirc.nt..lls.

rhn d<ripnon ot ,p.ptulk .nnctu" r ( [ i n i u4 i nd ( tdo (h . A5 B . h r r { . n , rh . r

.d rhn .h4E wirh bIi.I .oi sid.rarions cf r[ft oih.rpd6!s: inr,ellJr ac.umul.tio.s ot v2iou5 sub.n{c.s:nd exucllul., deDosnion ot.2lcium. both ofwhi.h .i. oft.n sfiard wirh ..ll iniury, and rsra.

IIITRACEIIULAR ACCUMUTATIOIIS

m i f t i { r d f n \ ' \ { ) r r n . L l n h , i i s N l $ r ( , p l(il l\ \!^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](

or rqtr r.J J.f.Gr n)l,l fs. Nrhri,,s.

. An nrofmi .\olr.tu$ nnnndr . Ll.N!r.d iJ

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

s l i . i f J . r $ . i f u . r r L $ ! r r 1 n 5 n p ( d i l r ( . r ! D

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

. a11nht,11''r,hlnrtd* J$,trirnl,r, ,lL!^ ,r( t|\ qd 4nubld'r' ' l l,rtr tt\Dx( or th,: L'4 |

l t u c h r \ r ! f ! n i J i N s r h s !

.ft $r(ri(J x) hsr,.sJ$. !r\.tr J ro.Msren,lo r , r d r i k , t d d r ( t , ! J n 5 r r i , s .

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

r,!r\!{,J$ D.,, burr f0n !rcfc. .hus r..qini,lg nr

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

6p d

a?)

-x-d

a3)q

a

d

.21

qoi

ot ;

{ , a

4 6 . p " . ; .

i

ccl. po&nins). hq.h Ee 6 ir!e^'bh In fh. rv$etoi,n, frny chr,sr nrr prt.edr rtlLdatrh, rid n$ ht

hdi. nqohenatnn rahapie' r5).

rit l.r micrc$opi

rh. o4.iic $ v.i6 tpi€ny 63d i

ndioqlhal.'klh.nid.n'iff.dbyal

F odic Eid-s.hin d.in lfiich dviord). Ivlcuola do nor d:in tor.it

Fdych.ng.i.froncommon]Y$3ninlh.|iwl:nd'hohaan ,M ld rdychdng . in th . I

gh3 'o6 rg l l ' n3

5n : .ndg ro8 r€ ,dv l f i ychan ' .b .eenbv loh i]n lhe .y lop |8m

rorha6rl Fiph.ry lFiq. r-2531.oe$ionrllv6dieuo l t6 |h rup lucand th3sE |osd

3tld"). TM od'$ pmsm ol tutrv .

njury 1.,c., diphrhaia) a.d shos morc unlromly

cholen.rol rnd cl'ol.ndyl Endr- ctlLul,r .[ol$rnn

wnho('Enili.:nr nn:clLulari(umulanon. How.v( phisNyri. ftlk mi) b-om.orerlo.ded wnh Llpid lr.elrindA,.hdl.i.rol,,nd.holsiql6'qt in lrwn Jirrqo, p

srh ft Lrpid debns ofidonc .elk o' ,brcn,l te.e., ordtrd) Iorh. of

lipiJ. Thcr manorhag6 mar b. 6lled !trh mrruk.Dembcn€.bouid vicuotes ot tipLd, rnpairL,s i formrrpperrr.. ro ih.n qlopl,$ lrrn .,1k\ h\ atr?.)!LnM, \mooth mu5dc ccrk rnd rusophases are rirL€dwnh Lipid ya.uol.\ omposd or .hole$nol ij,d .hol.rie4Le$r5;ihen sNe r$erorkrorr phqus rhtn.[]rtrrtdsn. ytllo! color d'l $nn,6utu n,ihr rrhoBcn$^or thc l.si{D lchaprr r0l. h hredtrry ind a.qutr.dhyp(hp,de'nL. srndrams. n,.rophtrsn,.rnulr.iN .elluhr .hole$(.li 'htn rr$rnt ,n thr \ubrDnhr

tentloDs. du(6 orrhN f,nm,\ mr{.rhi3s ntrnr mrf s.rtkd a.d,.,,,s.rrot ins. MonhaLoFtrll! ri6lr pnr.in ituhuGhis

