ROBBINS

ASrc
Pathology
t
SAUNDERS
ELSE\]ER
Kumor
Abbos
Fo usto
Mi t che
Chapter 1
Cell Injury, Cell Death,
and Adaptations
Introduction to Pathology
Oveaview ol Cellular Responses to Stress
and Noxious Stimuli
Cellular Adaptations to Stress
Hypertrophy
Hyperpl asi a
At rophy
Met apl asi a
Overview of Cell lhiury and Cell Death
Causes of cell Iniury
The Morphology of Cell and Tisrue Intury
Reversi bl e I nj ury
Necrosis
Patterns of Tissue Necrosis
Subcel l ul ar Responser t o I nj ury
Mechanisns of Cell Iniury
Depletion of ATP
Damage t o Mi t ochondri a
I nt l ux of Cal ci um
Accumulation of Oxygen-Derived Free Radicals
(Oxidative
Stress)
Defects in Membrane Permeability
Damage t o DNA and Prot ei n5
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 invstieation of
t he causes rcrral oeyr
of di seare a. wel l rr rhe underl yi ng
mechani \ ms qat bogenesi st rhar resuh i n rhe pre. enri ng
\ i sn\ and
(ymproms
of rhe pari enr. Parhol ogrsrs ure. r
variery of molecular, microbiologic, and immunologic
techniques to understand the biochemical, structural, and
functional changes that occur in cells, tissues, and organs.
To render diagnoses and guide therapy, pathologists iden
tify changes in the gross or rnicroscopic appearance (,rol
pDology) ofcells and tissDes, and biochmical altrations
in body fluids (such as blood and urine). Traditionally,
the discipline is dividd into general pathology and sys
remic parhologyi rhe former focuses on rhe fundarnenral
cellular and tissue responses to patholosic stimuli, $hile
Examples of Cell Iniury and Necrosis
l schemi c and Hypoxi ( I nj ury
lschemia-Reperfusion Injury
chemical (Toxic) Injury
Apoptosis
Causes of AooDtosis
Mechanisms of AooDtosis
Examples of Apoptosis
Intlacellular Accumulationg
Pathologic Calcif ication
Cel l ul ar Agi ng
OVERVIEW OF CEttUtAR RESPONSES IO
STRESS At{D I{OX|OUS STtMUtl
Cells are active pa.ticipanrs in their environmenr, con-
stanrly adjusting their structure and function to accom
modate changing demands and extracellular stresses.
Cells tend to maintain rheir inrracellular milieu wirhin a
fairly narrow range of physiologic parameters; thar is,
rbey maintain notmal homeostasis. As cells encounrer
physiologic stresses or pathologic stimuli, they can
uodergo adapiation, achieving a new steady state and
p.esenins viability and function. The principal adaptive
the latter examines the parricular responses of specialized
organs. In this book we 6rst cover the broad principles
ofgeneral pathology and then progress ro specific diseasc
processes in individual organs.
z CHAPIER 1
-
Celltnjury CetlDeatl and rdaptatioB
hrpertrcpby, hfierpLasid, dtrophy, and
netdplasid.lf rtu adaptive capability rs exceeded or ifthe
extrnal stress is inherendv harmful, r"1/ t',r,ry devetops
(Fis. l-l). Wirhin cerrain limits injvy is reuersibte, and
cells rerurn ro a stable baselin; however, severe or per-
sistent stress resuks in irrcuersibLe iniury ^nd dea,th oI rhe
affected cells- Cell dcath is one of the most crucial evenrs
r! rne cj i rrpuo l or dr\ ea\ e rn rn] t r\ \ ueororqrn. l rTEi t t i s
cru\ e\ . I nct udrng r\ hemra (h(k
ot bl ood
fk)w), infctions, roxins, and immune reactnrns. Cell
death is aho a normal and essential process in embryo
s. ner' .
rhe de' el upmenr of org; n' . rnd t he mai nrenance
The relationships between normal, adaprec, ano
reversibly and irreversibly injured cells are well illustrated
by the responses of the heart to different types of stress
(Fig. l-2). Myocardium subjected to persistenr
increased
load, as in hypertension or with a srenodc va,ve, aaaprs
by undergoins hypettrophy-an increase in the size of
the individual cells and ultimately the enrire heart-to
generate the required hisher contractile force. If rhe
increased demand is not .elieved, or if rhe myocardiLrm
is subjecred ro reduced bkxd ftow
lrschenial t'ron an
occluded coronary arrery, the muscle cells may undergo
inju.y. Myocardium may be reversibly injured ifthe stress
NORMALCELL
BEVEBSIBLE
CELLI NUFY
NECBOSTS
x
Figur l-l
SUBCELLULAR
ALTEBATIONS
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"r
hypertrophy
{/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.ardial
coro6 viabre myocadium masenta. Fairu,e 6 stain iill:f""""""#: i:::#i'i,::lihenvrtetraorium
chroide' an enzvme 'ubsiate that
CHAPTER I Cel nl ! r y Cel Deat h, and Adapt al ons 3
i s nr l d or t hi . r t o. r L t c l u' r r n r \ I nr or nt l r r . or ! ! i h
er cr r l r hr t i . r , r r m. r r unr i cr go r r r ocr r l nc i nt ur r Li al . r r r
, , r / r r i r . r . , r f t l f r r , , r
f ! ) l ns . d
r ) . ! l u\ r ( ' r . \ i ) t ( . t { ! ) .
r h, r i \ r ( \ \ . ! r f J nt ur \ r i i c. r r r r x r r r l r t l t t r r r or pho ogt
hur r l v , r hr i of . r r f r . r l \ t . r I ! ' ot t Ll r . r r r r l r l s r uc s . Tl r r ' .
n r r r i hl r r r l ur t d
r c s r mbl e r r or r r r r l r r r r t r t t ' r n. r ph. L, gr c . r l l v r h( , * f \ . f .
r l , . \ . r r . . . r l . ' . I l . . , " , r ' r . r ' . . ' l
nr l cl i nj u, \ ! . r r h. r . t r l ct h. r l c, nL. r l , nr j ) . r . r . \ \ 1h. r h. r r
spc. f i r I r nr r , ) i \ t r $s r ( l Li . . s . r t l . r pt r r , n r r eeusr s
i c\ . , \ l l Jl . , , r r r i , r c*r bl c Lr i LLr v r l r r . nr l ' n( , r
( , nl \ ( , n
r h.
i r . r t ur c . r n( l s( , \ f r Lr ! oa r h. \ t r . \ \ bur r l sr ) on ' . \ . l , ) r h. l
r . r r l . r l , l cs. , ncl r LLJi ng . cl l r r L. , r n, ct r bol , ' n, . l , Ju, J sr ppl r .
. r r d n! r r i r L( ) n. r l sr i r u\ .
I n t hr s r hr pt c r s c dNc ur ' 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 nd t hc , , r hr . i ! s r \ . , , , c t h. r , r i s r , ' . . t r r l r r nr r
qU. nr c\
( n
r h. \ xr i ous k) r r ' oi . r ( ! t r . . Ll
( i . r N. r g( . i f c r i ( l
i r g uc r Lbl c er l l uj u, r . s ubt el l ul . r r . r l t . f . r i , ) , , \ . . r nd c ( l
Jor h. \ Vc eor r i l uJc r i r l r t hr . c , , I 1r r r
t , , ) . ( t sf \
r h. r ( , r f i f cr
ccl l s r nJ r *uer : i r r r r , r ccl l ul . r r . r ecr r r r LLl . r r r nr \ .
f . r r h{ , l ogL.
ci 1ei t i . . r t l , n. . r r r l ecl l . r g, ng.
CEttutAR ADAPTATIONS TO 5TRE55
AJ r t r . t i ons . r f r . \ c br hl r . l r r r r s c r r r t t Lc n! nr bo. \ , 7c .
phr nr ni pc . r r er . r bol l e r . r r \ r r \ . . r l ! , r ! l i , ) ns
( ) r
e( l Ls Lf
f u\ l ] l ) r r \ r t , , . h. r r g( \ i f r h. i f . . \ Lr onf r . nr . / ' r \ v, 1, , ( r
. r , 14, 1, r / ' , r - r r \ ! . r l l \ r ( ' p, f ! nt ( \ t onn\ oi r . l l s t o r or nr r l
l t l I r ! l r t i ( nr b\ h, , r dr n( \
( t r ( n( l , A, i ( , ' r r hemi c. r l nr r l
. r ( ( t r \ 1f . i . .
( hL hor nr n r nt hr r cLl or l . r gcnr or t oi t hc
bt . r * . r nd LLt cr us Jur i ng pr csnr no 1. / ' . r t r r l , , . ! a r Jr l , r . r
1; , , r j . r r ' f . st ) ( ! r i . \ k' \ i r f $ r hr l , r l l ( ^\ . . l l s n) nr od! l . r t .
t hf r r \ r ( L. r LLf c r n. l hr n. r i ( , n i r d r hu\ . ' . r t c i nl u r r . Sur h
, r r hpt . r t i ons cr r t r l c socr r l r l r st r ct i or r r .
Hypertrophy
| 1\
l ) t l
t l t ) t ) l : \ i \ . 1) t 1r 1. h\ t \ t 1t t l ) . : j : t t ) l , . l 1s h' r l t t I t t t l
, 1. 1. , t : . h t l r \ ! : . t l t 1, , , , , r , 1. ur . I r r dr t r . r st . hr pr r phsr r
i r l l r c r r r r l r r i t , ' c h. r r , , r t t , , ar l hi . , r i n. r ' . r ' . , r r c l l
r ) f i nl ) ( r : 5r . r r { J r f , , r h. r \ . r \ . r pr r r c hr pr r t r , , phr t hc r c
. . l l \ .
i $r
br gAi r . f l l \ . . f l . r r s. r l hy r i r
r nr r c r s i d . r r r r r r r r r i , r \ r r r t ur r l
f r 1, r . i r r \
. r r r l , n! : . r r r ! l 1c \ .
l l \ t ut l . r \ r r i \ r r r . r J r pt l r r r c s p. r s t i r . r l L' . . r I r l J e { ) l
t pl i e. r r r on. s hc r r l hr pr r r r r phr , , i t un s hc r er Ll r . r r c
nc. , 1. . , l r l c oi d, r , r l L, , r t 1\ t \ l t t , , t ) l ' \ , , n l t
/ , \ sr ) 1, , ! k
t ,
t nl r ) L) sk
r r l l r er u' t t l L t I c, i ) | r r . r ( . r \ c! i t ur i r r i ( nr . r
J or r nl , , r b\ s pt . i l i e l r or r r or t , r L n r i L , r r r , r . l l \ t ) ( . r n)
phr . r r r t l hr per pl . r r i r t . r r . r l so r t . ur ni r ( r l ] ( i : , r r r l , ) h\ ,
<, ush bot h r cr u t i r r . r r r r r L, r r , *r l i / , \ ' / , , , 111, 1, / , r , r
( i r ! . r n.
l l r u: . r ht r , . , s nc phr ' i r i I r g, r ml . , r gt n, mt , ) i r h. ' , r . f ' , \
( 1! i . i
t r f i r n, r f . \
( i . ! LLf \ . r s
. r . ( i r \ . { t Lt r i r f
( ) f
cdr ( i g. n
\ r i f r ul r t ( ( l \ nr ( ! , t h nr r r scl t hr pr r t f uphr . r n, 1 \ u( r i t h
r r r u' t l c hr pt r pl . r s , r i l : r { . I l l . l n ! ( Dr s t . r h. \ r f i . r l . J
n, u' r l t ceLl s i n hr xh t he skt l er . , L n, uscl c . , nLl t hc hcr n un
r r r t l t r go r nl r hr ponophr i r r ust on\ f nJ r r oc. r s. J
r l t n, . , r J bt r usi i n t hc r Jul t t hs hr r c Ll nl t cd t r p. , r r l
r , . l L! i dc . l hc r r t or c . t hc . \ i d s c r s ht l r t t er t . r r r l ev c J op r
r ppl c J phr r r l ur r I l r br hr pol l . phr 0i , r r r l r Udu. , l \ l . . l c
nl , , , usel c t cl l : r , Ll uccd b\ . , , r l , , . , r l ' cd \ 1) r l l i u( 1. l j \ . r , r l
l l cs
ot pl r ho| r , r Li r cl l ul . , r hr pcr r r opl r r r f el r . l c r l , c
er r J Lr c r nl . r r gc r nc r t r hi r , t r . u^ \ i r l r l r r l . r t c nr , r r , , r
, r ( i r I r r \ . r l \ c l i \ . . r sf 1\ . r f r g. | - l r .
I I c r r et h. r r i s r r r s l r i \ i , r s r . r ( l i . r ( l r r pr nf upl r i Lnr ol r r
. r r I c. r \ t
( \ ( ,
r \
t ) ( s
, , i l i t , r . r l r : ar , , , / , . r r r r ' . r 1 t r r r sl r s, su, : h . r s
' 1 , .
'
, /
. . i : ,
r r l r t nt r gi c r L' cLpt r r s. l hN' st , nr r : l L r L, nr
( ) n
$gf . r l l r , r ns
Jui r r or p. r r hs. r r s t h. r t Lr . r r l r o t hi r nr l r r , : r i l n oi . r nLr nr bcr
' j ; , . . . r . l '
i cl l LLr r pi , t t , r ns. i r c r r r l r ng gr Nt h a, r . r ( ) r \ . r f { l \ r l , ! l | Lr . r l
pnr t t , ns . I hr , ( \ u
r \ r hf \ \ r t l r ( r s
( ) f
mor i pl , t , ns . r r J
,...; i
-
'r
Y-t'-:--.
. - - ' . . . .
phF
ol oqi . hype( r ophy ot t he ! t er u5 d! r nq p. eqna. . y A, Gr oss appear dn. e ol a . or na ! t e, ! t { / , qh0 a. d a q, avi d ul e, ! i ( / e/ t ) t hi t
was r . movcd l or ponp. . t l m b. . di ng B, l ma l . p ndl e 5hnped l t er ne r moor h mus. . . . r l r . nr a nor ma l r ct r f comp. r . t h s wi t h ( c)
ar ge, p l mp hyper i r oph ed smool h m! ( e . e s i r onr a qr av d ur er us ( 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 betwen rh demand and the
cellt functional capacity. There may also be a switch of
contracrile proteins from aduk ro fetal or neonaral rorms.
For errmpl e. duri ng murcl e hyperrrophy. rhe o-myo, i n
heavy chain is replaced by the
p
form ofthe myosin heaw
chain, which has a slower, more energerically economical
contraction. Vhatever the exact mechanisms of hyper-
trophl, a limit is reached beyond which rhe enlargement
of muscle mass can no longer compensate for the
incieased burden. When rhishappens;n rhe hearr, serer!1
"degenerative"
changes occur in the myocardial fibers, of
which the mosr important are fragmentation and loss of
myofibrillar conrractile elemenrs. The variables that Iimit
conri nued hl perrrophy and cau. e t he regre*^e chrnge,
are i ncompl erel ) under, rood. There m, ry he f i n, re hmrr,
ot t he vasrul i t ure ro . : dequarel l suppL rhc enl j rged
6ber, . of rhe m, t orhondri a i ", uppl ' ; i eno. ' * ' "pi o,
phate (ATP), or of the biosynthetic machinerv to provide
the contractile proteins or other cyroskeletal elernenrs.
The net result of these changes is venrricular dilarion
and ulrimately cardiac failure, a sequence of events rhar
illustrates how a ada?tdtiaft to strcss .dn ptoxress K)
fi,nctionally
signifuaftt.ell inia^' if the stress is tlot
Hyperplasia
As discussed above, hyprplasia rakes place if rhe cll
population is capable of replicarioni ir may occur wirh
hypertrophy and often in response (o
rhe same stimuli.
Hyperpl a\ i r crn be ph! rol oqrc or parhol og, c.
