%igure &"&

(ature and 'everit! of In urious 'timuli &. %ltered Ph!siologic 'timuli Increased de and, trophic sti ulation Decreased nutrients, sti ulation #hronic irritation (che ical or physical) ". #educed $"; Chemical In ur!; Microbial Infection Acute and sel!"li ited Progressive and severe (incl. DNA da age) Mild chronic injury 3. Metabolic alterations, genetic or acquired 4. Prolonged life span with cumulative sublethal in ur!

Cellular #esponse Cellular %daptations $yperplasia, hypertrophy Atrophy Metaplasia Cell In ur! Acute reversible injury Irreversible injury cell death (necrosis, apoptosis) Subcellular alterations in various organelles Intracellular accumulations; calcifications Cellular aging

%igure &"5

$yperplasia &. Physiologic ' $or onal ' #o pensatory (. Pathologic ' )*cessive hor onal sti ulation or +%s ' %ertile soil !or cancer

$ypertrophy &. Physiologic ' %unctional de and ' Speci!ic hor onal sti ulation (. Pathologic ,. +enes that induce hypertrophy a. +enes that encode transcription !actors c"!os- c"jun b. +ro.th !actors /+%"0- I+%"&- %+% c. 1asoactive agent 2"adrenergic agonist- endothelin"&angiotensin II

Atrophy (Physiologic or Pathologic) &. Decreased .or3load (. 4oss o! innervation ,. Di inished blood supply 5. Inade6uate nutrition 7. 4oss o! endocrine sti ulation 8. Aging (senile atrophy) 9. Pressure

Metaplasia &. :eversible change (. Most co on ; colu nar to s6ua ous ,. 1ita in A de!iciency 5. May induce alignant trans!or ation

%igure &"A

%igure &"9

Causes of Cell In ur! &. @*ygen deprivation (. Physical agents ,. #he ical agents and drugs 5. In!ectious agents 7. I unologic reactions 8. +enetic derange ents 9. Nutritional i balances

#eversible Cell In ur! < the $A44MA:= o! reversible injury is> &. :educed o*idative phosphorylation (. A/P depletion ,. #ellular s.elling

Irreversible In ur! and Cell )eath &. Morphologic changes ? cell death (. Necrosis ? al.ays pathologic ,. Apoptosis ? nor al !unction- not necessarily assoc. .ith cell injury

%igure &"D

+able &," *eatures of (ecrosis and %poptosis *eature #ell siBe Nucleus Plas a e brane (ecrosis )nlarged (s.elling) Py3nosis, 3aryorrhe*is, 3aryolysis Disrupted )nBy atic digestionation %re6uent Pathologic ay lea3 out o! cell %poptosis :educed (shrin3age) %rag entation- nucleoso e siBe (&AC"(CCbp) Intact- altered structure Intact- released in apoptotic bodies No @!ten physiologic

#ellular contents Adjacent in!la

Physiologic or pathologic role

%igure &"&C

&. #ellular response to injury depends on> " type o! injury " its duration " its severity (. #onse6uences o! cell injury depend on> " cell type " cell state " cell adaptability

Mechanisms of Cell In ur!&. Depletion o! A/P (. Mitochondrial da age ,. In!lu* o! intracellular #aFF- loss o! #aFF ho eostasis 5. Accu ulation o! @("derived !ree radicals (o*idative stress) 7. De!ects in e brane per eability

,. #ell injury results !ro !unctional E bioche ical abnor alities in> " aerobic respiration " integrity o! cell e branes " protein synthesis " the cytos3eleton " the integrity o! the genetic apparatus

%igure &"&& )epletion of %+P Depletion o! A/P to G7"&CH o! nor al levels has e!!ects on critical cellular syste s> &. Plas a e brane energy"dependent NaFF pu p " NaFF accu ulates intracellularly " =F di!!uses out o! the cell " os otic pull cell s.elling (. #ellular energy etabolis is altered " increased rate o! anaerobic glycolysis " glycogen stores rapidly depleted " lactic acid accu ulation dec. intracellular p$ ,. %ailure o! the #aFF pu p in!lu* o! #aFF 5. Depletion o! A/P structural disruption o! the protein synthetic path.ay detach ent o! riboso es reduced protein synthesis 7. Irreversible da age to itochondrial and lysoso al e branes any