o<urh.c.usex.ses r. prernkd (o$e.elko' beciur$e.ells slndstrerr..*r. rnounB.ln thd!]ddq, nr

hv pncnGn h.heI)nxjmal (nduted n'bul.s. Ho*.!ei Lr dsodenwrhh.r$ pror.ir hrl,$ ,tn* ih( Fl,fr{uLir 6hs rc.s.,

odchrh and womed| HqPir , sdq' M6Bducfu )

n.phrc.c srn'lrcmel, ths. is r mu.h |,fgft r.,bsordonnBiniie dn |.oktn

f u*wiih ry$om6, r.surn!F in thehisiotosic app€annRof pinl, hyalin. crrplasmi. ,lrople6 lFia. r 26). Th.prc.s is revtrnbl.t ifrh. proreimn2,b1E rhcpnn.jndropla! 1r ndlb.ltcd and disaDFa i Anoihq exanplen fi. m.rk.d a(umulaiion Df fltwl) sytuiai?dimmunoslobulins rh m.y uur in rllt RtR .f a,m.pl,sm. .elh, fohing roundtd, <Einophirn R!$',

Aaumuhtions of intraRllulf prot ins ir,l$ *n'n c.drin ryp* of..ll niur For.xinplq ih. Mrllorybonn or -,lco6.li. hyalii," k.n.osinoDhili. qroplermicinclusion in liverelkrhr is hisll).nr cdistic olilcoholic Lvd dff f lch,po 16). sucl, indusions.,e

.Ed int m.diat 61.inha lhn pEsurubrr rcskt desnd on. Th. tr.un,fibrillaryinslefound in rh. bmm r AD[.mei disr.is rr r8sresakd ponr nclNian thr n,n&iis Dicro.tubur.2smi,rd prodn5 and n.urc6tam.n6, r afle-i.i ola disrupEd n.urcml cytoskeldon lch"pr.r2l).

Glyosm. Exesile rricdlul,r drposns sly<,scD aejiscilrd wnh 26normaftie5 in lhe mftb.lismoferh*sluos .r Blycoso. ln poorlyconmollcd dnb.re5 melllttrs. rh. prio. txrnpk ofrbncrhil glu.o* n.,6.1nn,

a!.pnhdium..ardia.mrcyks. end 9cdls orrh. il.$ of Lrnserhrns. rjly.o-s.n ako a..unula6 wnhin ftlk in r sroup ol cloklyrelakd s.n tic disord.6 .olldiv.lv rtt ii.d tu i\ d.os., tnhs. dk nss, o, xr.os.nos lchapkr 7). Inrh.s dk..ses, .nzyma.c ,LIe6 m d. srnih.ns crbrcrkdow, of sty.4.n rtsuk f n$,. edtpitiis,wirh $.ond,v riurr :nd c.ll &nh.Pign.nc. Pi8qenisarecolocd submancarhi arcenh...rosenous, com,n8 non ou6id. rhe body. or .ndos.nous, sytuh6n.d wrhin rhr b.dy nl.lf.

t Th. monconmon (!s.ious piEmsr k.,1601 lanexample G coal dus), a ubiqunous atr polluiinr olu6$ lif.. wh.n inh,l.d, n tr pLigr.r mitroph,s.. fd ianlpotud rhrcush lymphnn.hfn.l! r, rh. r.Fional nach.obDnch iat tym ph nods.Assrcsates of the pisr.fi bl.cktn ihe dn,nins llhphnod(,trdp monan p1ftnchrfre {dnthaatisl.Heavr

.Da ora fibrcbhri. Eadlon rhat can rcn'[ 'r a s€rioDs luns dn.i!.elled corl worldr pn.undonidij (Chapr.r r3).r Endogd.ur pismlns indude liNfu$in, mrlanln,and enain deivrivs of hemoslohn. Lipofutk, ot"q..r:nd{.rr pdmtni," s ,n inn,lu6l. hrcwnnlyellaw srin ' fr,..11urar m.teri.t rhn a(mut.Gsin. v .ry or n$ues lpanlcuh ) rhe h.rd,l1v.i, ridbnin)as a fundion of.Be ofurophl. L'pofurin rprcsenis.anphxaollipi,l dd pn,.in lhr d.,iv. frcmihe rr.. ndicalra&lyud peroxitlation of poljur$runted tipids of subcdtutr mrnbrine. ii il i(n iijurious b thr ftll but n impomn, airft ndn:r iniurr. rhc bn,wn pism.nr 1ri3. t-17),