.
The two rypes of pbysiologic hypelpldsia zre tl)
howonal l.ypprplasQ, erempl6ed hy rhe prohferrron
of rhe
sl Jndul ar
epi rhel um of rhe rema, r D' ca{ rr
puberty and during pregnancy; and
l2) .ompensahry
blpetpldsia, thar is, hyperplasia rhar occurs when a
porrion of the rissue is .emoved or diseased. For
example, when a liver is partially resected, mitotic
activiry in the remaining cells begins as early as 12
hours later, eventually restoring the liver to its normal
$ei ghr. The rri mul f or hl perpl a. ra I n rhr( \ et t i nB rr(
polypeptide growth facrors p.oduced by remnant
hepatocytes as well as nonparenchymal cells in the
l;ver. Afrer resro.ation of tbe liver mass, cett prolif-
erarron i s
"rurned
of f ' by v: nou. growrh I nhrbrt oh
(Chaprer
l ).
.
Most forms of pdtrolog,c hyperplasia are caused by
ercessive hormonal or growrh facor srimularion. For
exampl e. af t er a normal men, rrurl peri od rhere r. a
bur\ i of urenne epi rhel i rl prol i f eranon r har i r normat t y
tightly regulated by stimulation through pituitary hor-
mones and ovarian esrrogen and by inhibition through
progesterone. However, if the balance between esrro-
gen and progesterone is disturbed, endornerial byper
plasia ensues, a common cause of abnormar mcnstruar
bleeding. Hyperplasia is also an imporrant response of
connective-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 to
the 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 infecionsi
for exarnple, papillomaviruses cause skin warts and
mucosal lesions composed of masses of hyperplastic
epithelium. Here rhe growrh facors may be produced
by tbe virus or by infecred cells. It is important to note
rhar rn rl l rhet e -rruari on! . rhe hl perpl asri c process
remains 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 that
disrinsuishes benign pathologic hyperplasias from
cancer, in lvhich rhe growrh control mechanisms
hecome drrregul ared or i nef f et t ve r( hrprer 6t . Nev-
erhel e\ \ . p' t t h' rl ogi c hyperpl a\ . r Lon, r' rul e\ a rerri l e
soil in which cancerous proliferation may eventually
aris. Thus, parienrs wirh hyperplasia of the
endomerrium are ar increased risk of devetoping
endometrial cancer, and cerrain papillomavirus i;fec
tions p.edispose to cervical cancers (Chapter
19).
Atrophy
Shuakagp n the stze ol the cell bv the lcts, o7 rcll sub-
ttancc is hn6wn as dttoprl U hen I .ufncrent number .f
cells is involved, the entire tissue or orsan diminishes in
size, becomins arrophic (Fis.
l 4). Ir should be empha-
sized that abhough dtlophi. cells nay haue diminished
function,
they ale not dead.
Causes of atrophy include a decreased workload (e.g.,
immobilization of a limb ro permit healins of a fractura),
l o* of i nnerva"on. d' mi ni \ hed bl ood, uppt ). i n. rdequare
nurri ri on. l o$ of endo( f l ne \ i i mul d on. and rs, ns {, en, t e
atrophy). Ahhoxgh some of these srimuli are physiologic
(., the loss of ho.mone srimularion in menopause) and
others parhologic (e.g.,
denervation), rhe fu;damental
cellular changes are identical. They represenr a rerrear
by the cell to a smaller size at whicli survival is stilt
possible; a new equilibrium is achieved between cetl size
and dirninished blood supply, nutrition, or trophic
Arrophy results from decreased prorein synrhesis and
inc.eased protein degradarion in cells. Protein synthesis
decreases because of reduced metabolic activity. The
degradat i on of rel l ul ar prorernr occun mai nt y by rhe
ubiquitin prctcasome patbuay.
Nr\ttie denciency and
dr' u\ e mry rcri ! are ubi qui 0n hgr\ e\ , \ ^hrch aFach mur-
t i pl e copre, of t he , mal l peprrde ubi qui rrn ro cel l ul . : r pro-
rerns dnd rrrger t he\ e prorerns f or degradari on rn
proreaqJme\ . Thi \ pdt hway i \ rl so rhougl o be respon-
i bl e ! . r l he f f cel errl ed proi eol ysi \ , een i n a vari ery of
. rrahol c condi i i on. , . rncl udi ng <anrer crcheri a.
In ma,y siruations, atrophy is also accompanied by
increased autopbagy, with resulting increasis in thi
nu.nhet ot autophasic uaruoles. Aurophagy r..retf-
eari nB-l i ' t he proce+ i n whi ch rhe srarved cel l eat r i rr
own components in an arrempt to find nr:trients and
survive. We will describe this process later.
At r ophy. A, Nor ma br ai nof ayo! ng adul t .
B, Atfophy of the brain in an 82 yea.old
male with atherosclerotic disea5e. Atrophy
oi the brain is due to aging and .educed
blood supply. Note that loss of brain sub-
nance natrows the gyri and widens the
sulci. The meninges have been stripped
from the right half oi each specimen to
revealthe surface of the brain.
Metapl asi a
Met apl asi a i s a reversi bl e change i n whi ch one adul r cel l
t_vpe (epithelial or Dresenchymal) is replaccd b) anorher
adult cell typc. In this tvpe of cellular adaprarion, cells
sensitive to a particular srress rre replaccd bv other cell
t l pe. ber er ahl e r o ur r h. r . r " d r he. r dr r ne , nl nr r menr
Meraplasia is thought to arise by genetic
"rcprogram
ming" of stem cells rather than transdifferentiation of
already differentiated cells.
Epi t hel i al met apl asi a i s exempl i f i ed bv t hc sguarrous
change that occurs in rhe respi.arorv epirhelium in habit-
ual cisarette stlokers (Fig. 1-5). The normal ciliated
col urnnar epi rhel i al cel l s of t he nachea and bronchi are
focally or widely replaced by stratifed squamous epithe-
l i al cel l s. Vt ami n A de6ci ency may al so i nducc squanous
merapl asi a i n t hr respi rarory epi t hel i um. The
"rugged'
. rrrri 6eJ \ quJr, ' d. eDrt hel um mr) I -e . l bl e ro srrni r.
under circumstances thar the mo.e fragile specialized
epirhelium would not t<rlente. Ahba gh the netdpldsti.
.q!n4out qtth.luh ha' rtuiutl ddua' dRc<. tnltut,tdt
f n
t et t rue nTl dnt sus a' p / , ' st . . urh . r\ mucu\ n\ rel r^n
and ci l i ary cl earance of part i cul rre marrer
gpi t hel i al
metaplasia is therefore a double-edged sword; morcover,
tbe influeft.es that indu.e metauldstic tra sfolmatlfi, if
pe/sistent, ndy predispose to ndligndnt trdnsfalnation
ol the e?ttheLium. ln fact, in a conmon forrn of Iung
cancer, squamous meraplasia of the respirarorv epithc-
lium olten coexists with cancers composed ot malignant
squamous cells. lt is thoughr thar cigarcrte smoking ini,
ri al l ycauses squamous met apl asi a, and cancers ari se l at er
in some of rhese alrered foci. Meraplasia Deed not always
occur i n t he di rect i on of col umnar t o squamous epi t he
liumi in chronic gastric reflux, the normal stratified squa-
mous epi t hel i urn of t he l ower esophagus may undergo
nrcraplasric rransformati()n to g:rstric or intcstinal rype
CHAPTER 1 Cellnjury CellDeath, and Adapta ons
col umnar epi t hel i um. Met apl asi a may al so occur i n 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*-'--L
Figure 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, often
I n re\ pon\ e r, , , n. rer\ ed $, , rkl oadr i nduced b)
mechJn, . . rl , f f e$ rnd by
ero*rh
f acron; , ' . cun. n
tissues incapable of cell division
.
Hypelplasia: increased cell numbers in re5ponse
ro hormone. rnd , , rher growrh {act or. i , , crur.
i n
tissues whose cells are able to divide
.
Atlopb,: decreasd cell and organ size, as a result
of decreased nutrient supply or disuser associared
wirh decreased synthesis and increased protolyric
breakdown of cellular organelles
.
Metdplasa: chrnse in phenotype of d,fferennarcJ
cel l \ . ohen a re\ pon\ e ro rhroni t r-nt at i on rhar
makes cells better able to withstand the stress;
u, uJl l ) i ndu. ed b) Jl t ered drf f erent i ari on prrhwrl of
ri *ue nem Lel l \ i mJy re. Lrl r i n reduced f rn. rrurrr or
i nc' er' ed propen. I t f or
maLgnrnr rranrf ormat ron.
OVERVIEW OF CELL INJURY AND
CELL DEATH
A. , r . r | , d, i r r he hFgi r r nq ^ t r h, . hJpr er . . , j t ni ur , , . , Ji r \
when ( 1.
dr e. r f t \ \ d. o, c, . r r l y r h. r r r hr \ . r r e n, , t , - Ber
abl e t o acl apt or when cel l s are exposed ro i nherenry oam
agmg agen! s or suf f rr f rom i nt ri nsi c rbnormat i ri es. Di f
ferent injurious srimuli afiect rnany metabolic pathwavs
a' d . el r uhr or aJnel h. . I n, u' t n' , 1 p. oq" r , , , , , " . . gn ,
r e\ er . r h e ' r JBe . ' nd, ul r r : r . r r e i n, el l dei r h , , ee Fr g t - t . .
.
Rercrsihle cel! oiutt.ln earll stages or mild forns
of . ni . , t r he f un. r r , , nr . r nd n, , , r f hol ngt chr nt r , , r e
r eve^ , h1. , r r he dr mJt s, ns. ' , m, , 1u. i . r ; , , , r ed A' r \ , \
srage, although there mav be siBDilicanr strucrurar and
l unct i onal abnormal i t i es. rhe i nj ury has t ypi cal l l nor
progressed to severe membrane dam.ge rnd nuctea.
.
Cel l deat h. Wi rh coDri nui n8 damage, t he i nl urv
becomes irreveBible, at lvhich tinre rhe cer carrnor
recove. and ir dies. There are two types of cett death
netrcsis aftrl dpoptosis tuhich dif[er in tbeir mo4lhot
T.bre t-i Features of Ne( rosis and Apoptosis
. 6 ' ,
rt_ilr
l
* " \ . , ,
'
',c]t
':"4': I
-''
t
''
. f : ^
a
, " _r l
9
Apopror,c
_{.)
@rild
l "
/
^t.)-
Q,) "
,,^".,i eit'
Phagocytoss
ot apoptotic cets
ano tragmen$
APOPIOStS
NORMAL
tt
Enzymalic drgeslion
and leakage oi
cer ! l ar cont ent s
NECROSTS
cellu ar features of necos s (/eft) and apoprosi5 (.bhO (Adapted
from Walker Nr, er al: Patterns of cet death. M;thods A;chv
Exp Pathol 13:18-32, 1988. with permission
of S. Karger, Baset,
os!, ncdtdnnns, an.r robs n disease dnd physnk,sy
(l i i s.
I 6 and Tabl e 1-l ). \ (hen dam: ge t <, nrembranrl s
c!toplasm, and digest the cell, resuiring in zerrosis. Cel-
l ul ar cont enrs al so l cak our t hrough t he darnaged
plasma membrane and clicir a host reaction (inflam-
mat ur). Necrosi s i s rhc maj or pat hwav of ccl t deat h i n
many comrnoDly encountered injuries, such as thosc
resul t i Dg f rom i schemi a, exposurc i o roxi ns, vanous
i nl ect i ons, and rrauma. ! (hen a cel l i s depf i ved of
qrol vrh
l Jrrol ' "r rhe , el l \ DNA . , r prore. n,
rre
d. rmrgcJ I ' eyond repJ, r, rhf cel l l , l l , , r, et r t ' r , nl rher
l ' hvnol og' . o.
f&ho1.g(
rt,l e
Pyknoes J k:ryoi i hcrr i ki rvol \,s
Eozvnrr.c d' ge$1oni nri l l erk ou( ot cetl
Inv.r.bl ,v pdrhol osr.
l .ul nrnrnon ot,treve6rbtc
tragmrn!anon no nu.leosom.n,?e lrigDcnb
Intacti altrcd $ruduc, spaiallt orien&non of
l.b.tr niil br rele.sed D aD.pron. bod,e!
Olrcn phriologr., merns.l ct,m' .anng un*,:nied
cells: tr[r he
f]thoL(aj( rft.r
y,fre
nrnj! ol
.eLl rDrur!. c\peor lr D\A dinrtrsc
typc of death, callcd dpoplo$r, which is characrerized
by nuclear dissolution without complete kxs or
mernbrane inregrirl. Apoptosis is an acrivc! r,,crsy
dependenr, rightly regulared type of cell death that is
' een i n . , me . pe. i f i , \ l urri on, . $rc, cds l r. , / , ^^ r5
al wav' . a
f at h"] . u, t ' h\ ' et t .
ap, , p! . ^t t t ct uc, f t any
nuthal lu't, tn n' dnd E h"r neccssanly a':,riaral utth
pdtholoei. ell Mftry.The rnorphologic fearures, mech-
anisms, and rignificance of these two dcarh pathways
are discussed in more derail larer in the chapter.
CAUSES OF CELI. INJURY
The causes of cell injLrry ranse from the gross physical
rrauma ot a moror vehi cl r acci dent t o t he si ngl e gcne
defecr that resuhs ir a defecr;ve enzyme underlying aipc-
ci 6c merabol i c di se: se. Mosr i nj uri ous st i mul i i an-be
grouped into the following caregories.
Orl gen Depri rari on. HV, , rt t . o. , , r1gen deri , i rncy.
rFrert ere\ $i rh derobrc n\ rJdri re re, prrrrron , rnd r, rn
! xrremel y i mporranr and common cause of cel l i ni ury and
d, JrL. Hl povJ rh, , ul d be Jr, nngui rheJ l r, , n rd. . nt a.
$h, . h, \ - , l o$nf hl , , ud\ uppl 1 n a r r s. ue duc r o r mpeded
arterial flow or reduced venous drainage. n0hile ischernia
is the most comrnon cause of hypoxia, oxysen deficincy
can also resuh from inadequatc <ixvgen atn,n- o I rhe blooj,
r . i r pneur . oni i . , , r r edu. r r on r n r he o$gr n- ar r yi ng
cr pJ. f l ) , , f r he bl ond, J, I n bl . oJ l , ^ . anem, r , r cr r bon
monoxi de (CO) poi soni Ds. (CO
f t rms a st abl e compl ex
wirh hemoglobin that p.events oxygen binding.)
Chemical Asents. An eDormous number ofchernicat sub-
srances! an i nj urecel l s; even i nnocuous subst ances such as
glucosc or sah, ifsufficiendv concentrated, can so derange
t he osnnri c envi ronmenr rhat cel l i nj ury or dcarh resul t s.
Oxygen at sufficiendv high p:rtial pressures is also roxic.
Agerts commonly known as poisons cause severe damage
at the cellular level by altering mernbrane permcabitiin
osmotic hofteosrasis, or rhe inregrity of an enzyme or
cotacror! and exposure to these poisons can culrninate in
t he deat h of t he whol e organi sm. Ot her porent i al l y roxi c
agenrs are encountered daily in our cnvironment; rhese
i ncl ude ai r pol l uranrs, i nscct i ci des, CO, asbest os, and
soci al sri mul i " such as et hanol . Even t herapeut i c drugs
L. r n, , r u\ c, el l or r i , ! r c i ni ur y r n r suscepr r hl r par r enr nr r f
u, ed er((\ \ i \ el r or i nJnf ropri : rrl 1 rr h. rpre- 8' .
I nf ccl our Agenr\ . f he. e rrnge t rom . ubmi . r, , , ot i c
vrruscs to meter'loDg tapeworms; in betwcen are rhe rick
ettsiar, bacreria, fungi, and pmrozoans. The diverse ways
by nhich infectious pathogens cause injury are d;scussid
i n Chapt er 9.