8. Proteins ay beco e is!olded trigger the Iun!olded protein responseJ that ay lead to cell injury or death

%igure &"&( Mitochondria can be damaged b!&. Increased cytosolic #aFF (. @*idative stress ,. Krea3do.n o! phospholipids " phospholipase A( " sphingo yelin path.ays " lipid brea3do.n products Mitochondrial damage results in&. %or ation o! high"conductance channel ( itochondrial per eability transition) (MP/) (. :eversible in the early stages ,. MP/ can beco e per anent .ith continued sti ulus 5. Irreversible MP/ death blo. to cell %igure &"&,

&. Most intracellular #aFF is se6uestered in the

itochondria and ):

(. Ische ia and to*ins increase cytosolic #aFF " in!lu* o! #aFF across the plas a e brane " release o! #aFF !ro the itochondria and ): ,. Increased #aFF activates a nu ber o! enBy es> " A/Pases hasten A/P depletion " phospholipases e brane da age " proteases brea3do.n e brane and cytos3eletal proteins " endonucleases DNA and chro atin !rag entation

%igure &"&5

/ffects of #eactive 'pecies&. 4ipid pero*idation o! e branes (. @*idative odi!ication o! proteins ,. 4esions in DNA

%ccumulation of $.!gen,)erived *ree #adicals (@*idative Stress) &. Absorption o! radiant energy (. )nBy atic etabolis o! e*ogenous che icals or drugs ,. :eduction"o*idation reactions " supero*ide anion radical (@(") " hydrogen pero*ide ($(@() " hydro*yl ions (@$) 5. /ransition etals 7. Nitric @*ide (N@)

Mechanisms to #emove *ree #adicals &. Antio*idants " 1ita in ) " 1ita in A " Ascorbic acid " +lutathione (. Storage and transport proteins " /rans!errin " %erritin " 4acto!errin " #eruloplas in ,. )nBy es " #atalase " Supero*ide dis utase " +lutathione pero*idase

%igure &"&7

&. Injury to lysoso al e branes results in lea3age o! their enBy es into the cytoplas and activation o! these enBy es (. 4ysoso es contain> " :Nases " DNases " proteases " phosphatases " glucosidases " cathepsins ,. Activation o! enBy es leads to enBy atic digestion o! cell co ponents

)efects in Membrane Permeabilit! #esult In&. (. ,. 5. 7. Mitochondrial dys!unction 4oss o! e brane phospholipids #ytos3eletal abnor alities :eactive o*ygen species 4ipid brea3do.n products detergent e!!ect on

e branes

%igure &"&9

+wo phenomena consistentl! characteri1e irreversibilit!&. Inability to reverse itochondrial dys!unction (. Develop ent o! pro!ound disturbances in e brane !unction 2istological #eversible Cell In ur!&. #ellular s.elling (. %atty change 3ltrastructural #eversible Cell In ur!&. Plas a e brane alterations " blebbing, blunting, distortion o! icrovilli, creation o! yelin !igures, loosening o! intercellular attach ents (. Mitochondrial changes " s.elling, rare!action, s all a orphous densities ,. Dilation o! the ): " detach ent and disaggregation o! polyso es 5. Nuclear alterations " disaggregation o! granular and !ibrillar ele ents

*igure &,&0 Morphologic changes in reversible and irreversible cell in ur!. A, )lectron icrograph o! a nor al epithelial cell o! the pro*i al 3idney tubule. Note abundant are nor al structures in this cell type).

icrovilli ( v) lining the lu en (4). N, nucleus- 1, apical vacuoles (.hich

K, )pithelial cell o! the pro*i al tubule sho.ing reversible ische ic changes. /he icrovilli ( v) are lost and have been incorporated in apical cytoplas - blebs have !or ed and are e*truded in the lu en (4). Mitochondria are slightly dilated. (#o pare .ith A.) #, Pro*i al tubular cell sho.ing irreversible ische ic injury. Note the ar3edly s.ollen itochondria containing a orphous densities, disrupted cell dense py3notic nucleus. (#ourtesy o! Dr. M.A. 1en3atachala , Lniversity o! /e*as, San Antonio, /M.) e branes, and