io the risue th:r r c,ll.d bron rt.pb By .t<..a6 a! p.iriuchrr

trd,ron dcn{ BEnuks 1Fi8. t-2-Br

hrcwn-bh.t pisnhrfollow'rs rh. rrtr,fu{

c alyTed o\id ioi of twonn. b dihyduyph€ny.lihirre. k n lmrhdkd Lxdusiv.ly by mdindvrsro.1r,r in ,hc cridsmn ard ads a; ";.* "g;"hlrhfur u|fa{ord cdHtioi. Akhouah f.trn,trcsJR ihe onlr eurce of mdrnin. 2di,.r hasr rcrirndrsr $. skr on a..umuhE thr pism.nt{..e.,,i r.&kr.t,15!?n dermat nacroph4a.. H.a,,,/.,i is r h"moctobm d.m.n, rhr EAotd.i !. a$ ,,, tr,,En rnd i(!mutrrcrLi rsues *h.n *.( n a tFat or ssrenN rxrts! of;on. rron i5 nomnty nortd wtrhii cdtr Li js!)or!!rwnh lhe prorein apol.rrl,, Idn,ns f{nin nicdles.H.mosiddn pisme rprilcnE rars. assrcsres ofrhen reiinLi nitc[6, Qdit,- lisu:trtd br tish rnd

ideni6.d hy fi. Prusfn 6lu. hnnf,h€micit rci.rioitF,s. r 23r. Akho+h h.mosjdnn:(unuhnotr n

Lhir pichdr a..n,nmal h rh. monofucle,i ph,sorrk! or .he bonemarow. sph.i,rid 1!!.r, wh(E.h{. n.xGn'v. Rd

t ld! cx.fi*5 0l ;on, and .ons.quendy of h.mo.siderir, rcsult nom h.noiihrs(. The b.$ example tsrh. common brun.. afi{ rysn ot thr {}drc.yB 1rrhr nr of hcno ase, rh. Ed c.I d.brn n ph2sGy-'.!cd hy @.'ophases: thr hem.slohn.ofttu n ihen.rabolird br lysgona {ith a..unutanon of thr

y ol.cLonrhroushwh,.h dr bruis F$6 l.ll(h rhn. r,nsforh{ions.Thc orisinal rc,l.blue .olor oI h.moslobin is ranefomed ro v:ning3hdaols(n-btu. by$etN,t torm,rion of bjrilqdin tq(n bLld and brlnuhin 1rd bite)rrt,m rhc h.n. noier],r rh. non jons oI h.moeobiorcuDular * Bold.r yello* I'tfrGldcrin.r vhenerd rh.ie is srncni. oye oad oftron, trmosidriin r d.p.!nd in Dan), o's:ns.nd rnsu.s.a<Ddi.i.n crled ,.zo'Lro$ {ch,prd lz). rr n found. hd in $e nononNl.,r phascyks of rh. |1vrt,bon. maiioq $rrn. and tymph nDde*nd f Qrr.rtd nicrcphaBes fircu3hour orher orsrn\. wnh ,ro-

s($ivc ac.umuh.on. p,i.n.hrn,l.(11!,hrcushouirh. body lbur prin.p,ll! rh.liys. ranc.:s. heiit.andend(rift ore,n, bdoh. "hronrd" sidr.ctrnut,ring pishcnr. H.nosidero$s o.cu6 in rh. rninsol lr)inq.a5€d:b5o4'rioi of di.hr! ;on, l2) impan.d ui.rtsionof non. 1r) hen.LFi.1ioias,.Dd t4)r:nstusions ld. u,nrlu{d cd cdk conibidornonr, ln mo*'nn:neof svi.ni. &ooidero.

eciherarenchyn.l.ells or mpff orgii fundion d6pn an 'mr6rivrr.ctrmul,ion (Fis. r-23). Howve( nor. .-dsiyca.cunulaiionsof non,i.ei h r,tulitan hno.hto.q,,cD 1(hipkr rb,, {rh n$u.,nFn m! ud'na h!.r6bb, i. ht,d b,r.rc. rnd dBh.r* ne tu!