Immunologic Reactions. Although rhe imnrunr sysrem
defends rhe L,ody againsr pathogenic microocs, rnnrune
react i ons can al so resul r i n ccl l and t i ssue i ni ury. Exam
pl es i ncl ude aut oi mmune rcacri ons asai nst ones own
t i ssues and al l ergi c reacri ons agai nst envi . onment al sub
st ances i n generi cal l y suscepri bl c i ndj vi dual s (Chapt er. s).
Genetic Defects. ceneric defects can result in pathologic
changes as conspi cuous as t he conseni ral mal f bmmr; ons
associared with Down svndronre or as subtle as the single
Ce I Injury Ce I Dearh, andAdaplations
ari no aci d, rh, rrut un i n hemogl ubrn \ grung n. e ro
\ i . kl c. el l r ner i J. a, enet i i def e, r \ r r ay i . r Ll e r r l l r r r l ur r
because of de6c;ency of functional p'oteins, s'ch ai
enzymes i n i nborn errors of met abol i sm, or accurnul at i on
of damased DNA or misfolded pnrteins, both of which
trigger cell de:rh when rhev are beyond rep:ir. Variati{'rs
i n t he genet i c makeup can al so i nf l uencc t he suscepri bi l -
i ry of cel h t o i ni url - by chcmi cal s and ot hcr envrronmen-
ra1 i nsul t s.
Nurritional Imbalances. Even in thc current era of bur
geoning global affluenle, nurritional deliciencres rrmarn
a major cause of cell injury. Proiein-calorie insuffciency
among underpri vi l eged popul ari ons i s onl y t he rnost
ohvi our crl rpl e: , pe. , i i . \ , rrmi n drf i r, e, rre, arc n, r
in devek)ped countries with high stan-
dards of l i vi ng (Ch: rpt er
8). l roni cal l y, excesses of nut ri -
ron are also important causes of morbidity and
Drortality; f(r example, obesiry markedly increases thc
risk lor iype 2 diaberes mellitus. Moreover. diers rich in
rn mrl f . rr ; re, rr, rrgl y i mpl , (Jred I n rhe Jev, . t opmenr or
arh(-u\ cl ero! . a' wel l ar n rn. rer, ed r. rl ncrrhi l rt t ro
rnany 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
(Cl hapt er
8).
Aging. Cellular senescence leads to altcrarions in replica-
ri ve and repai r abi l i t i es of i ndi vi dual cel l s and t i ssues. Al 1
of rhe, e . hange. rc, uh , n a drmrni , h, J rhrl rry ro , e, 1, , nd
r o dJmr ge JnLl . er enr ual l l . r he der r h , , f Lel l . r nd of r he
, t rgJI i , m. Tl -, me. hJni , nr urderl vi ng . , )l ubr , rgi ng rr
, l i scussed ar rhc end of rhrr rh, rprer.
THE MORPHOTOGY OF CELL A]{D
TISSUE INJURY
lr is useful to describe rhe basic alrerations that occur in
damaged ccl l s bef ore wc di scuss i he bi ochemi cal mecha
nisms that briDg abour rhese changes. All strcsses
aDd noxiou! intluences exerr rheir effecrs first ar rhe
mol e. ul l , ' r hl ochemi . al l e\ el . Lpl l ul dr
l unct t on
nay be
l osr l ons b, l , . re ccl l dearh "ccut s. and t he nuryna, , st .
chances of ce iniury
lot dedth) lds
fdr
behind bo,b tFiE.
1-7). For exampl c, myocardi al cel l s becomc nonconrrac-
' rl e rf rer I ro 2 rrl rut e. ot \ hemu. Jl rhnut sh rnel oo n. l
di e un ri l 20 t o l 0 nr nure' of i * heri a hrve
(rJp. ed.
I he. (
myocytes do not appear dead by electron rnicroscopy for
2 ro 3 hours, and by l i ghr mi croscopy f or 6 t o 12 hours.
The cellular derangements of reversible injury can be
repai red and, i f t he i nj uri ous st i mul us abat es, t he cel l wi l l
r er ur n r , , n, r nal c' P, r n. r enr or c\ r e' \ i vei n. u' ) . ho$ever .
cJu, e\ cel l ' ro pa. . rhe nrbul our
"p, rnr
ur no rerunr" rnro
nrcuersible iniury ^nd rell drarb. The events that derer
mine when reversible injury becomes irreversible and pro
gresses to cell death remain poorly understood. The
cl i ni cal rel evance of t hi s quesri on i s obvi ousi i f we can
an' wer i t rr mav be ahl ( ro devi , e , rrJregre\ I nr
t re\ e
t
; ng. el l
i nl ury f rom harrng perm. rnenr
del et errou, r, , n, e
querces. Although rhere arc no definitivc morphologic or
biochemical co.relares of ifferers;bility, xuo phenomena
CHAPTTR 1
-
Cell Injury Cell Death, and Adaprations
The rclationship between cellular function, cell death, and the
moryhologic changes of cell injury Note that cetk may rapidty
berome nonfu nctional after the o$er of injurv atthougtfthey ar;
ttill viable, with
potent'ally
reversible dam;9;; a tong durarion
or In,ury may evenludlly lead to irreve4'ble Iniurv and cett de.th.
Note also that cell death typkally precede5
uttranructural, tight
mi<roscoPic and
grsrly
visible mo.pholoqi. danqes.
consistefltly cbaracterize it/eyercibilitf:
the inabili, to
rcu erse mito.hondlial dystlr.r'b, (lack
of oxidarive phos-
phorylation
and ATP generarion)even
afrer resolurion of
rhe original injury. and
profound
drsnrbances n mem.
brane
functio
. Ls mentioned earlier, injury to rysosomar
membranes results in the enzyrnatic dissolution of the
injured cell rhat is characreristic
ofnecrosis.
Differnt 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 ATp
and lo* of membrane rnregnry rr typicilly assocrated
wj t h necrosi 5. Apoprosrs r. an , c ! e and reeul ared
procesr nor assocrated urrh ATP depletron and n har
many uni que f earure\ . whrch we wrl l descri be. eparat el v
l arer rn t he chaprer.
Reversible Iniury
The two main morphologic correlates of reversible cell
iniuty arc ce ulat swelling and
fatty
thange. Cellutar
rwel l i ng i s rhe resul t of f ai l ure of eni rgy-deprnu. nr ron
pump\ i n rhe pl asma membrane. l eadi ng ro an i nabi l ny ro
maintain ionic and fluid homeosrasis. Fatty change occurs
in hypoxic injury and various forms of roxic or merabolic
i nt ury. and i ! mani f e*ed br rhe apperrrnce ot \ mal l or
l arge l i pi d racuol es i n rhe cyropl asm. I r occurs mai nl y i n
cel l s i nvol ved ' n and dependenr on f at merabohsm, such
as hepatocytes
and myocardial cells. The mechanisms of
fatty change are discussed later in rhe chapter.
Morphologlt
C.llul.r 3w.lllnt
(Fig.
1-B). th6 first manitostation
of
almost 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 affects
manycells in an organ it causes some
pallor,
increased
turgor. and incraase in weig ht of the organ. Microscopic
examination may rsveal small, clsar vacuolos within
lhe cytoplasm; these ropresent distndsd and
pinchsd,
off segmnts otthe ER. This pattern
oI nontethal injury
is sometimes called hydropic chngc or vacuol.l
dog.n.ration.
Swelling of cells is rversibte. F tlY
chrng. is manifested by th appearancs of tipid vac-
uolss in the cytoplasm. lt is
principatty
encounrsred in
cells
participating
in fat metabotism
(e.9.,
hopetocytes
and myocardial c6lls) and is also reversibl. Iniured
cells may also show increased eosinophitic ateihing,
which bocoms much more pfonouncsd
with progres-
6ion to necrosis
{describd bslow).
The ultrastructursl changss of reversible
cell injury
ers 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 as
swelling and the app6arance ofphosphotipid-rich amoF
phous
densitiss;
{3) dilation otthe ER with detachmont
ot ribosom6s and dissociation of
polysomss;
and
(4)
nuclsar alterations, with clumping of chromatin.
E
Figurt l-7
Figurc 1-
Morphologk
(hdnges
in tveBible .nd nreveBible (ell
injury {ne(oris),
A
Noftat tidney tubutes wrth v'able eo'theti.t
(e
r. a. Eartv
rrelenrore, 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 ofthere
stage 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
-.a
+ES\
ei+=N
, r \q{i:,v/
.-66d
CHAPTER I
-
Cel lnju44 Cel Death. and Adaptal ons
o
ffi
ow
I
,",rt\
; c
d 6
e 2
6 4
E I
d ;
E 3
Clumping
A normal .el and the.hange5 in revereible and i.reversible cell injury (ne<roris)
Necrosis
The term narrosls was first used by morphologisrs to refer
to a series of changes that a.companl cell death, largely
resulting from rhe degradative action of enzymes on
l , i hJl l ) I nrured cel l , . \ ecronL t el l . rre unabl e r, , mrrnra n
membranc inregrity, and theircontents often leak out. Thc
enzymes responsible for digestion of the cell are derived
either from thc lysosomes of the dying cells rhemselves or
frorn the lysosomes of lcukocytes that are recruited as part
of the inflammatory rcaction to the de:d cells.
Morphology
I n one common pat t ern of cel l deat h resul t i ng f rom l ack
of oxygen, the necrotic cells show increased
eosinophilia 1i.e.,
pink staining from the eosin dye, the
"E"
i n
"H&E").
Thi s i s at t ri but abl e i n p6( t o i ncreased
bi ndi ng of osi n t o denat ured cl t opl asmi c prot ei nsand
i n pant o l oss of t he basophi l i a t hat i s normal l y i mpart ed
by t he ri bonucl ei c aci d
(RNA)
i n t he ct l opl asm
(basophi l i a
i s t he bl ue st ai ni ng f rom t he hemat oxyl i n
dye, t he
"H"
i n
"H&E").
The cel l may have a more gl assy
homogeneous appearance t han vi abl e cel l s, most l y
because of the loss of glycogen particles. When
enzymes have digested the cytoplasmic organeiles, the
cytoplasm becomes vacuolated and appears moth
eaten. Dead cells may be replaced by l6rge, whorled
phospholipid masses, called myelin figuret that are
derived from damaged cellular membranes. They are
thought to result from dissociation of lipoproteins with
unmasking of phosphatide groups, promoting the
uptake and intercalation ofwater between the lamellar
stacks of membranes. These phospholipid precipitates
are then either phagocytosed by other cells or funher
degraded into fatty acids; c6lcification ofsuch fatty acid
residuas results in the generation of calcium soaps.
Thus, the dead cells may ultimately become calcilied.
By electron microscopy
(see
Fig. 1-g), necrotic cells are
characterized bv discontinuitis in Dlasma and
organel l e memb16nes, marked di l at i on of mi t ochondri a
with the appearance of large amorphous densities, dis
rupt i on of l ysosomes, i nt rac), t opl asmi c myel i n f i gures,
and prof ound nucl ear changes cul mi nat i ng i n nucl ear
Nucl ear changes assume one of t hree pat t erns, al l
due t o breakdown of DNA and chromat i n. The
, -*l-'
. ! .
'@,
:
FEomenlaiion ol
::iffJif*'t.;-ai
' . o
- r
) . - .
- !
f l ) o _ i , . - : i i
/
N<oss
- ' _r , . . : o- ' ^ - 3
|;ru*.-",t:,"6q,4
l 0 CNAPTER I aell niury cellDeath andAdaprarons
basophi l i a of t he chr omat i n may f ade
( kar yol ysi s) , pr e-
sumabl y secondar y t o deoxyr i bonucl ease
( DNase)
activity. A second
pattern is pyknosis,
characterized by
nul ear shr i nkage and i nr eased basophi l i a; i he DNA
condenses i nt o a sol i d shr unken mass. I n t he t hi r d
pattern,
karyorrhexis, the
pyknotic
nucleus undergoes
f r agment at i on. I n 1 t o 2 days, t he nucl eus i n a dead cel l
comp et el y di sappear s.
SUMMARY
Morphologia Alterations in Injured Cells
.
Rcrcrcible cell iniury: cell swcllins, fetry chansc,
pl asma membr. rne bl ebbi ng and l (xs of mi c(,
vi l l i , mnochondri : rl s$cl l i ns. di l ari on of dre El t ,
eosi nophi l i a
(due
t o decreascd cl t opl asmi c RNA)
.
Nerrosa' i ncreased eosi nophi l i ar nucl ear shri nk'
age, f ragment : t i on, : nd di ssol ut i on; breakdown of
pl asma membrrne . rnd orgrnel l ar membranes;
mycl i n l i gures; l eakage and enzvmat i c di gest i on of
ccl l ul ar conrcnt s
.
Ar(rn)s's: nuclcar chnrnrnnn condensation; for
mat i on of apoprot i c bodi es
(f rrgment s
of rucl ei . 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 r
i nsr an. c ! n r hf , schcnr l c mr r r . r r t l i unr . r cr r hs i n r l cr r h of
r he enr i r . nssue i nd vr l r et i r es . r l r cl r t i r e or gan. Thcr c ar e
sr l cf . l nr ( t r t hol ogi cl l l r dr sl ncr p: r t t cnr s of t r ssuc nccr r
si s, \ ! hi ch nuI pr o! i dc ! l nes . r br i r t t he ul der l r i r r s er usr .
Al t hough r he t cr r ns r hr t dcscf l be r hese pr r r er r r s do nor
r ef l ect undcr l yi Ds nct hani sms. r he t er ms. r r e used oi r cl
r l d t hej f i l Dl j . ! n( nr s r r c unr l cr st r r r d bv bor b p: t hol ogr st s
Moryhology
Coasulativenecrosis is a form oftissue necrosis in which
. t he
component cel l s ar e dead but l he basi c t i ssue ar chi
tecture is preseNed for at east several days
(Fig.
'l
10).
The affected tissues take on a firm texture. Presumably
t he i nj ur y denat ur es not onl y st r uct ur al
pr ot ei ns
but al so
enzymes and so bl ocks t he
pr ot eol ysi s
of t he dead cel l s;
as a r esul t , eosi nophi l i c, anucl eal e cel l s may
per si st
f or
davs or weeks. Ul t i mat el r t he necr ot i ccel l sar e r emoved
by
phagocyt osi s
of t he ce l ul ar debr i s by i nf i l t r at i ng
l eukocl t es and by di gest i on of t he dead cel l s by t he
action of lysosomal enzymes olthe leukoc},tes. Coagu
lative necrosis is characteristic of infarcrs
{areas
of
i schemi c necr osi s) i n al l sol i d or gans except t he br ai n.
Liquelactive necrosis is seen in focal bacterial or,
occasi onal l y, f ungal i nf ect i ons, because mi cr obes st am
ul at e t he accumul at i on of i nf l ammat or y cel l s and t he
enzymes of l eukocyt es di gest
( " l i quef y" )
t he t i ssue. For
obscure reasons, hvooxic death of cells within the
cenr r al ner vous syst er n of t en evol es l i quef acl i ve nFc' o-
si s( Fi s. 1 11) . What ever t hepat hogenesi s, l i quef act i on
compl et el y di gest s t he dead cel l s, r esul t i ng i n t r ansf oF
mat i on of t he t i ssue i nt o a l i qui d vi scous mass. l f t he
pr ocess was i ni t i at ed by acut e i nf l ammat i on, t he mat e
r i al i s f r equent l y cr eamy
yel l ow
and i s cal l ed
pus
( Chapt er
2) .