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 1 March 2005 0 :25 PM! " 2005 #lse$ier

%igure &"((

+!pes of (ecrosis &. #oagulative necrosis ? preservation o! the basic outline o! the coagulated cells (. 4i6ue!active necrosis ? trans!or ation o! tissue into a viscous ass " +angrenous necrosis ? a li b that has lost its blood supply and undergone coagulative necrosis ,. #aseous necrosis ? a distinctive !or o! coagulative necrosis- ost o!ten a !oci o! tuberculous in!ection 5. %at necrosis ? !ocal areas o! !at destruction Ischemic and 2!po.ic In ur! &. Ische ia tends to injure tissues !aster than does hypo*ia (. I! @( is restored, all o! the disturbances are reversible ,. I! ische ia persists, irreversible injury and necrosis ensue Ischemia,#eperfusion In ur! &. Da age ay be initiated during reo*ygenation by increased generation o! o*ygen !ree radicals (. :eactive o*ygen species can !urther pro ote the M/P ay lead to cell death ,. Ische ic injury is associated .ith in!la ation- production o! cyto3ines- increased e*pression o! adhesion olecules

%igure &"(,

%igure &"(5

Chemical In ur! &. So e che ical can act directly by co bining .ith so e critical olecular co ponent or cellular organelle (. @thers ust be converted to reactive to*ic etabolites " P57 i*ed !unction o*idase in S): )*a ples> #arbon tetrachloride ##l5 ##l, F #l" Aceta inophen is deto*i!ied by interaction .ith +S$

Morpholog! of %poptosis &. #ell shrin3age (. #hro atin condensation " the M$'+ C2%#%C+/#I'+IC !eature o! apoptosis is chromatin condensation .ith chro atin aggregrates at the periphery ,. #ytoplas ic blebs and apoptotic bodies 5. Phagocytosis o! apoptotic cells or cell bodies

Causes of %poptosis Ph!siologic&. /he progra ed destruction o! cells during e brogenesis (. $or one"dependent involution in the adult ,. #ell deletion in proli!erating cell populations 5. Acute in!la atory reaction- i une response 7. )li ination o! potentially har !ul sel!"reactive ly phocytes 8. #ell death induced by cytoto*ic / cells Pathologic&. Injurious sti uli ? radiation, cytoto*ic che otherapy (. 1iral diseases ,. Pathologic atrophy in parenchy al organs a!ter duct obstruction 5. #ell death in tu ors

4iochemical *eatures of %poptosis &. Protein cleavage " cysteine proteases (caspases) (. DNA brea3do.n " !or ation o! oligonucleoso es (&AC"(CC bp) ,. Phagocytic recognition " apoptotic cells e*press phosphatid!lerine in the outer layers o! the e brane " cells ay also e*press thrombospondin, an adhesive glycoprotein " these are recogniBed by MN

%igure &"(A 4cl," *amil! Members &. Pro"apoptotic Ka3 Ka* Ki (. Anti"apoptotic Kcl"( Kcl"*

/N%:& %as (#DD7)

Caspases &. Initiator caspases caspase"A caspase"D (. )*ecutioner caspases caspase", caspase"8
%igure &"(A Mechanis s o! apoptosis. (&) are so e o! the ajor inducers o! apoptosis. /hese include speci!ic death ligands (tu or necrosis !actor O/N%P and %as ligand), .ithdra.al o! gro.th !actors or hor ones, and injurious agents (e.g., radiation). So e sti uli (such as cytoto*ic cells) directly activate e*ecution caspases (right). @thers act by .ay o! adapter proteins and initiator caspases, or by itochondrial events involving cytochro e c. (() #ontrol and regulation are in!luenced by e bers o! the Kcl"( !a ily o! proteins, .hich can either inhibit or pro ote the cellQs death. (,) )*ecutioner caspases activate latent cytoplas ic endonucleases and proteases that degrade nuclear and cytos3eletal proteins. /his results in a cascade o! intracellular degradation, including !rag entation o! nuclear chro atin and brea3do.n o! the cytos3eleton. (5) /he end result is !or ation o! apoptotic bodies containing intracellular organelles and other cytosolic co ponents- these bodies also e*press ne. ligands !or binding and upta3e by phagocytic cells.