I P l||olo6K c tctf,c^no||Prholosrc .aLdici .n ,\ i .ommon prc6s rn r wid.v,itrry or dn.ri nr6: n impl'( ihe,bnorhrlJoo5irioi oI.alc'um $16, bserhtr wrh !hnF!.noun6 of

15. vho th. d€pDnn is.altd4rtupri.

akti.atn 4 it 0(6 h th. absen . ol cdLiun n tabott.um kYrlsofcilc'um).

In conMn, rhe d.pniq of c.tcrum shs in noffirlrsuer n rnawi as ,.iar,r. .,L,lnaiDr ana otna,dtudf '.l.ds saft .le ,24n2nt i, tdla\n a.tabol'stlhfi.rcakma). tt st lld h. natd rh{ rhrl. hyptr il.em,r isnou prtrcqunn€ n'd)*roph(.,td6oi.n. n

Dylrophic Crlcifision. DyrnThi. calcific,iion n€n.ounkrtd in ,.s or nEroskofr |n.lnibk jn rh. alr?rc"J otdvdrd rhqostFrasn, i!!Eia&d vnh inrmtrniury in rtr rnta and taFr({ies and ch.iidsizd 6r a..umulatjon of lirraslchaptd l0r. Ahhoush dynroohic c'lciti.l.on nay b.in ,n.dhhr rind na rndtrrirnc ,ny*n 6!rrr Fn c.l, n iun . , mr nQ b . i \ 16 . . t , t rF rn d ,+un (o i . r o r.rampl.,.aL.,ri.rti.i c.n d.lerop 'i asns or dlhrssdhe,n !,hd, 6uhrq in iv.fttv .onprt,ni*d vatle

Eoinr. Dvnrorhi. .al.i6.aron of rhr hnL. !116 nof ioni. {.nai n ihc cueny

d f t 6 n t h . 3 s r i r t3 y m p 6 h d . n

s[yc'|.|ficdio..'F!6.6inn!6||uhl.nd/ol.n'a

r|1t prrl,.gd$ir of dErophic ..Ld6crioi i 'rvohs;,r!,roz i,r nud.anon):nd prop,t ro,. hdd ofwhichmay be €,iher i.riftl luhr or cnhtclluhrjhe uhrmrk

{aline dLun oh.s,r,r.. InnDhn iD cxna.ettuhr sG drm r ii(mh4n€ bourd vsi.le5 abor]00nm in dianftr: in

.r.r. ,nd Li p,rhok4j. .aL.licatioi rhry tldve lrofrd.gdq,ir3 crk. rt is ihouahr rh:r c,tcim n ,nnBlylDcnrited 'n rh&vsicler hl n! rfiiDiry Iqm€mbnrephospholipidr. *hi[ pholph.cs a.cumuhk rs i rtsuhor ibr nio! of Dcmbrao..bound pho'phrri\6. rnnB

,n oI iDra.dlubr .aL.'ficrtioi o.d,ir old.rd or dlng.r1l\ { hale ron then rbiLft ror.*uhk inratclurrr .ncium. Ah.r{ariq, prcpagrDn otqst fomd+rnd€ni on rh. coiftnrrrian ol(:r rnd PO. 'n iheexricdluhr sprrts, rhr p(vn.( or nineHt rnh bnoqrid rhd dqtu !l .orbsenmtioi, w[i.h .nhrn.s $c

M d s h . . . : L . L 6 . r r i o . . r nqer iD BrmaL issu6 shen.ver d.rt nlrrqel(nn.The n)ur maior c es or hrp.r.lrlcm; nc l |l 2 re"s1'.-4tar.f pa thrtuil haMD.. nu. o siher pi'mrr

or pndudion of pr*hy.oidhornonr rcraird Ftran br oih- trrta'rn niioq c)dsttudDt af bane dR rc rh. rtfd\ 01 k(]sr(d