Although gangrenous necrosis is not a distinctive
pat t er n
of cel l deat h, t he t er m i s st i l l commonl y used i n
cl i ni cal
pr acl i ce.
l l i s usual l y appl i ed t o a l i mb, gener -
al l y t he l ower l eg, t hat has l ost i t s bl ood suppl y and has
under sone coasul at i ve necr osi s i nvol vi ng mul t i pl e
tissue layers. When bacterial infection is super:mposed,
coagul at i ve necr osi s i s modi f i ed by t h l i quef act i ve
action of the bacteria and the attracted leukoc!,tes
(so
called wet gangrene).
Caseous necrosis is encountered most often in foci
of t uber cul ous i nf ecl i on. The t er m
" caseous"
{ cheese-
l i ke) i s der i ved f . om t he f r i abl e
yel l ow
whi t e appear
ance ol I he ar ed of aeLr osi s { Ti g.
' l
12) . On mi Lr oscopi c
exami nat i on, t he necr ot i c f ocus apDear s as a col l ect i on
of f r agment ed or l ysed cel l s wi t h an amor phous
gr anu
Coaqul at ve ne. r osi i A, Awedqeshaped ki d. ey nf ar d( yel ow) wt h pr er er vat i on
of t heout l nes. B, Mr <r ot cop . vi ew ot t he edge oi
the infarct, with normal kidney
(N)
and necrotic ce k n the nfarct
(l).
The .e(roti..e k show p.ese.ved
outlines w ih loss ol nuclei, and
an inf ammatory lnf ltraie I
prete.t (difiicult
ro d s.ern at th s maqn f.ai on)
I
$+'il+lffii
4
i L. r' . ' -'
j
": l
:i".,.
'
,..-' .;..i..' ..i.i ,1,.
il,
i
r lt
';"' "i'u:
':
ii
. : i ' . .
r: ' , i . -
i f .
_ a! 1:
, :
- . ,
,
: J . I
: - . - :
- . : ,
rqrrsfofmri.. utn prorcrns,hdush rhr drn,s.d
' h. cncuhnon ,ro
lidB ' n.' n5 ' ,fdfl(rn8 n$ucsp(,f( nrtrou5 u,ns
arr,li:( DUeh, fnr.rimoh.
.oDtains a unlqkrornm ofthr mzrn.(etiD. kim!
?id of' h. lonkd .
mo.e' n rotu";. "hei.rsh.or .
hile dud tp+lilm onirn' , kmFi,r,r R,;rut
roforh of rhe .nzym. ikatin. pholphnzr,
and h.p,
6ibl. initrs ind 6tl
deed in ih.n isues rrt rtne(d in incm*d 5!run
lelels ol !u.h pror.'ns, ind m.asurcmcnr oI erum twek
n 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 or
lh. ..ll as , u.n. HolBer! .eit in z*.nb znd
jr..*s
ntt,l!ns ony sub.dtuhr
ol8,n.rh!. Ar+oleh em. ot ' hG;tk ron, (cur,r
r d. r dhar i nr uq, o . EJE( r n, nLhr ont r r u, mor r dl
iniurn and ,ill.orl' ds arc id,pl1y
n :nd ' ntr.nine o'
ther rtnion! arc d\o^w.l
auropbaSr. Aubptisy EG6 ro tvsos.nal disenion .f
rh. c.ll\ osn .onponenr rnd is .onm$.dtnh ,gr
efopr,431, nwh,chrcdl
suberi.o hom rh cdriJc for i,riicd/uta! dsruqioi
lFis.l-15). Aurcph,sy n rhousir b L. a suryi!,tm.th-
.rrn n nm.s or nuri.nr d.privarion, su.h rbar thr
fiflrd cll liy6 br sms ib own .oftns, tn ll1r
prtu!$. nr,cdtuhr o|e?nr s Jd
ir< hrsl fqu{rcrd fr,,m lhe+' oolz' nn altoDLoq.
,,. {o/. fomrd trcm nbo,on! fft,4' on\ of rh. rc;h
ER LRERr Th lr.uok tu*5 wtrh y,o",-s
b brm;
c,tdthasatya'an4 :nd rh. c. trl, .omlon.ns re
di&*.d by lysdonll.nzyms. Auhphasy iinni:Ed by
ev.Er prckrsihr$nsenrntntd.pnv,.on.
tf nis nor
(o
arcd,aroph:8) m4 resisnrt.d drnh h) rpop
hn.d ellrh,r Lr lrn
n,, ions.imp. br Inins on B"$n or6ndL!.
Thr.i4n6 n lr5o,on6.an brcrl do\n msr
Do
rii!,nd crbohydrua, at' housl sohr tiD& rcrfu,n
uidicdEd 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,rhon
p3rti.rs hhd.d fom rh. .rmosphei. .r incul.ted
,i pL2sotrsosom6
of
mr.ophases rar d.sd.s (disus.d
tarrr.
L)sosones,r.akorepariroi.! whercr etls*qu6Er
mdribr\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.dy
d2nr :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.tes
arc nerabolized ir tllr llve by the crehrcme
p-1J0
m,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 b
ur inci.rins dotrs. TIn:daphrion ddue to incRz*d
eorun.
th)ptuophy) of $e sER ot h.Ddo.yr.! .nd
in(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.6
by rhn prE q
on! exanpk n.rboo ter' ch torid.. dis.
.usd l,r.i In addnion, d! p.oduc6
forn.d by this
oxidrtiv. f.tabotism in tud. recrvr oxyeln !;f!
rRosr,
qhrh
cin r!ft rh.
([
.rrs adji' ed ri, om
. r r bot r , { her ! on
pounds hrndl.d hy th. sE. syn.n. Thu5. if DdmE
hkins ph.nobarbnd
Iq.Dit.Dsr rncrt1s rhff ;Lohol
rblc, 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, mrGhon
dier drrrundon
Fhy.
:n ,mpon,
inrury and daih. ln en. ronldh.t Dnholmic d,!di
iion!, hou.v.l rhG n,y b.,h&aioi,s n iha lumb.i
si-. shrF, 1nd presumrbly
lundion oI nirrhondni.
r or $r npk, i ne uLr hr Fnoph
in ' hr fumbn oI m,Mhondfl: D.dk.conrd(tq miro.
lhondnr d..rtas. ' n nunb.r dunnr cdlutar irioDhr
rrob,bb !E
arcphisr. MtrEho;d.r m4,,s;-;
elftmlr' ri' 3f ,nd ;hnomrt lha
,ous,dri,t,r, drti
..noa,nd i.ohotic tivd dk..5e
mer:bolic di**6 0I strtdal nusb. thc nno.hohdtidl
nlotdltE', d.ks in mirEhondn.t mdrbotjf n
Ad4h| 9(4h0andhd.| o' ba0!btR.dl rw|
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*onconsn6ol
rctin rnd nlsrn ril,mha. nnrotubuks, a v.riour
d *..t iftlmldi.E 6lan.n6t svd,lorh.r nonpl,ly-
n.r;cdandronfiLmenrous fomsatonr,.ih
Drorein5
.ko cornibuk ro rh. cdluhr siffolJ. Th. .rlosLddon
is impoit ni for n,ny c.llula! Iundions. inctudns
.
lnfec.llulrr hnsDort 01 .@ndl.r .nd nokcuhs
.
Mirhli.i oI 4.5i. cdt;rchn durc
1r.g.,
..tl
por,rirr, ,lierinsunhiq up end dcsn)
.
THnsmission of rtll{.l| 2nd err<xnaallul,r
.
Miinrtftn.. of mahanical $rtnsth tor i55u.
cdls ,nd rstr6 i..pond b .nvnonm.t t sis.ts
k.3.,
she,r sca in bk,od
y6skor
iD.Fdtd
prtsuc
ii .l' !an) by con$antly rtmad.lins dtir inrac.llular
$:ffotdjns. Abnorm.tnm of rh.
qbskd(on
oaDr in,
vrriry oi pitholosic $1r!. Tij.e abnom.lri6 har 6.
mn1i.s.d s r .b.ormat aDF3rrne ' nd lundi.n oI
.d15 (hrp.nophic
cardiomyop,rhyt cl' .pEr l l), 3btr.
:nelks. d.fdi!. ftll
ldonomn. dr inr..dlula ccuinuhiicn oI 61,!irh,
nrnri2l ,s in ,coholic tiver diksr (c[apE 16).
p4.
o.h.rions in th. ol8rnianon of,nrtubuLscane *
*erility by ,.hibnins .p.m honLty, s uell s d.fnaiy!
mobirn' of!irr in,h. 15pnrory.ptrh.t,um, Kat ns,n
!hronr nfld nn5
d!. ro ' mFrr.d !qEnc oi rnhrLfd
6.ckia lkrtuseEt, or t\. idnotile dlir, stndrtdzr.
Mtrrcrburs,i. rrn,.s$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:g6
ro*ard ui,r.ftyi* unh subr'tue fru$srdd@pts
it
,h,*o+osis .nd inflanmrtion. sii.r hicrorubul.s
r.rm ih. mnoic spmdl.. dius. d'2r bild b microrubuhs
(e.s.. vincr rlk,lods) ,i. 21o .rtiDrotileHtive ,nd m.y
thercfor. b. u{Iul .s.Dtnumor r*.nB.
Iru
r,t rr
Slbclkl$ Ahdddr i. <.ll hl{E:
Elld ol r4udoBA!.it oi ds.;cl6.nd
SoD. iorms ol ..n injury ' tu* prni.ut.r
olgimlr6 ,nd hay! uniqu. mrnilsbriotu.
.
,4!rrra3'r In nurienr d.priv.d alh. olsanells
n. .nclosd in vicual8 thar fu$ with lKo.on6.
Th. are,nclI6 ar. digsrd bDt in .on.;as indi-
s.ii6l.
pism.nt (..s.
LNtusjn) rh.ins.
t
l|.rntl'y of strli c.ll6.rEd to bnrs drt
rrcn.hboh?d,n,h.5tR 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 in
div.c ad{t iions rrd r.$on$ to chrcnic i4ury.
'
clioJtslsal clrd,.rbzr son. druss ,rd roxinr
:isnbly r.d lunaions ol
cyt6k.l.bl fiLmens or rcsfi in .6nodal rau.
I
rEctatttfls of cEr.L r ruRy
Now thr s. h,!. dieu5*d rh. cau$s ofRllinFry rd
narasis.nd .n no.pnotqic' nd tun(oni.orEtaks,
w. ie{ consider in norc d.r,il th. moreutar b.sn ot
cdl i,iury rnd lltd illun,ar rh. impoit nr prin.ipt.!
wiih r r.w krr,.d "xanpr6 orcommon
ryp.sofiriury
Th. bi&hrhicn mehanisms linkine my
sivm
iniury
with ihe rcsukiq c.lltrlii rJ Gsu. mnife$.iions,ie
complex, ifueKonndEd. .nd ishrly nrrwoytn wnh
mrny nhc.lluh! mdaboh.
paih
aft.n dil6.urt r
pinroinr
3Deri6. mohculrr akd,
rionscau$d by r pini.ular insuk. Nvenh.lsi nlcral
s6d,r
prin.ipl.s
:r. rct.vrnr ro nai f.ros of cdl
.
Th. eltulo ft:panr to i,i',h,' n'nuh d?p?n& oh
the
,p?
ol inj,4, it' dyn o\ and * rfu?7ifr. rhus,
low da*.aI!xi!5 ora bn.fdunrian.Inchlm; nav
LrJ $ Beribl.ellniurx wl' e.:s lars*toxn dok;
sult n trrcv.sil'r.
iniuq rnd e1ldeft.
.
rh. a,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 ftqrnr
ourona d.tsndins on th. c.1t 116 thun *tuEd
sk.l.El muele in dr 1es "<omnodaks .onDltir
i$hemir for 2 ro r hou6
ynhout
rak6ibt. inlury.
wh.r,s c,rdi2. muste dies rfrft onir 20 h t0
nintrk.. Th. nunnio' rt (cr horhonat) naiu5 ca, rlso
b. impon,nr. d.ir), ?
sj.osen.rcptd.
h.p,r{rk
w,[ ror.r,rc n(h.mn mrh bflkr rh,n "nr ${ h]!
run
brm.d n! hrslu.or molRul.. ccndcnty d.tcr
nin.d diy{siry i' mdrboli. p.r6way5
can .Ls b.
' mpoftznr. For inr2n !. when expord rc rh. s1m.
dok or i raxin. individ$ts who lnh.
yarianc
in
s.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 oI
5uch inrmctio,r ir.dr.J Dh:;ase;omis.
.
c.tl inqry ks\ns
hon f,rctiorul
dnd brrr.nnal
cbhandhn' in ote ot rat o{ sr{al .seanat dqt
tat .onpo"nB
\Fie.
l-16). Th. Do$ mponrir
i:4dr or inird.us rimuli aG lt) mne[.ndria. rh.
sita of ATP
s.r*arion! 12)rtllnchbBn ! on *hl.h
rh. ionic and ormdn hoi(Ebsn
olg.n.llcs dtptndi
1rl
prorin s)nrhsiq
i4)
rhe
cyt6keleroir ind (t)
ihe
sndic
app,i B oI th cdl.
Mr r
-
dr ntq .d M d^d4hc
tllnn
I
- l
I
I
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 bv
a\id?,n. ph6phootrnon
or adtro,ne dDhos;hri
IADP) du,inc rlucion oI oirsen in d. d.d;on ;,ns
por syirrm "r
mndhondna. In rddr on. ,h. rtvcothc
pflhv:,.rnE
n.tur. crr ' ' rh.ik.rc.oroxv6
u;inr
slu.,*
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 $r h ,
sr t : kr et y. ot F.
.rprcfy
i..e.. rh. hs) r. rbk ro 5urvilr to$ of oxv!.!
ind dni.r*d ord . phosphoqh
on bnd,hr;_arc
phosphr<
rn rhr rom of AT? r
(qu,red
far
yinually
ill syn$eac ind dcqriddvr
pr r . s! { i r hi n, ht . . l . ' ' ( t ud, i sm. mbmnr , ; n5Fn.
n(6rry ror
ohosDhot,Dd
nmov.t. D.ptehan a[ afP ta ter &ca t4c ta ]o9r ot
"mct t"Ek h^ vdnp2ad
4frd,
u ia4 n.;t
.The
rcnlrr of th. phru
ddb,an. dd*
dAd.t nt so.tua przp
E i.d(.d. rEuhrc i,
iir,lr ut.r rclununion of ,odiqm ,nd .ftu\ or
por.s' uD. Th. nd
s' in
oI5otur. is,.comDanird 6v
rio.o$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.rcv
e!ft, A5r.onr,tu.nc,,nr3e
!h, gtv.ar.n(o;
rft Bprd\ d.ptd.d, .nd tidr .fld ;d;Eu|JA
r.idins to dri.lid inr'c.llutar
DH md d.crikj
activity ol @ny cdlul,r .nzvmc.
.