Phosphatidylserine /hro bospondin

/.amples of %poptosis &. +% deprivation (. DNA da age" ediated apoptosis ,. /N% !a ily o! receptors 5. #ytoto*ic /"ly phocyte" ediated " per!orin " granBy e K

%igure &"(D +he /.trinsic 5)eath #eceptor,Initiated6 Pathwa! %as4 binds to %as ,F %as co e together and !or a binding site !or an adaptor protein (%ADD" %as"associated death do ain) this then binds to the inactive caspase"A ultiple caspase"A are brought together and they cleave one another active caspase"A this then triggers a cascade o! caspase activation activation o! e*ecutioner caspases /his path.ay is IN$IKI/)D by a protein %4IP .hich binds to pr"caspase"A Kut cannot cleave and activate it

%igure &",C

+he Intrinsic 5Mitochondrial6 Pathwa! Increased itochondrial per eability release o! pro"apoptotic olecules (AI%"apoptosis inducing !actor) and cytochro e c #ytochro e c binds to Apa!"& (apoptosis activating !actor"&) this co ple* activates caspase"D AI% enters the cytosol and binds to and neutraliBes various inhibitors o! apoptosis Kcl"( and Kcl"* directly IN$IKI/ Apa!"& activation

%igure &",&

Primar! l!sosomes contain&. Acid phosphatase (. +lucoronidase ,. Sul!atase 5. :ibonuclease 7. #ollagenase

7ipofuscin pigment ; granules o! undigested aterial derived !ro intracellular lipid pero*idation

'ubcellular #esponses to In ur! &. 4ysoso al catabolis (. Induction (hypertrophy) o! S): ,. Mitochondrial alterations 5. #ytos3eletal abnor alities " thin !ila ents " icrotubules " inter ediate !ila ents (3eratin, vi entin, des in, +%AP, neuro!ila ents)

%igure &",7 Intracellular accumulation of abnormal amounts of substances&. a nor al cellular constituent accu ulates (. an abnor al substance ?e*ogenous or endogenous ,. a pig ent +hree t!pes of abnormalities&. nor al endogenous substance- rate o! etabolis is inade6uate (. nor al or abnor al endogenous substance accu ulates- genetic or ac6uired de!ect in etabolis , pac3ing, transport, secretion ,. abnor al e*ogenous substance is deposited and accu ulates +!pes of %ccumulations&. 4ipids " steatosis and !atty change (4I1):, $)A:/, MLS#4), =IDN)R) " cholesterol and cholesterol esters (atherosclerosis, *antho as, in!la ation and necrosis, cholesterolosis, Nie ann"Pic3 disease type # (. Proteins " reabsorption droplets in P#/ 3idneys " synthesis o! e*cessive a ounts " de!ects in protein !olding ay lead to Iun!olded protein responseJ ,. $yaline change 5. +lycogen " glycogen storage diseases " DM 7. Pig ents " e*ogenous pig ents (carbon, tattoo) " endogenous pig ents (lipo!uscin, elanin, he osiderin) SSSyste ic overload o! iron, he osiderin is deposited in a condition called hemosiderosis and is seen .ith> &. increased absorption o! dietary iron (. i paired use o! iron ,. he olytic ane ias 5. trans!usions any organs and tissues-

%igure &"5,

Cellular %ging &. /elo ere shortening uti ately results in cell cycle arrest (. /elo erase ; lengthens the telo eres by nucleotide addition

Pathologic Calcification &. Dystrophic calci!ication ?occurs locally in dying tissues- N@:MA4 seru

#aFF levels $RP):#A4#)MIA

(. Metastatic calci!ication ? occurs in nor al tissues- al ost al.ays results !ro " increased secretion o! P/$ " destruction o! bone tissue " vita in D"related disorders " renal !ailure Metastatic calcification occurs in the following&. +astric ucosa (. =idneys ,. 4ungs 5. Syste ic arteries 7. Pul onary veins