I,ncrd*J honc .*ahornn snEHted rnh 'nuhLpleEFl,,m4 leukemia. or d'ffur irehbl ndii2rnr 0lrtbn'n t)-t?ht.d afoa$ nrltd.anon d sr.d/orr iin !h'ch mubhr D pKutrod: and 14) r.,"/ /",hr. if trhth

trrds rc se.onla4 htp!4aath\-

ih.bdybure ncip.rv rn 6 r'a id4rit:trisu.6 ot

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

d6po.rr in rh. kidnry l4r'.ahhdr.) 6n 6u$

tufu tYAhnoml htEellul.r D.rodtioB

. Abno.m:l deposiis oI mi.rirls in (ll5 udtissnaar. rh. rt k of.i!!*iy! irtal. or 'Lfetiv€

. tiit .r,,ce ,c.umtrliiio. oI lr.c riclyeid.srrom ex.esiv. mhke or

d.r.{iv. ranspod lohr. be,trk at d.t 16 inlynd.sis of hn5pon prorinti h.nif6tarion

. Aohtdol deto'tion: resuk ol delfrarrcasbolism r.d .xc.sik mDL.i jn maqo.pMses rnd snotrh iufl. ..[s of y.sd qilts

t D.poinion .f t'oe,t! rcibsorbed pbRins inkidn.) tubtrl.s! nDuncslobulitu in plasma alh. Deednioi or srlrosd, i! meroph,ses otpIi.na wiih der.G in ly$sml .nzym.s 'aib(ak dorn sly.orn l*ly.caen *o!,k dneast. D€poltio. ol pis,e,aj typica lly ind ise*ibk pismenr, such .s carbon, tlPotusr l6rt2lJow!p.oduct or lipid p€roxid:rion), non Gsually du. bovgroad, as r h€nordebrn)

I Dt*n,pLn .ak'li.aho,: deposni.n .1 .2t i\o* snc oI ftll iniury inJ ne!trn

r Md,r,rr ar./,rdrnr d.pcnion of ekiunin ndm,l fisu6, eued by hrptftl..nirlusuallv a con$,tuenc oI pf,rh rrcid hormone

lrl^ru r - dr 44 Gr M dadFds

I

I I

II

'3i

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

I Glruuf, AG Gt2nukt 'snq i5 th. rc,,h ol a ptat.4,v. dkh4. t4 th.p'atile tiv. @po!^ '4d t'l? \pan at atk r4.t th. 4kd3ot,odtr,lqs.rpdra tt *oseta6 t'd,6 that duec<y4rro|on .t .. uht ann d.hdl.t d,hdp. tlel-r0r. Thi prf65 or rs'ng R.onrn.d from ten ;humin!,rnd<r krs n,motemod.'o b. rcsurned b,, , 'mtr.d 'umbrr ofiens. rh. d€r'hr r8inB b.on,rcl.d b' prn'cutrr sm6 rrr5 5puftd

k . ! t rF f iw ! rndir d.vi.ins wars to hriplhte, pr6.s ihrt w,a onc..an.id.Gd inexcbbl. S.v.r,l m<hanism ft tnon or3uspd.d rc b. rsponsibt.Ior ce ulft ising,

. DNA dam|.. ctltllr as'nE is assjned withn{.s ns DNA d:m:8., sh'.h roy hipFn dunmnomrlDNA (ph.rion rnd (rn b.dh:nc.d bv t.;Ddi.rrs. Alrhou8h m6t DNA drmas tr rF;d bv

r rid rt;umrh,;.s alls5s.. sone a$n8 syndrom4,rc i.*iak,l wiihdehcB in DNA repff n&hannms. 'nd th. tift .brnor mod.r:nimrkc'n !t incrtistn if rslonms o DNAdrmrse rrc.nhrrc.d or prok,ns,hr j:b u. DNAIe inroducd ln t r, 'h. nFru.nhon rhr h,5 moilconls.nrb, potons.d tire sp,' in mo* sFi.s Gr[,nf '.!rkrror. Renrln i hn b..n pbp,{.d rhrtcron. rcnr(on iDts*5 a te\.t of *($ rh,r:rtv*s proEi[ of ih. situin fimitn 5uch r sr2, rh.ttunfton as hrron. d.aeotik.. TrEe DroriB mavd.r.ryhte rnd dseby ictiv,c DNA rt;r mln ;{hB jrb,ttr4 rh€ DNAi n rh.,ben!.oftn.; dp,eins, DNA n Fmn.In drmr.. D.leued 1lhb aphatan A nom:tc ! h,v.a limtred lrpaciry for trptnrtron, :nd :ft.r r n*dnumbd or divnion. c.1k beoni,r6ted in . (mi.nilly nondividns n.te, kna*n .5 r.rliart Ja.J..'.. Ag'ns i.1$mi!rd wnh progGriv. rptic,nve