F.ilrn olth. C., p' -nte2dstoiniuxolc.l.wnh
dim"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 of
pdyen*
nro honoen.q wnh a co6.oue rcdr
tion in prckin
synrhsis. utrim.klx rh.. i; iftv.Bihl.
d,mis. b mn(hondi,at rnd
teemrt
mnbEn.s,
S\e
I
I
I
I
cyro$li. t ..i.iuh n nom:lly n,inbintd 6y AT?
depsd.d ca lcium r: nspoftr ar .orc.r r onsfiar3rc
,s nu.h rs l0,000rnes lower tia. d..onc.nt,,Dn of
.ft,cdltrh.rLiun orol*quaErtd inrlrllubr dno
chondill .nd tR sLium. latumia .nd ..nain !,in5
cau$ a! increa* h cyGolic
qlcium
.orc.rnnion. ini
arlly b.c,Ds of rcl.rk af Crr' trom ihe intrftllul,r
ioi.i ,nd lzr.r 6u1dnc 6oa iicr,*d innux ldos d.
ptasn n nbtane, lnoa*d qtasali. Cl a.rvtt.s a
,!rD.r ot r.ymeJ. wi$ potenmllr ddd{ious allular
.ffrnslFl8. l-19).Th.r.n?ynsindud.phGpholipird
lvhi.hclu!
m.obr.ne d.m.$), prctes*
{-hich bEaL
down borh nembran and qroskd(t porins),
cndonucle*s lwhrch.i. rtspo$ibl. Icr DNA rnd.hre
nrin tisndbrionr. rnd ,Jdo!in. riph.sph:m!6
IAII:*5, rh(.b) hrnninB 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 FEe
R: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 (l dBo| rFdsAreeei gi eti pi gptnl '
D.rag. to ilito.hondria
Mnahondi. aE rhe cdlt supplicd oI lif. s!$rinins
.n.Ey in the fom of ATP, btrt rh.y in i.o.riri.i phy.^
in e injury and de,rh. Mnehondnl .an b. d.mas.d by
incr.{a of .yroeri. ca-, E.div. oryen sF .s ld$
cu$.d bdowl.nd oxys.n depi!,!on. d so rl' ty r.
snsnive ro vntu' lly rll
rypA
ol injuious nihuli. irclud
No maior otr+
qu.nc*
of hnchondlial damse lFig. I-13)l
.
Mndhondfil drmrs. often iauk in rh lom1non
of e hlgl.onducrinc. chinn.l in ,h. mircho.di.l
m.nbhne, ..lhd rhe nnrthondrhl
Fm..biliry
kn-
sid.n por, Th. op.nins of ihn ch$ncl l.ds io rh.
bs of mnEhondi,t membran. pordii,t
and
pH
cnaas.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 Drcteins
rh,r ,ir c,p,bh at 2diy.nrg apoFoti. p3ihw2r,
includins ./khtuh. . khe m.jor prckr invclv.d
in d<.rcn r:nstsn). lncrs.d
tsin
ibi|nr of ih.
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 2nd
d..thr in i6 norml lc,mn insid. nnchdndn., ft k
6snti,ltor.nergys.n.n o!andth.lifeof rh.cdl,
bd -btn iiftrhond.ia r. danzs.d so ev.rly drit
./r(hrom. . l4ks our n rismh cdL ro di..
I
e
I
I
I
oe
t
l ?
I
@
t . *
E-@s@
HF@
ft..o. or rcrdEorye.i ' Bi 6 (R6) h
ar m!ry or n @iEdd ro {tsrdid.
loj)
3,o, b1 drndn d md ikft! ro d.r rh!
c,rc orrzd Fl dd ddai Bi , B
: b &r { d d i d | } ' @n o d | g i a o l
oren i n! hn tu.rodo,444! b |n d
hllr tu rojor r4roidn liryna d!
n
(etk
4 al dty
rnr(I nucl .,c a!i d5 n wel l *
a \:n.D of! ut.r Dro
tei ns,nd ri pi ds. In rddi i nni fR bdn.L i ntri rt .i !t,.
cdrrync r..ciioE motlcuks rh,r r..r vnn tft adicri
,i r n tqrnmi v.d(d nto ne Dd' cn5.rhui D&D.crunr
rh. (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;r
rion. bu' rr n. d.sEdd rnd rcn"\ld bi ; un
dd.dn srtem' wh.i $. produd,vn
ofRos,na..*5
ai rh. saveryins
rn
ms $. in.#ctiv.. rl1t 6uh n,n
.xa$ of rhd. fc ndisls, l.adim to a .ondnion .al.a
rEitltE
ti.s_ Cjll iniuq in maiy circumsD(A
'nvalv* drmrsr by fc rrdrcd.: d.s snu'dons irctude
1dieu5*d b.lou). .h.mist inJ
Ed' :i ,on mED. roxl $
ellulirrs,ns, m(rcb:t rilrnsbipf]sqr^
rttG:,nd
i t r j t r . f l ur y ! ' uj dh' l n[ ' mn: | o0d| 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 Bur
dufln8 no.mi mnmhondnrl fr.hbotisn. Du.iru
(!r
eumol(, ssk \hr .*ks is
Fqrnri,lrrrd(ed nniGhondnibr' h..ddrionaf
th. Drcss. m1ll
,m"uns otro.r ntem.d' :k
5rE,e5 ri
p.!saE,l
bv
p.dsl rcdufinn or oxy*!n, d;f rn.tud; rFrcrd:
ndn,L
loir, hvdia3d p.fid.
lHror). rid oH.
vr do,r. fE dfr' rcil dunns .(D n mriedrut;r
readlons 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.r
rcnr, \ ny(). lonirns Edir' ion !rn hrdrotya ur.r
ii' 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 bv
l.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 orcttbD6rlhrDrcr
2), crn rfl 13 r fk cdi(Jt or !,n b. .onrert.d;b
highly rcadrv. nnnt sFls
Gll, hilrdr(lop.d naq zer,,n,,h, h, tno!. h2.
rddral and ' h.i.by hnm,. ,nrury Fre nd k rE
inh.cnrr urirbl. md dery sponrnsudy. Th.rc ,i.
are ev.r,r ion.nzyn i. and .nz',n.ric sysrDs rh,r
.onr,b,r. b inad'v'doo of fft ri/i.at r.ediom {*.
.
Th. hrc of iFnmn.ou! d(ay or suDrord.6,c
n' 66n' ly n(i.&d bl rh. :cucn af,uFordr d;
muh* 51t oDr Lt uund
m ni ny <
qp;
l 6ht , . nq
r h. Kr doi r o; 2H -
H, or + 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 ro
rtd(.d
sluiathioft
(CSH)i5
r rtfl(tion of ih. ondr
!y. shk of d. ..ll an'l rn ihrotunt rsr.n ol r!. .e r
ab i$ m..tabolir t. r.dicats.
, dc6 the dtE
.
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$tior.d,bov., toz .nd .oppd ei.arzlrt
rh. rjormrion of Ros. The l.vds of d.* rcrive
mdrl. .r Edued by bindine oI rh. bns ro *o$se
and tnnsDod
Frat
ins (..*..
Ensf.rin. ferinn.l.do
frn, /nd ftrulopsm,nr, rhsebr d(ls' nc rh. roF
ROS have mny dlves..ft b on cIs lnd hiv. a.n
b.en inplicd.d in &.ivaion of cdls by i vri.B ol
phy'
idlogic rimuli. Hq.v.4 rhirt dioff arc
tsnicDlidy
cwlnr 6 .an ntw! h,llidkA la
h.e
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.ur
5ultydivt mrdEEd prckL' *6, Lntrn& Guhrns,n
Fc{:diel rcrction my.hodnetly suk p.lyFp.
.
DNA
t
ace,hror. Fi.ebdiel edions sri
rhyoin. in nucl.ar rnd niu*ondrial DNA
produc.
nnsl..nruid br,l.5 su.h DNA din:s. hn b(n
mprlrkd in <i drh, isms. ?nd matn:nr rrii
ttelect In il.nbrane P.me.bility
t.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.vrBt
h*h.m..l mtrh:ntrm! m4 .onr' bure io m.mbEm
t 7
.
Dut.Lan ph.sOhobA
,nthe'k
The
,rcdmioo
of
ph6pLolipids
in ]ts m,v b. rJulrd urr.D.vs
rh.( n a Gll in ATP levels, Lidjng to d6rc&d enersy.
d.p.nd.nr .nzym1ft ,c.iyni.s. Th. rcdued
phasplo
.ffd '[ a JI n.hbr.!.s
indudi4 lh. mnhodiii ih.n*lv.!, rhus .x.ft.
.
I|.t%.d phosphnlip'd
bt akdoan. s.!n .tll
miuy r "$Gnted wiih mcrc1*d /.gr.d:non of
n mb.an. phGphalipidr, p66.bly
due ro ectivrtion
of.ndos.noxs phspLolipas
by rncrc.sd LveL of
.
ros. Oxyc.r t* rrdftt sue injury to cell mem
br.n.s by tipid
tsroxiddon. di$u$d.rrtff
.
clb:ldtul db,omlitEs. cytoskeld2l 6lh.nb
sfl. iMncho6 connetins rh.
Dt,sm,
n.mbnn. ro
d. ..ll lnErioi Adrvrion oI proEa$s by incrcakd
cllosl,c car. n1/ cau$ d:m8e io dend6 01 th.
.
Lipid btahdoa ptod"*. T\.r! inclu,l. unaren
lild hE h' ry icd!. nrlarnr' nr, rnd
\,aphoiph"
lLpids, .r,bolk
orcducB rh,, rrt Lrou ro
r..umut?k in,nrqrt:d alsfi aut! !f Dho5DholDd
dcsEdnion Tr.y hiv. : ddlrsld .fh:cr oir man
br.,d.Th.):re rrhtr inqtrinro ' h. hpd h GFr ot
,h. mdbEn. or.:.hrns. wrt' mrmbtsn pho5Dhc
lipidr, p.knirll) .,ueng .hans6 Ln p.rm.rb' ltry,nd
.lg'ophFiolo*'..lrdarions.
Tht m,&,mpofttrersar h.mbrrft drmsedur ns
crr,niuq ei. . ni,*hnnd' i.t n.nbdn., ' hr pG5Dl
m.mbmn
,,nd
n.obnnes oI tysosonn.
.
Mnothandnat nmb E l,es,, As di$uscd
2bov., d,masr b mn&hond t meDbrr.s 6utu ii
ds.rsrd piodudjon
of ATq cuhin2tins in nEosiq
did trkJft llf prcre' B fi,' r' es.r rFprotr. deerh.
.
Ptdsd' 4erbrale 4,44. r,hrmr nehbEnr
dama$ Lrds b 16. oI osnoic b,l!r..rdinflux of
lluids 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.t
rhu .nzymB inro rh. .ytoDl.sm rnd ..tivlrioi oI the
&' d h,drclij6 n ft n' d' c nr,!.lul?r pH
of rhe
inrurcd ks. i*h.m(l e . Lrs,{,,ms conn,n
nNr6. DNrr! prorcraj
stuc6dai,,
ind o,hs
m6 t . adr n, . na.
mn. dis6tion of cdl compordb, .nd lh. alls die by
Dan.ge !o Dl|A and P.ot.in.
c.l l \ ha( m(hrn6ns ' fr KFi rd
i l i hk drmrg. r ' oo 5-{. ro br l ofthd
ke, rhn
mdi ,non i ntury or oxi tl ati ve $6.t.h.cdl i nri d ns
l uni d. prnsDn
Jd d,.! b, rp{' o
k ri s{.d by ' momFny l ol l .,l mo,.' ns.*hrchnar
b
Ih. rcsuk of,nh-,Ed nuurci i or.r.nn r' *er 3u!h
i 3t r t EdKr i s' n! eA6. nr hr r ' 3mi d( n; l u4 r j p
er ry au* rpopro3l j ' h!y n. d' *u,qd hEr n rh.
hj ury redi {
4ei s4
l a
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 + Dlti
Drery, nd6'q und.r lm. .ondnioq t..t4. ot
.
I'nlB of aLir,: riwnt oi 6zyr' d^r
drm,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|{rtY
At|D rEqosls
Th. tund1on,l .on*quen.s niy b. $v.F ar ihij
n.s.. For in*rnc., h.:d musL ea
60 smnds ot corcmry
(tueion.
Hou.!.q to$ of6.
,.djrry dc nor ni cdtd.rth. rt lyFxia co,tintrs.
n 9 l 6 i E, { D&Pk ! ! g u x t l . q
wnh bsolmicrovirri rnd th. formitian ot
"bt.bs"
ce
Fis. 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$run. , 6?., r
E orta,alt Ltth-.
dLtuia;atak kAt;bt.'
II inhnn
t
'sk,q nEr-rble nitt dna neoa'i:
.e. krcv.slbr. ioiury r ssi2i.a wnh sv,.
smll,n8 at inchond'i,, .rmjv. dmrc. ro Dlimr
m.mbBn6. ind 3*ell,na or |lsom3 i!4. h!. !9r
MassiE,nnur oro ! u;' nro ihe !t[ hr Go; D5rh
n n:inly by mrtEit blt iF rs,..lrc;ndbu6: 16.
b$ty by d.a$ ot
prcrpdproric
moleul.r fioh t..kv mirehondnl The
(rlr5
compomii, ,ft
|rosrcstrel'
d.scd.d, and .r.
n wrde.prt:d kaL;s ote u[r.n4me5,nto itr..sa
elurf !p{e. Iinally, rh. d..,1 elk my b.sm.
rcpr,lcd hr ha n,,!6
(,mNfd
or ohosDhohDd5 ,n
rh. rom orm' dm riBd.5 rh.,t rR rh.neilhd;hrco
.,rordb) kur.(y' e, ord.srJJ?d iqnh.r ohryn;5
l*ieni..8.perft,rion
Injury
It cells ,rc rtvd5ibty
iur.d,
th. E*orrtion ot blodd
flow.r r.$rt in ft i..ov.a. How.v.i und.r etuin
.unenrc.q ih. rtsbGion oI blmd flav to ishenr
bur orh.fl
(
L rbt. ri5su6 rtluE, prrudou.,ly,
r
.\4*bakd rrd r.etehd riuD
Liif lh. lo$ of els ;z r'ddl,o, ,o tr.p thd M nrc
w6ih, d'aed dt th. dtt oj th. t\h.nL
@Lod.. rhb
\o.el| d r.h.dur.pnratoh nBry 6r.t,i,i,tt,,mpoF
t.t prees
ftr m,y .ondbute si8. i.,nrly b issue
d2naF in myEfdiit and erebr,t hfdions.
s.vaal D{Mnnns nav ,rou{ ao' rhc .xrctrb2iion
of 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.n
rhl supplr of arys.n is increakd, tl.E mri b r cor
r.5pondi4 inaq* in . produd
on of Ros, 6F
lirny b.our mtrdhanJnn drmrft had5 rc
tu.mpt.re rcdud.n ui oxlsen, ,nd beru* or ,h.
:don or o\jdr*5 in ku!&}16,.n,lorhtu kk. or
prrc.chynll
cdh. Cdlul,r.nioxidr d.f.n* hEh.
,nnns mar,:ts bconpomi-d by ishrhia. hvor
ina tb. :ccunuliti.n of fF. mdidL.
.
rsheff iiiuD is isri.rd
yith
,r&,e'1o,,
whrh mr inr$( w(h r.Frfuion b<:ur or
mlEs.d innu\ olhut()re5rid pL!tu
erokrG. rllt
prcducb of2dvaFd l.uldyr! frav..u; rddnlonal
tissr inrury
lch2 d 2). Aaiv.tion ol t6. thrtn.at
qs., may 3ko coniribur b ish.mi, co.6sion
r!ry 9om. in' boJ,6hrrr prornjryrc;.6trm
i(h.m,. r,iu6 t,{ unt' owi rt:!n::nd *hei btdd
To illusEar tll..volu o! an' l biel' tiic.t neh,nnh!
orcdliniury, w..oDdude ihis s(n' n by di$using s.me
comndry 6n{nised d"nd6 of rcv.slbt. c.1t injury
lt hemi. and tlypoi. tniury
k.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
by
rnaeDbl
3ry!ur15n
an.on' nu.
lalbcr t6! cl6..ndv
tnrn 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 or
rl' i6iEd by th. ,ccumubbn 01
mchhvrn6 rhr Eoltd
normith k
(morJ
b\ bttld
Ha' rh.rt'orc. E
^da
tnp6 n,e4 jasq
i,n do6
b?dir.
The bici.nic.l :nd nruc0r,t ch3D!6 rn
oxys.nJ.piived .e s -.rc discursd in d.tait .anii ind
rh! aquene or.v.nr s ft,pnubrd blo*
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 ; the
hrlua
ol
qdy
ddsyd+e4d.at a,]
st.ns,
ta.hdta?
ltl tM punps
lerdhs tu crt 5w.t' ne. rnd
rcn, hn,6Leicr
,
by
r.duld 5hLn' ns ror drbohrdnns
1. ts.
by ' he p.nod c
rnd 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 thr
d+osn d antihodn!..!e activ.kd. ' nd .x,arbik ' r
elliriuryand i!flrmndrn.