ri.an(of (ll i. cn i lron.h, drtn haveih.cip{,\ ro und.Bo ni{. Dund! of (!ti.ruon,h:n docdlrkon ord.rFopte.In lodEr,c.l! fton Drkm wrh\ymr st dtm.. ^ a,. dn tk.!5ld4iz,l bv Den,ruE .sin& h,v. . mrkrdly r.dued m vitrc liliip.n. ln htrn.n celk, rh. n(hannm of crlicrtiv.rn.knlr hvoh.i tn(ompt.re rcpt,.r,on ,nd qm3rs!. shon.niig or Flom.r6, wh'ch 'tinrEtyE5u 6 in (lrrcl. nftr. LLz*.r *.,hon r.FnedequenG.r DNA r@nr ar the tin.,r.,ds oi chron6om6 thr ft imtsdr,,Ior(n5unnc a. lonol.rcEpr auon of.hron6om..nd5 and lor;!oE(r;,h..ndr rom run,,n :ndd.sredn'on vhd!,mrtr.; sEp,cft, a 5m' R'i!n of ih. rcto6'.d, and rcloh&s b€oft pros(snet, !h,d.n.d.a5 rb.,dotuG beom. lhotr rrh..n&ut(hlomD$Ds crnnoi b. p'ord.d and ft sn ar bbkhDNA, whi.h5l3n,Lcettcych,r6t. Tt. tenqhs otrh.t lon.Es ir nomall, miinnin.d by nuc[;nd. rddjtion n di.rd by in h,yi. cald r.lou.r6e T.toh.rak r. sp€bti*d RNA.prct in .om!l.x rh,r u$sn! uw' RNA r a EmDhk for addme iddrid-."'h. endi of chomastu5 Tdom.;s rchv& tr.xpr6..d in sem c.115.!d is Drtknr.t tou Lvii3 iD$tn .dlr but n n usurlly ,b* in nsr 3.maricGsu.s (Fi& l lrL lh.ftfor,.5 ce[s i*r th.n ktom.6 eon. shoner rd th.y .xn ll). e rycL. i6uh.ing in an mib't,D ro s.n.,k n.w e ! ro fetradrmrsed on6. (o'\.et', r 'mnoit:t qncs idlj.rdomd,n n rcad'vded 2nd cton.n.d. sgs6ring 'hn Etomftetongnio, mrsh, & ai

non. Thr D d,xus,ed nor. t!l[ d5uchiIunnsobk r,otr,howav.r,rh€;trflffih,;"irron{rr rd\ir and relatuE tmg'h ro as,ne rnd€nar h,3)d 'o h€ fultr 6Db|Bhed.

_. R?,1"4.1 'q.nefttik @nad, at ti$,. t.n 1r..R(.nt studies susg.n thai *nh ase, iI. pt6

r6n.6 preqEiwt ibnli w rh i(eiR en dr ft; udi

lcDKN2Al pocin .ccumuhi.r m snn c.lk, and rh.yprusr6i v.ll loF rhnr cip,ur, r, elf ff.q pt6 B iphrs,otas,cit mh,b br "f..[.rk prcB($ron! i, p.di{s5 n chrpkrb, dctcuon ort6i ot Iuid,ln muE.rioli or Dr6 r. rsiar.d with.1. a.t,uktia" al n4.boln dn-q.. c.llilar tlespan r rlsc dd.rminrd by a b:l:ne b.*en dim,e.rtsurine from m.rahohc.v.i,5 Nlrflng wlhm (he!!ll rnd (olnEncnng molduLr rop,{$ th.r c,n(p:n rhe drm8.. on. eroup ,,I pohnrlly ror. produci or nonirnd:bornm n HcA5 v. haE di$usrd .rdff in tl'. chaerr. fi.shyproduG of oxddivr phosrlD4l.tion du$ covitenr mod,ri!,ironsofptuFn', ,p'ds, rnd nud.K tud!.rnftx.d or d,iEdam.e..outd rc,uh fron ftF:Ed.n ! rann .d r . rpo< !a ro !u \h ,nntsdi.aon,ro4wrh proara! \! rdu(on ofrnrcudani d.f.6. mah, hs. D.msed (llul,r olgm.ll..,.ctrnul.r * <llr ae. This Dry,ls b. th.6uhofd(linins tundion of d. prai.1ofr., th. prot olrlc