(heni@l
(loxi.)
Iniury
ch@ic.ls indua atl inify by ont of No
s.q.ral
.
sone .h.dkrk rtt di4tly
b
.o,binnE uith r .n
nd nob.qlat !'nporent at eelhht otpn L. F.l
ex.n p h. in m.rcu ic chtoridt poison,ns, h.(u
ry
bi.d s
orhe,utnrydry
sroup!ot,r,ff
crl m.nbnne pc
knr. lasin! inhihirion of ATt.d.tsnden kanspun
ud in(.ed m.nbmne p.mei5it,rr. Mdy .!ti,
r.oplastic .hnodd"pt' tic ,s.ni! ar{ indue cdl
d.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
bblast
att 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 mixtl-
ru,ction cxi&*s in d. smooth endopt.smrc rcticutuf
or rht rild,nd ods oB!s. Ahhou*n d. mhbdna
miehr crur mrmbiine dim,s. rnJ \.ll niuq bt
n,l lipi&,,he m6r
inpon,ft mahannm of cdl ,nitrry invoh.s rh. tor
hnion of fc r.di.ak. t /ro, ,rrd.bLniL taa]!,.
lhich -as ukd widely n ih. d4 dcaDins irduf) bur
is m* binn.d) ,nd $. anate.sic aetuntnott.n
hdong in rhn c.Esory. cct
,
lor .xrnph, is .ony.n d
t, rh. hxn frce Hdielccl, pincipnly in the livei
The fre radlcrls c,u$ ,uidararytic membnn
phcs
photipid 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 ,ng
or,ht lntu,h m,r,ph5mi. rcKutum rnd da!*Do.n
or ihleo* lion tn. smoorh tndoDlIEi. diculum
h:ve NurrJ Th.r n r.duc.d lipid expon from rh.
h.p,rNyt
q
i.2 r5uh of lhcn Ln,bil1ty io synllaia
rp.p!.t in b tom .onptex6 *nh ristyc.nd.s 3n,l
th.icbr fa.ilr,k lipoproitid s(Eion; th. rcsult is ih.
"Iatq
liv.r" .l ccl
F,ierins.
MnEhonddil iniury
rcllo{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( ER
Th.tnd6uhqn b..alciDn nfl ux2nJ dlniuallyell
I
|'oPlosrs
,{potrdk n 2 pnhy.y oI cdl d.rtfi rh ninJu..dbya
iishny rceulartl suicd.
pm*sn
in which alls d6tin.d
ro 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.
.ppamnc. rhd r rsponlihl. for rhe.rme
l,r"rrdsti
"fllhs
olf). Thc prasm.
m.nbnne oI rh. lDoForic dl
rmiins inbd. bui ft. m.nbnne r rk.r.,l io luch a
qay
rh,, ih. rtl1 rd n! 6asm.n6 b.come avid blgds for
phes,16.Th.deadell
nrap,dlycle,i.dbelo*
jB.on
116 hav. kal.d ou+nd ih.rttort .rll &.rh by rhis
lrthury
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, y
r hoe rtFon
Ge
Fiq 1i rnd l:bte t-1. Howd.(
lpoptosis and nercsn enetin(.mxnr, ind rF,pn\ir
induce,l by en prdolosic *inuti m1y proeGs ro
siiuenons, dk a
b dimin.t
poEninlly
h.rmfulcdls rnd..lls rhr hrlc
ou ived lhdr ukIuln s. k tr ,te, a paihotosic .v.nt
*h.n rtft 1r dflased b.yond reprq 6p..nllv wh.n
$c damac..ffec ih. cdlt DNA or
prorin!
iD rlsc
situarions. rhe trrcprmbly dime.J d1 k.liminai.,l.
Apoprsc in PhFiokgi. sirurioB
D"oth bt tpopto3i' t a noffil ph.notutur that s.e6
to .li,uak elk ttat . rc kns- 4..ta1 and to nain.
bha,.d4 ",hh{ ofwno$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,,$.
indrding inpraninion, ors.n4eneri delel
opndnrrl indution. md mdanoDhasis. ftr itrn
"prcsnnmd
Rll d.,,1" *r! lrieinily oined to
tl.roit d.dh oI 3ptci6( cll
9p.s
.i defin.d rnes
dunne rhd dcllropD. of3n os
1
B"n.ric
G'n for rhis panem ol d1l dtrh. rcs.dl.$
ofthconkxr, br r i!.ft.D used inkrch..s.rb! wnh
-prarinhld..ll
d.arh."
.
ku,tqho4 of tanotu d,t."d.,t tissr.s utan
h,,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 $c; urrul purp.r,
lnd r)mph&y6 d th..nd otan in
d.* snu{ions,.ells undnso.pcptosn h&:us thry
aE d.privd of n(a3zry luiiyar sisnak. such is
.
Etinituti.r at
natdtnb
h.,,ful ltttzddive 1\n-
pro.r't
J, .nher b.forc cfufie '!y hay! .ompl.ted
ih.n matunaonj in od{ io
preven
on \ ovn dsu.s (chaptn
5)
.
arl d.oth 'd4.a1 by .ttob'n T |tntho.rts. a
d.f.n$ m(h nm r*iini
yirues
and &mo6 ihar
s Bto kdind dihi!&
ynulinfd.d
rnd n oplis
Apopb* in Prd'ologk Cond itms
Anotbrs.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 ^nf t i n! nmdhr ni 5m5, hi
nduc. : N! , 6b.
lnlh.rsiiudions,clioinanonof
ihecett mav biilxft r
alrmaive rhr risk' ns nddois r ih. danaFd
DN^. trhnh mn poeE$
rc mit' sDni FaFbl' ii
I on. I hN ' nrunou!,nmuti .run rtuDrci5 if rhr f3u/r
i! mild, bur l,R! dons or rh. $;i*i.uli --h h
i(uclrll Jqrh liduuo!rpoFo,rof .:n..i clr 6
r d6 Ed rffn of.h.mdhsiDtur
!h,rh B!,k
br d,hrsrs DNA
.
A.,un,tatua ut ar{otlta!
,D,.,,J. loDroDertv
rolded puEns
m4 rnr h..rur oi h,Er;,; rh;
s.na
o.odins ih.!d pror.ins
oI h&1u* of exrtinsn
r&ro6i sNh * drnaBe caukd 6y rEe mdists. rra,
ste..cumul,iion oI ther prt,Einsn
rhe ER t.ads b
rmndnnrsll.d ER rres, whichcutnin:6
in rDo,
.
a niury in eia'a '{..th,as,
DaiticuLny vnal
inf.dio' s, in whi.h lcs of irleted caltl ii t.rc;h dF
ro,poprotic d.rth r[rD:y b. indu.d by rh. !rs 1.5
in ad.no\trr rnd humrn ,Fmunodfi.,hq \,ru,
Dk(non,)or br rhe hoe,mmurc rc
..rdth
losn atbphn pa2t.h\wtv' san,.tk
dur
n rh. DJG . Dro!,1
8rand,:nd
ttidnq
r|ethanismr
ol ADoptorii
Apopro,s n 2D adiv. en,vh.ti. prss
in which nuctco
pDreins aE brclcr du-! d dd the cdt r fBg,
m.nrd. 8for disrusins d. notrcutar Ddrisms.it
i5 u*tulrD rc\r$ ,he moroh!r,ar ofrhr orhwry orlrtl
| nHl E&i mdr hsdi d. , . pol di c6| t . nl y
asim9hlb cnQhrm (Fio,
1-22). Nat.r rhd rdou;
cld
pi*6'.
rh. 6n. .rpidrv
IrnnL iom doobmic
bud!. lnd r[gftnr im .r.crdc bod- 6in.id .r
h.. Frs r-a). B*a@ tu. rEo
.,1' d.ndphl gocyl o..dgi i hoti
Tl. tund,nt!.al .v.n in aDoDror
of D2ynes carhd 6p,s5
Go n J b43uk ihey aE
ih,r cteeve
pr.r.ins
rfiu 6r.ftjc
i.sidtral, Adiv,rd .asprses ct..Y
cdnranns in riy.tior of nu.Lr56 th.r d.snd. DNA
and orh- d.ms ' hr
prtam.btt
dnror nl d.oDro
k ,, rnJ crol .t.ri t pruEi ns
Th.i drdddusD,*j
drFndr or z fine1v iu!.d bahnc. b.
ipoproiic mol(ular pathwiys. Two dis;.t plrt$ys
conve4. dn .:sDdr .ctiv:inn ctled rk -ro.han*bt
prthwd lrd thc dzdh re..pta, patru,l
Ahhough ,hE
.r.tb ,ndu!.d und.i
n!ot!. d /ti rcn, motKut$. rnd
i d.dnri rctrctcsi nphFi otosyrnddi *:s.l Fi *.
I nt),
rh. Mi ,udond;.t (tnbi osn)
rrtl *ry of A@.6tr_
Mroth,ndfl rcono n nl errl prcr.,n5 rhl n.!i ;bror
' nduci ns.p.pml i ri
th*
pmri ns
i nctud. ctr4ti rome.
,ntl enHsrnk oI .i dogrri u5
o' oetc
,nhrbro6 ot
epop,oJ! Th.hoK b.sRn.r l u^natrnd d.nh 6
dti smi n.d by rh.
Dgm:b nr of mnchcndri .. whi ch
is conirohn by : frmity of moE th" l0
,rorins. dr
prora*p(
of !h!h ! B.l .!. vh.n.c , nadeDnkd ot
stu$rh
fa!' Durnd rophtr hahi {.5, orrr..\p"(d ro
nut,r uia.ceorabt.
,mounE of ni +otd.d proE tr,;
snpaf
$ri o6 B1d
;r. memb.6 0t rh
Bl r 2 hm,
n
m rum anvi rc N" pro.aDodoucn.rbr
,,frhe
fi m,b !rl ed B.] i nd Bar;whi h i t,m.nr. ru.n
,n,o i h. mi r(hondfl :t m.nbmn., rnd form !h:i n<t5
,hol sh sh(h r/chDft . :nd orhtr mrehondm
pror'ff elF inro rht labsot. o6tr iJ.t d $nsos
,nh,btrrhl ad' .rpop' ou. mo (!
s 3.t2 rnd B.t
\ L!rt
bdowr, ri rh ' h. hn. .nd rcru[ . t.rtcc oI mi b.
dondi al prcki n5.
Cytahroht
a i %edtr;th som
coiados, rclvaks cr$&.9, whnr othn D.otcins btel
rhr i (ni ,i .r or 6+re .,esai Dh rh:i funft,un 5
phFero8i c
i nhrbi tuF ofrpoprd5 Th nd 6utr , rh.
a(i va' i on of ' h. .npr( !*ad., ul nh,Ety k.drm o
tI .dt5 ' i . .\Dord ro so;h
ri c,o( and dh.. $ntrn nstut\ rho
,n,hc; ; r.
l popl oti . n.Db.G oa th. Bcl 2 f,Ei t{ rh. rso nai ona
orwhi ch,i t D.L2 ndt,rd &l xL.Thd.poEi nsanb*
I
I
IT
F
.ll^mr
-
d
n4crM,ddi{ah
BE nEcfti (ffirerc)
2 l
tr
pe.d,.Fp' otr
p.;nr rl i nh,br n(ab.
onia Bar .nd B.k, .n,l thur Lmn $....2p. oI mno-
chond,ial prc.rpopion. pbi.in5.
Cdl5 deprived of
growth , 06 io' on|J adiqc |h
i . . nr bd Jr ! , 5hoq r . du( ed kf L of &t 2 , nd &t \ ,
ihur tunhq tihiry fi. b,lrn.. ro!,/ d.lrh, The mno-
chon,lrial prftw,y kms o h{ th. p3rh*ay th* is
rtspomiblr ror md mrDm of rpopt6n, 's w. !I.11
Tl. D..rh Ra.pror
lExh.n.r
Prrlwry of Apop'on,
s, c:lled ' lsA Grp
tcr, ih,i riss.r aFpbsn. Mo* of th.r ,rt ndGc ol
rhl runor nercsn hcto'
ITNF) r.Plor tamil) rhrt
s: con$fled
"d.rth
dom,i,." so nin.d b.qu$ it ned
od.r proEins. Th. prctorypic drlth r.ptoc arc th.
typ.l INF K.!br hd F.5(CD95). Fzsliprd
lF*Lln
e meDbiin. ptukin
.xpr.sd m'i.t) on ,c v2rd T
rynph&yi.r. vLc! lh6. T cdts rc.qniz F,s*xpr.sins
DBdsj F:s moLcuLs rrc crcs linl.d by rh. F:sL ,nd
lh.y 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
]
all
np.5.rlpJq 3 m,y !|aE:nd adi
m.mbdar,h. Bd 2 frm' ty.rl.d B' d, as Gdrsrb
th. nn(hordi:l paih%y.
Dr canbin.d.dvarion of
6orb prhq.ys
delivns 1 ldhil 6|0- b thecdl. Cdlul,r
i* calle,l FLlr, b|ck
rctiv,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 Geptor
pdw,y is irvohed in d'minaiion of alt rt2lriy. lyh
phcytd d i. killns ol blgr <ll5 by em. cybrxic
cld.n r or ,^poplotic C.lls, Apaprctic cdls unJqso
nvqal chans.s in tnar m.nbnn* rh promoE th.;
ph.sE)tusn. h nom,r .dl5 phcphatidylsine ts
prtrt,t on d. inn.r band of th.
phsm
m.nbi,nt. hur
in ipoptori. alls fiis phospholipld
"nip."
oui .nd is
.xpced on the out r Ly.r oI d! D.mbrane, *h.r I
is ftor,rtd by nacroph.s*. Glls lh ft dring by
apoflo5n.l9 ss.tc solDbl. fuo6 thr Edun
ph.eo.
cn6. Thn f..ilitrr6
pronF.Lrnn.
ot th. d.rd cdls
b.forc rhe' und.o *."ndaa m.mbcn. drn,se ind
r cr . . . nl r l ur ar conk' 6i whr hsnr sut r , n, nnr m
manunl \om. rpop,d( bod' .!.,p65 adhFnr
sllco.
Rsed
b
phrs&rrs, ,nd
mrophlsa rhrmells mr prcduRFrodns,l' n
h,nd
ro epi iptutic.dh
lbur
no' ' ol,!.(lltaid hrB(th.drd
c[. for .$uLfmmi. Num(us mraophrs. R.p' cs
t u hr nr ol Yd ' n ' h. b' ndne, nd
.nsulrm. or apoproti. cells. Ih[
pu.s
oI phae{q,
I3D
,0
$ .firdc,t lhr drad rttL Jn
rla. and Lnfl,nnddi i5*.
ahMush w. hiy. .mphisird lhr dktindions bNen
n<rels :nd :pop' un!, ' h!\r Nv fomsafklld.rh mry
!(!trrr,d & rthkLr mchJn nrr t). Fof,nshn(. DNA
drnasr rftn ,n
4)ptosi5)
ad' v,r6 :. .nuym c.ll.d
polr ADPkibos) polym&,*, which depl.G .dlula!
5upph6 or n' corimnjdr ad.!ine d irucl.od., l..dins io
i hllnATPl.yrls and uh' m:kly ndosn. h h.i&n
i,,.onnoo siE.tiors such as ikhcmi.. ir hd bc.r suc
psEd
thar .any cdl d.,il can b panly rftbcd ;
apopbrni rnd drnEn n rhedomimn Nprolcelldsth
hr., wtrh,.*nine i$hemir
Ennple. ot Apoptcij
cdLd.ith in m,nr liruarions r lnown m h..auFd bv
rpopions. inJ the $t.d.d ex' mpt.s li*.d bdow i[!r'
hftrhr rc|. ofthid.rth p' wry in nomat physiolos,
cronh Fdor D.p,ivarion, Hcrhon.snsniye alls
depired ofrh. claart homon.,llfiphan6 th:i rr
nor i'huhEd by rnra.ff ,nd qtokines.
rnd n.u.ons
del)r ed of ne r
ero-d
lador d1. by ipop.6is. In 3tl
rJ by th mtrcllon
d r pr,h4!r rnd r i rfl bfahr ' i i rfl nr,on oI prf
rp,,phtr( mmh.6 or ' hr 8.1.2 frn' ly rnd d(r.5.d
synihels oI B.l 2 rnd B.!x.
ol .dlls r' cdirtio' or
.henoih.Ep.uti. i3.n6 indu<s DNA dam4e, dd it
brp,,prtr,cdrarh.
when DNA ! drm:e.d, ' h. pst prukr:(unutft!
n
cdh. h rid f.$s th. R .r.|l
kr rh.c,
phrk)ro2llow
ntu n' r.pan
lchrpE 6r. Howvei n rh. damag. N
id
B(r'
ro br npincd su(c.sfutl
r 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
is
nuhted ofub* (ar
n k in cdrn
gn..6l.
r ia ind
p,bl.afindu.ins
rp.ltosn, !, thar.etk *iih d.m.s.d
DNA arc allow.d m $ryiv.. tn such rtlh rh. DNA
I iEnnc.io.s drr
re,d to nedprdn ..ndonnltun (ch.ptn
6).
A.cuddlrion of Misfotd.d
prd.inr.
Dtrri.g nomal
.h1Fror.! in th. ER .onnol thr
nrop.i
Iad,ns "t n.prr 5)n' hs,4Ll prok,r,
rid nD
rordrd plrrncoridF
rrc ubquhnaEd :nd 6Qdrd for
pn,k,
)ns
lf, hoestq unfoldrd or m' ,rot,lJprckn!
aamuhr f lh. ER be' u! of in
.ork rt, at.d r rny' /r?/
pnr.t
' .,porn.Ih! 6ponn r!"vrs ' en' nBFrh
of .hrp*oia rnd
rcbrdDbt r r.rdrticn.lhusredu.in!rh. ltvclsotmn.
folJcd prote' ns
i' , ih..dl. How.v.i I rhn Eeotr. r
u!:bk io copt wnh th a.cunut,rion o! misfodrd oro
idni rhr 6uh is rhe:dlv,iiq ofcaspNe rhr t.a,l to
ipoprtxn. Irri..llul,r a.cumulanon oI ahDom:ttv
6ld.d pbkL' s,ciukd by nuhtionr, rsiis or unknow;
.d .s: t iitrr. ol
dF,$q inrluding
Alzhdm.( Huniingron. ard
prrkinson
dinass, ald los
iiblr
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.n
d4rd ii rll ndiyidurls lf rh.k l' nph&r4 .n.ounkr
nft riris<n5, rh. e 5 d' e by ,r,pi4k 8olh ,h. nro
!h,{dr;tprhrr} ind ' h. Fa, dorh reRplor pnh4?r
hav. 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,B
nE*nEd on ,he inr< , f nri(ed han c r rnd tumor
(lh
l(hiprrsr up,{ r.n,rron,cT
ci [ . d3, , . r ] z. . . nEr r hf r i r sd<l 5. cr anzr m. , . kr .
pnrons.t
asFrt,r. rtndua and ai. able ro,tiyri...l
run cnprs. rn,hn 4:r,
Ihe
(TL
L' ! hrts{ (t5
by
d,R' ry Lndu!inB ft rff{ror phi!.
ufap,,r' ons. wtrhour
en8lsig 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 b
ehf,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@r
don :nd Enonl of ddd ftll! br ph:sr)rs
.
Mto.'.rlr;al
nrhB.)
pcthM,
B he$ red
by rx or rurivil rdniL, DNA drmra. ind
:(unul,i,mor mist6ld?d 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;qs
iid d.ms. by cybbxi. r
tmptuir;t
n iii
trrFd by .4as(m.n' oI d.:'[ E.oro6
lm.mb.d of rh. TNF i.c.Pbr hnity) by
1' 3m& on adirc.nt..lls.
rhn d<ripnon ot ,p.ptulk .nnctu
" r ( [ i ni u4 i nd
( t do( h.
A5 B. hr r { . n, r h. r
.d rhn .h4E wirh bIi.I .oi sid.rarions cf r[ft oih.r
pd6!s:
inr,ellJr ac.umul.tio.s ot v2iou5 sub.
n{c.s:nd exucllul., deDosnion ot.2lcium. both of
whi.h .i. oft.n sfiard wirh ..ll iniury, and rsra.
IIITRACEIIULAR ACCUMUTATIOIIS
mi f t i { r d f n\ ' \ { ) r r n. Ll nh, i i sNl $ r ( , pl
(i l l \ \!^di $r.,tr |
(h(
i uJus. rrJ r i i ,! [( \,d,h!
!/(J l ,r rh(!l r\r!J !( \ or m., h(
I
rh{r.u. rh( mrD
rrL\r!
of i [rrmi rrt](
or rqtr r.J J.f.G
r n)l,l fs.
Nrhri,,s.
.
An nrofmi .\ol r.tu$ nnnndr . Ll .N!r.d i J
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 1n5
np( d i l r ( . r ! D
Di o, org.n, rrLrnr h(nr(.i [i ,tr .h(r tr dr.i r i t!]
. a11nht,11' ' r,hl
nrtd* J$,tri rnl ,r, ,l L!^ ,r( t|\
qd
4nubl
d' r' ' l
l ,rtr
tt\Dx( or th,: L' 4
|
l t uc hr \ r ! f ! n i Ji Nsr hs!
.ft $r(ri (J x) hsr,.sJ$. !r\.tr J ro.Msren,l
or , r dr i k, t ddr ( t , ! Jn5 r r i , s.
N. \ l i Ji . t r ! . , b1! r l
r,!r\!{,J$ D.,, burr f0n !rcfc
. .hus r..qi ni ,l g nr
ol drnr;
(.(.t.
trrJ
Th! nantl i nq or fn$.h.ri se dqi trrn o l k !!$(
ri {\tr{\ oi rtl r.drui r 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
o
t ;
{ , a
4 6 . p " . ; .
i
ccl. po&nins). hq.h
Ee
6 ir!e^' bh In fh. rv$e
toi,n, frny chr,sr nrr prt.edr rtlLdatrh, rid n$ ht
hdi. nqohenatnn rahapie' r5).
rit l.r micrc$opi
rh. o4.iic $ v.i6
tpiny
63d i
ndioqlhal.' klh.nid.n' iff.dbyal
F
odic Eid-s.hin d.in lfiich d
viord). Ivlcuola do nor d:in tor.it
Fdych.ng.i.froncommon]Y$3ninlh.|iwl:nd
' hohaan, Ml dr dychdng. i nt h. I
gh3' o6r gl l ' n3
5n: . ndgr o8r , dvl f i ychan' . b. eenbvl ohi
] nl he. yl op| 8m
rorha6rl
Fiph.ry lFiq. r-2531.oe$ionrllv6dieu
ol t 6| hr upl ucandt h3sE| 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$rnn
wnho(' Enili.:nr nn:clLular
i(umulanon. How.v( phisNyri. ftlk mi) b-om.
orerlo.ded wnh Llpid
lr.elrindA,.hdl.i.rol,,nd.ho
lsiql6' qt in lrwn Jirrqo, p
srh ft Lrpid debns of
idonc .elk o' ,brcn,l
te.e.,
ordtrd) Iorh. of
lipiJ. Thcr manorhag6 mar b. 6lled !trh mrruk.
Dembcn.bouid vicuotes ot tipLd, rnpairL,s i formr
rpperrr.. ro ih.n qlopl,$
lrrn
.,1k\ h\ atr?.)
!LnM, \mooth mu5dc ccrk rnd rusophases are rirLd
wnh Lipid
ya.uol.\
omposd or .hole$nol ij,d .hol.r
ie4Le$r5;ihen
sNe
r$erorkrorr phqus rhtn.[]r
trrtdsn. ytllo! color d' l $nn,6utu n,ihr
rrhoBcn$^
or thc l.si{D
lchaprr r0l. h hredtrry ind a.qutr.d
hyp(hp,de' nL. srndrams. n,.rophtrsn,.rnulr.
iN .elluhr .hole$(.li 'htn
rr$rnt
,n thr \ubrDnhr
tentloDs. du(6 or
rhN f,nm,\ mr{.rhi3s 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
$e.ells slndstrerr..*r. rnounB.ln thd!]ddq, nr
hv pncnGn h.he
I)nxjmal
(nduted
n' bul.s. Ho*.!ei Lr dsodenwrh
h.r$ 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.,bsordon
nBiniie dn
|.oktn
f u*wiih ry$om6, r.surn!F in thehisiotosic appannR
of pinl,
hyalin. crrplasmi. ,lrople6
lFia.
r 26). Th.
prc.s is revtrnbl.t ifrh. proreimn2,b1E rhcpnn.jn
dropla! 1r ndlb.ltcd and disaDFa i Anoihq exanple
n fi. m.rk.d a(umulaiion Df fltwl) sytuiai?d
immunoslobulins rh m.y uur in rllt RtR .f a,m.
pl,sm. .elh, fohing roundtd, <Einophirn R!$' ,
Aaumuhtions of intraRllulf prot ins ir,l$ *n
' n c.drin ryp* of..ll niur For.xinplq ih. Mrllory
bonn or
-,lco6.li.
hyalii," k.n.osinoDhili.
qropler
micinclusion in liverelkrhr is hisll).nr cdistic ol
ilcoholic Lvd dff f
lch,po
16). sucl, indusions.,e
.Ed int m.diat 61.
inha lhn pEsurubrr
rcskt desnd on. Th. tr.u
n,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
ae
jiscilrd
wnh 26normaftie5 in lhe mftb.lismoferh*
sluos
.r
Blycoso.
ln poorlyconmollcd dnb.re5 melll
ttrs. 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 clokly
relakd
s.n
tic disord.6 .olldiv.lv rtt ii.d tu i\
d.o
s.,
tnhs. dk nss, o,
xr.os.nos
lchapkr
7). In
rh.s dk..ses, .nzyma.c ,LIe6 m d. srnih.ns cr
brcrkdow, of
sty.4.n
rtsuk f n$,. edtpitiis,
wirh $.ond,v riurr :nd c.ll &nh.
Pign.nc. Pi8qenisarecolocd submancarhi arcenh..
.rosenous, com,n8 non ou6id. rhe body. or .ndos.
nous, sytuh6n.d wrhin rhr b.dy nl.lf.
t
Th. monconmon (!s.ious piEmsr k.,1601 lan
example G coal dus), a ubiqunous atr polluiinr ol
u6$ lif.. wh.n inh,l.d, n tr pLig
r.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 llhph
nod(,trdp monan p1ftnchrfre
{dnthaatisl.Heavr
.Da ora fibrcbhr
i. Eadlon rhat can rcn' [ ' r a srioDs luns dn.i!.
elled corl worldr pn.undonidij (Chapr.r r3).
r
Endogd.ur pismlns indude liNfu$in, mrlanln,
and enain deivrivs of hemoslohn. Lipofutk, ot
"q..r:nd{.rr
pdmtni," s ,n inn,lu6l. hrcwnnl
yellaw
srin
' fr,..11urar m.teri.t rhn a(mut.Gs
in. v .ry or n$ues lpanlcuh
)
rhe h.rd,l1v.i, rid
bnin)as a fundion of.Be ofurophl. L' pofurin rp
rcsenis.anphxaollipi,l dd pn,.in
lhr d.,iv. frcm
ihe rr.. ndicalra&lyud peroxitlation of poljur$ru
nted tipids of subcdtutr mrnbrine. ii il i(n iijuri
ous b thr ftll but n impomn, ai
rft 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 pisnhr
follow' rs rh. rrtr,fu{
c alyTed o\id ioi of twonn. b dihyduyphny.
lihirre. k n lmrhdkd Lxdusiv.ly by mdindvrs
ro.1r,r in ,hc cridsmn ard ads a; ";.* "g;"
hlrhfur u|fa{ord cdHtioi. Akhouah f.trn,trcs
JR ihe onlr eurce of mdrnin. 2di,.r hasr rcr
irndrsr $. skr on a..umuhE thr pism.nt{..e.,
,i r.&kr.t,15!?n dermat nacroph4a.
.
H.a,,,/.,i is r h"moctobm d.
m.n, rhr EAotd.i !. a$ ,,, tr,,En rnd i(!mutrrcr
Li rsues *h.n *.( n a tFat or ssrenN rxrts! of
;on. rron i5 nomnty nortd wtrhii cdtr Li
js!)or!!r
wnh lhe prorein apol.rrl,, Idn,ns f{nin nicdles.
H.mosiddn pisme rprilcnE rars. assrcsres of
rhen reiinLi nitc[6, Qdit,- lisu:trtd br tish rnd
ideni6.d hy fi. Prusfn 6lu. hnnf,hmicit rci.rioi
tF,s. r 23r. Akho+h h.mosjdnn:(unuhnotr n
Lhir pichdr a..
n,nmal h rh. monofucle,i ph,sorrk! or .he bone
marow. 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 ts
rh. common brun.. afi{ rysn ot thr {}drc.yB 1r
rhr 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.cLonrhroush
wh,.h dr bruis
F$6
l.ll(h rhn. r,nsforh{ions.
Thc orisinal rc,l.blue .olor oI h.moslobin is rane
fomed ro v:ning3hdaols(n-btu. by$etN,t tor
m,rion of bjrilqdin
tq(n bLld and brlnuhin 1rd bite)
rrt,m rhc h.n. noier],r rh. non
jons
oI h.moeobio
rcuDular *
Bold.r
yello*
I' tfrGldcrin.
r
vhenerd rh.ie is srncni. oye oad oftron, trmo
sidriin 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
$rrn.
and tymph nDde*nd f Qr
r.rtd nicrcphaBes fircu3hour orher orsrn\. wnh
,ro-
s($ivc
ac.umuh.on. p,i.n.hrn,l.(11!,hrcushoui
rh. body lbur
prin.p,ll!
rh.liys.
ranc.:s. heiit.and
end(rift ore,n, bdoh.
"hronrd"
sidr.ctrnut,r
ing pishcnr. H.nosidero$s o.cu6 in rh. rninsol
lr)
inq.a5d:b5o4' rioi of di.hr! ;on,
l2)
impan.d ui.
rtsionof non. 1r) hen.LFi.1ioias,.Dd
t4)r:nstu
sions
ld.
u,nrlu{d cd cdk coni
bidornonr, ln mo*' nn:neof svi.ni. &ooidero.
eciherarenchyn.l
.ells or mpff orgii fundion d6pn an ' mr6rivr
r.ctrmul,ion (Fis. r-23). Howve( nor. .-dsiyc
a.cunulaiionsof non,i.ei h r,tulitan hno.hto.
q,,cD
1(hipkr rb,, {rh n$u.,nFn m! ud' na h!.r
6bb, i. ht,d b,r.rc. rnd dBh.r* ne tu!
I
P l||olo6K c tctf,c^no||
Prholosrc .aLdici .n ,\ i .ommon prc6s rn r wid.
v,itrry or dn.ri nr6: n impl' ( ihe,bnorhrlJoo5i
rioi oI.alc' um $16, bserhtr wrh !hnF!.noun6 of
15. vho th. dpDn
n is.altd4rtupri.
akti.atn
4
it 0(6 h th. absen . ol cdLiun n tabott.
um kYrlsofcilc' um).