. srtrdi8 i! modet osnsns, titc th. ,omGenorhabdrs .l.eaE. h,( 5hown thrr soqhhcro6.5uch,s iniuln 11,.8rc{h frdo(:nd nftanubr signllins tsrhweF r.inrr.d 6y $!* IDFnunlr knd b Edtrft tLt .prn. Th€ undstymsmEhan',mi r. noi illlr und{rmd,bur,hreEroMhrFou n,r anrnun tn2 rceon(i 'o rtllGr !F.s,nd du. Educ. th€ $rbiliry ct rh. DNA.

I slfrI||I

! Rdul6 tmm .onbiution oi rccumrtati'rell'Jrr do.e (.e, by fc 6diciL), rcdx.a€Paciry b divid. {rcplic,riv. b*rnc.), :ndrcdued abilig ro i.p1t it nu.d DNA. Aeuhrkn.f DNA d'ns.: d.lew. DNArtp:n nchannmr DNA rcFr my b. :a*:ndby calori. E:ridion {LnlM to pr6lon! .ging i!

. A.pa@iw tuda rcdtBd aprin ol ellsro divid. b..auk of d.cisrq imauns oI (16d,.n! .nd DrcBcsiv. rhofr.ni4 ot.ircmmnrl

. ot .r fddd, posrcsiv. cumDlation 01 mdlbolic d.marj psibL 1016 oI soqh futo6 rhrprcmd. 13iry in sinpl. nod.l oq.nisms

rr $ourd bQppr@ h. he v.rio$ torm ot cdluand adlphiians d.siibed ii rhi5

insnom:daphhons'n ell sia, eavth. d tundion: to tnr reve(ibl.,ndtri.ydiblc ro.ms of acur. cdl niuyr rc rht EBula&drrF or c.ll d.arh rcFrennrdl by ,poooa' Reflr.ne ismad€ b :I dre ik.ndons lhlolshoui tnis bm!berurt rI orc?n inj!ry :nd utnndrty d J,'(rt daQ{

,rururc?nd iunrn,,n

)61 Fb, 4u4 enbd k. bai,. alirbt 64t'iRtu' at khd4. tu4!q.1

Dii! N/ r4qaq t16 zas. zaal re.ht thl rttu E tq,r ot4qt6'@rb Qtu's o, ttt 3d. h6ttt ot Piota j

idr n olei tuL rd oxd{r a

! n | N . o L f r E N j c d d t r . l y t s n l 4 r ' : ( * p d . ' * e i . ' d d .

6t&"e4,,t1A.L *tudt rt, ,,ryhhdd6i.bIrm t

qqqw ot $. rch ot 4o&&ra r .d turtp, qd d{@t.tn. Fd4t'd4t r ni4rdin 6r

4n[ !<8. !J 6e. ,B' /o,!fu.! '

D4,11\ 16s tc@41 @<a' ot q4 ad b@ 4LD.@td.

r6a A 4ens d oe@ at e,. tu

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r@z tD!lr6@ 4 ltu Nt@ 4 tuftt ns,6

kel(l:ftknq xu6ud@

.* Fd.d e* rq ,ttu Fm, d rw &;'

ry.tu, d tbvd@ "t4ottu^t

Eo.Ic-. ,6t rk au ot DN^ atqx n au ry,jM Mddr q[ i0u di lrk

rfr d qtrd4 & h4hnna d &nr an | | r:.r r. ,@r

le.dtu w ot tk @ t@@ ol

Rlq&d&K"rcueaiFqrl"fu

1 6 [ D . s L d ] M e ' c u . e B r e r ! [

d4 ot h4rtut rn d qad htub.,]z l 4 D ' 9 l ! r y | r & [ e ' | M ' h ! c M . M . . L - - .

z 4 L l U ' c E ! i [ P f i o F M | G j b

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