In conMn, rhe d.pniq of c.tcrum shs in noffirl
rsuer n rnawi as ,.iar,r. .,L,lnaiDr ana otna,
dtudf '.l.ds saft .le ,24n2nt i, tdla\n a.tabol'st
lhfi.rcakma). tt st lld h. natd rh{ rhrl. hyptr il
.em,r isnou prtrcqunn n' d)*roph(.,td6oi.n. n
Dylrophic Crlcifision. DyrnThi. calcific,iion n
n.ounkrtd in ,.s or nEroskof
r
|n.lnibk
jn
rh. alr?rc"J otdvdrd rhqostF
rasn, i!!Eia&d vnh inrmtrniury in rtr rnta and taF
r({ies and ch.iidsizd 6r a..umulatjon of lirras
lchaptd l0r. Ahhoush dynroohic c' lciti.l.on nay b.
in ,n.dhhr rind na rndtrrirnc ,ny*n 6!rrr
Fn c.l
, ni un. , mr nQ b. i \ 16. . t , t r Fr n d, +un( oi . r or
.rampl.,.aL.,ri.rti.i c.n d.lerop ' i asns or dlhrssd
he,n !,hd, 6uhrq in iv.fttv .onprt,ni*d vatle
Eoi nr. Dvnrorhi . .al .i 6.aron of rhr hnL. !116 n
of i oni . {.nai n i hc cueny
d f t 6 n t h . 3 s r i r t
3 y m p 6 h d . n
s[yc' |.|fi cdi o..' F!6.6i nn!6||uhl .nd/ol .n' a
r|1t prrl ,.gd$i r of dErophi c ..Ld6cri oi i ' rvohs
;,r!,roz
i ,r
nud.anon):nd prop,t ro,. hdd ofwhi ch
may be ,i her i .ri ftl l uhr or cnhtcl l uhrj he uhrmrk
{al i ne dLun oh.s
,r,r..
InnDhn i D cxna.ettuhr sG drm r i i (m
h4n bourd vsi .l e5 abor]00nm i n di anftr: i n
.r.r. ,nd Li p,rhok4j .
.aL.l i cati oi rhry tl dve l rofr
d.gdq,i r3 crk. rt i s i houahr rh:r c,tci m n ,nnBl y
l Dcnri ted ' n rh&vsi cl er hl n! rfi i Di ry Iqmmbnre
phosphol i pi dr. *hi [ phol ph.cs
a.cumuhk rs i rtsuh
or i br ni o! of Dcmbrao..bound pho' phrri \6. rnnB
,n oI i Dra.dl ubr .aL.' fi crti oi o.
d,i r ol d.rd or dl ng.r1l \ { hal e ron then rbi Lft ro
r.*uhk i nratcl urrr .nci um. Ah.
r{ari q, prcpagrDn
otqst fom
d+rndni on rh. coi ftnrrri an ol (:r rnd PO. ' n i he
exri cdl uhr sprrts, rhr p(vn.(
or ni neHt rnh bnoq
ri d rhd dqtu !l .orbsenmti oi , w[i .h .nhrn.s $c
Mdsh. . . : L. L6. r r i o. . r n
qer
i D BrmaL i ssu6 shen.ver d.rt nl rrqel (nn.
The n)ur mai or c es or hrp.r.l rl cm; nc
l
|l 2 re"s1
' .-4tar.f pa thrtui l haMD.. nu. o si her pi ' mrr
or pndudion of pr*hy.oid
hornonr rcraird
Ftran
br oih- trrta' rn niioq c)
dsttudDt af bane dR rc rh. rtfd\ 01 k(]sr(d
I,ncrd*J
honc .*ahornn snEHted rnh ' nuhLple
EFl,,m4 leukemia. or d' ffur irehbl ndii2rnr 0l
rtbn'n t)-t?ht.d afoa$ nrltd
.anon d sr.d/orr
iin
!h' ch m
ubhr D pKutrod:
and 14) r.,"/
/",hr.
if trhth
trrds
rc se.onla4 htp!4aath\-
ih.bdybure ncip.rv rn 6 r' a id4rit:trisu.6 ot
d.snb.dindvnbphicca|c|f.di.n
c|ini.a|dv:rundion,.n.Giw
d6po.rr in rh. kidnry l4r'.ahhdr.) 6n 6u$
tufu tY
Ahnoml htEellul.r D.rodtioB
.
Abno.m:l deposiis oI mi.rirls in (ll5
ud
tissnaar. rh. rt k of.i!!*iy! irtal. or ' Lfetiv
.
tiit .r,,ce ,c.umtrliiio. oI lr.c riclyeid.s
rrom ex.esiv. mhke or
d.r.{iv. ranspod
lohr.
be,trk at d.t 16 in
lynd.sis of hn5pon prorinti h.nif6tarion
. Aohtdol deto'tion: resuk ol delfrarr
casbolism r.d .xc.sik mDL.i
jn
maqo.
pMses rnd snotrh iufl. ..[s of
y.sd qilts
t
D.poinion .f
t'oe,t!
rcibsorbed pbRins in
kidn.) tubtrl.s! nDuncslobulitu in plasma alh
.
Deednioi or
srlrosd,
i! meroph,ses ot
pIi.na wiih der.G in ly$sml .nzym.s 'ai
b(ak dorn
sly.orn l*ly.caen
*o!,k dneast
.
Dpoltio. ol pis,e,aj
typica lly ind ise*ibk pis
menr, such .s carbon, tlPotusr
l6rt2lJow!
p.oduct or lipid proxid:rion), non
Gsually du. b
ovgroad, as r hnordebrn)
I Dt*n,pLn .ak'li.aho,: deposni.n .1 .2t i\o
* snc oI ftll iniury inJ ne!trn
r
Md,r,rr ar./,rdrnr d.pcnion of ekiun
in ndm,l fisu6, eued by hrptftl..nir
lusuallv a con$,tuenc oI pf,rh
rrcid
hormone
lrl^ru r
-
dr
44
Gr M dadFds
I
I
I
I
I
'3i
qi
'o
4h.
n h!hd! Ei| i;
I
Glruuf, AG G
t2nukt
'snq i5 th. rc,,h ol a ptat.4,v.
dkh4. t4 th.
p'atile
tiv. @po!^ '4d t'l? \pan at atk r4.t th.
4kd3
ot,odtr,lqs.rpdra tt *oseta6
t' d,6
that due
c<y4rro|on .t .. uht ann d.hdl.t d,hdp. tle
l-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. dr
' hr r8inB b.on,rcl.d b' prn' cutrr
sm6
rrr5 5puftd
k. ! t r Ff i w ! r nd
ir d.vi.ins wars to hriplhte, pr6.s
ihrt w,a onc.
.an.id.Gd inexcbbl. S.v.r,l m<hanism ft tnon or
3uspd.d rc b. rsponsibt.Ior ce ulft ising,
.
DNA dam|.. ctltllr as'nE is assjned with
n{.s ns DNA d:m:8., sh' .h roy hipFn dunm
nomrlDNA (ph.rion
rnd (rn
b.dh:nc.d bv t.;
Ddi.rrs. Alrhou8h m6t DNA drmas tr rF;d bv
r rid rt;umrh,;
.s alls5s.. sone a$n8 syndrom4,rc i.*iak,l wiih
dehcB in DNA repff n&hannms. ' nd th. tift .brn
or mod.r:nimrkc' n
!t incrtistn if rslonms o DNA
drmrse rrc.nhrrc.d or
prok,ns,hr j:b
u. DNA
Ie inroducd ln t r, ' h. nFru.nhon
rhr h,5 moil
conls.nrb, potons.d tire sp,' in mo* sFi.s G
r[,nf ' .!rkrror. Renrln i hn b..n pbp,{.d
rhrt
cron. rcnr(on iDts*5 a te\.t of *($ rh,r:rt
v*s proEi[
of ih. situin fimitn 5uch r sr2, rh.t
tunfton as hrron. d.aeotik.. TrEe DroriB mav
d.r.ryhte rnd dseby ictiv,c DNA rt;r mln ;
{hB
jrb,ttr4
rh DNAi n rh.,ben!.oftn.; dp
,eins, DNA n
Fmn.In drmr.
.
D.leued 1lhb aphatan A nom:tc ! h,v.
a limtred lrpaciry for trptnrtron, :nd :ft.r r n*d
numbd 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 (l l i .
cn i l ron.h, drtn havei h.ci p{
,\ ro und.Bo ni {. Dund! of (!ti .ruon,h:n
docdl r
kon ord.rFopte.In l odEr,c.l ! fton
Drkm wrh
\ymr st dtm.. ^ a,. dn tk.!5ld4iz,l bv De
n,ruE .sin& h,v. . mrkrdly r.dued m vitrc lili
i p.n. l n htrn.n cel k, rh. n(hannm of crl i crti v.
rn.knl r hvoh.i tn(ompt.re rcpt,.r,on ,nd
qm
3rs!.
shon.ni i g or Fl om.r6, wh' ch ' ti nrEty
E5u 6 i n
(l rrcl .
nftr. LLz*.r *.,hon r.Fned
equenG.r DNA
r@nr ar the ti n.,r.,ds oi chro
n6om6 thr ft i mtsdr,,Ior(n5unnc
a. l onol .rc
Epr auon of.hron6om..nd5
and l or;!oE(r;,h.
.ndr rom run,,n :ndd.sredn' on vhd!,mrtr.; s
Ep,cft, a 5m' R' i!n of ih. rcto
6' .d, and rcloh&s boft pros(snet,
!h,d.n.d.
a5 rb.,dotuG
beom. lhotr rrh..n&ut(hlomD
$Ds crnnoi b. p'ord.d
and ft sn ar bbkh
DNA, whi.h5l3n,Lcettcych,r6t.
Tt. tenqhs otrh.
t lon.Es ir nomall, miinnin.d by nuc[;nd. rddj
tion n di.rd by in h,yi. cald r.lou.r6e T.toh
.rak r. spbti*d RNA.prct in .om!l.x rh,r u$s
n! 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
$tn .dlr but n n usurlly ,b* in nsr 3.maric
Gsu.s
(Fi&
l lrL lh.ftfor,.5 ce[s i*r th.n ktom
.6 eon. shoner rd th.y .xn ll). e rycL. i6uh.
ing in an mib' t,D ro
s.n.,k
n.w e ! ro fetra
drmrsed on6.
(o' \.et' ,
r ' mnoit:t
qncs
idlj.
rdomd,n n rcad'vded 2nd cton
.n.d. sgs6ring ' hn Etomftetongnio, mrsh, & ai
non. Thr D d,xus,ed nor. t!l[ d
5uchiIunnsobk r,otr,howav.r,rh;trflffih,;"i
rron{rr rd\ir and relatuE tmg' h ro as,ne rnd
nar h,3)d ' o h fultr 6Db|Bhed.
_
.
R?,1"4.1 'q.nefttik
@nad, at ti$,. t.n 1r..
R(.nt studies susg.n thai *nh ase, iI. pt6
r6n.6 preqEiwt ibnli w rh i(eiR en dr ft; udi
lcDKN2Al
pocin .ccumuhi.r m snn c.lk, and rh.y
prusr6i v.ll loF rhnr cip,ur, r, elf ff.q
pt6
B i
phrs,otas,cit mh,b br "f..[.rk prcB($ron!
i,
p.
di{s5 n chrpkrb, dctcuon ort6i ot Iuid,ln muE.
rioli or
Dr6 r. rsiar.d with.1
.
a.t,uktia" al n4.boln dn-q.. c.llilar tle
span r rlsc dd.rminrd by a b:l:ne b.*en dim,e.
rtsurine from m.rahohc.v.i,5 Nlrflng wlhm (he
!!ll rnd (olnEncnng
molduLr rop,{$ th.r c,n
(p:n
rhe drm8.. on.
eroup
,,I pohnrlly ror. pro
duci or nonirnd:bornm n Hc
A5 v. haE di$usrd .rdff in tl'. chaerr. fi.s
hyproduG of oxddivr
phosrlD4l.tion
du$ covi
tenr mod,ri!,ironsofptuFn' , ,p' ds, rnd nud.K tud!.
rnftx.d or d,iEdam.e..outd rc,uh fron ftF:Ed
. n! r ann. dr . r po<! a r o ! u\ h, nn
tsdi.aon,ro4wrh
proara!
\! rdu(on ofrnrcu
dani d.f.6. mah, hs. D.msed
(llul,r
olgm.ll..
,.ctrnul.r * <llr ae. This Dry,ls b. th.6uhof
d(linins tundion of d. prai.1ofr.,
th. prot olrlc
.
srtrdi8 i! modet osnsns, titc th. ,om
Genorhabdrs .l.eaE. h,( 5hown thrr
soqh
hcro6.5uch,s iniuln 11,.8rc{h frdo(:nd nft
anubr signllins
tsrhweF
r.inrr.d 6y $!* IDF
nunlr knd b Edtrft tLt .prn. Th undstyms
mEhan' ,mi r. noi illlr und{rmd,bur,hreEroMh
rFou n,r anrnun tn2 rceon(i ' o rtllGr !F.s
,nd du. Educ. th $rbiliry ct rh. DNA.
I
slfrI||I
!
Rdul6 tmm .onbiution oi rccumrtati'r
ell'Jrr do.e
(.e,
by fc 6diciL), rcdx.a
Paciry b divid.
{rcplic,riv.
b*rnc.), :nd
rcdued abilig ro i.p1t it nu.d DNA
.
Aeuhrkn.f DNA d' ns.: d.lew. DNA
rtp:n nchannmr DNA rcFr my b. :a*:nd
by calori. E:ridion
{LnlM
to pr6lon!
.ging i!
.
A.pa@iw tuda rcdtBd aprin ol ells
ro divid. b..auk of d.cisrq imauns oI
(16d,
.n! .nd
DrcBcsiv.
rhofr.ni4 ot.ircmmnrl
.
ot .r
fddd,
posrcsiv. cumDlation 01 mdl
bolic d.marj
psibL
1016 oI
soqh futo6 rhr
prcmd. 13iry in sinpl. nod.l oq.nisms
rr $ourd bQppr@ h. he v.rio$ torm ot cdlu
and adlphiians d.siibed ii rhi5
insnom:daphhons
' n ell sia,
eavth. d tundion: to tnr reve(ibl.,nd
tri.ydiblc ro.ms of acur. cdl niuyr rc rht EBula&d
rrF or c.ll d.arh rcFrennrdl by ,poooa' Reflr.ne is
mad b :I dre ik.ndons lhlolshoui tnis bm!
berurt rI orc?n inj!ry :nd utnndrty d J,' (rt daQ{
,rururc?nd iunrn,,n
)61
Fb, 4u4 enbd k. bai,. al
irbt 64t'iRtu' at khd4.
tu4!q.1
Di i ! N/ r4qaq
t
16 zas. zaal
re.ht
thl rttu E tq,r ot4qt6'
@rb Qtu's o, ttt 3d.
h6ttt
ot
Piota
j
i dr n ol ei
tuL
rd oxd{r a
! n| N. oLf r ENj c ddt r . l y t s nl 4r ' : ( * pd. ' * ei . ' dd.
6t&"e4,,t1A.L *tudt
rt,
,,ryhhdd6i .bIrm
t
qqqw
ot $. rch ot
4o&&ra
r .d turtp,
qd
d{@t.t
n.
Fd4t' d4t
r ni 4rdi n 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
,
$
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,j
M Mddr
q[ i 0u
di l rk
rfr d
qtrd4
& h4hnna d &nr an | | r:.r r. ,@r
le.dtu w ot tk
@ t@@ ol
Rl q&d&K"rcueai Fqrl "fu
16[ D. sLd] M e' cu. eBr er ! [
d4 ot
h4rtut
rn d
qad
htub.,]
zl 4D' 9l ! r y| r &[ e' | M' h! cM. M. . L- - .
z 4 L l U' c E! i [ Pf i o FM| Gj b
ttutw
al.a h6. 14
qtu
tu
&@4
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