Path 1 Notes

Lecture 1 Cell Injury

Inderjit
Review of Histology Refer to Ppts for Review
!i"ple #isual $%servation
o &e'ture
o Color
Not always a good indication due to the possi%ility of artifact during organ fi'ation
o !i(e "ass fro" scale)
o !hape
o Consistency
Hard vs) !oft* &e'ture* si(e etc)
!"ooth surface to rough surface tells what+
o ,ou can -.. !$/0&HIN1) 0') Heart) !ee Protein on the surface) &his is an infla""atory
response on the outside of the heart) Pericarditis2)
0picardiu"
&he outer "ost layer of heart constitutes the visceral layer of the pericardiu")
Co"posed of !i"ple !3ua") 0pitheliu" 4/0!$&H0LI5/6
!ee the /esotheliu" and the presence of Infla""atory cells hence 7itis8

o ,ou can R0/$#0 so"ething)

Necrosis
9idney 0'a"ple) :as a #0!!0L disease) #ascular Pro%le") 9idney suscepti%le
to hypertension which narrows vessels)
o #essel disease
&issue gone in #!hape "anner) #shaped scar in ;.) all the
tissue that the artery supplies has died off) #shape scar indicative
of vessel disease)
o Can add or re"ove
Liver 0'a"ple) !ee Nodules and .eep valley scars
Note Nodule surrounded %y Pin< stuff which is indicative of !C-R for"ation)
o Central island Nodule is trying to %ring %ac< the liver) Pro%le" is its not
hoo<ed up to the 7plu"%ing8
o !urrounding tissue is dying off giving !C-R for"ation
Classic 0'a"ple of this CIRRH$!I! 4scar = regeneration6
In #essel .isease of 9idney* why is the 0nd so !uscepti%le+
o Corte' %lood supply
/ain artery in -rcuate artery %ranches to corte') Is /ost suscepti%le) Corte'
%eco"es "ost -N$>IC) 7Is at the 0nd of the food chain8)
Corte' .ies ?irst 7end of food chain8
:hat is .isease+
o It is the R0-C&I$N to IN@5R,) .ont thin< of disease as the injury) ?or our purpose its the
Reaction to Injury)
0') 1NA LP!
!eptic !hoc< its the &N? and the IL1 released %y /acrophages that causes
this) opens A#s .ie 4hence its the 7reaction86
:hat are the critical needs of the cell+
o /aintain "e"%rane integrity
o Produce 0nergy
o /a<e structural and functional co"ponents of the cell
:hat are the different types of Injury+
/icro%ial
Physical
Che"ical
$'ygenB?ree radicals
1enetic
I""une
0'a"ple all the sic<ness associated with ?lu co"ing fro" own %ody
Nutritional
Hypo'ia
Is the Low a"ount of $'ygen) ,ou can see this /orphologically2) Hypo'ia can
%e seen)
1lo%al Hypo'ia lac< of o'ygen throughout the %ody
o Lac< of air
.rowning
1ases
Li3uid nitrogen e'a"ple)
o Ina%ility to ta<e in air
!uffocation
Cellular Cellular
Injury Injury
Reversible Reversible
Irreversible Irreversible
Recovery Recovery
Adaptation Adaptation
Necrosis Necrosis Apoptosis Apoptosis
Cell "aintains steady state of Ho"eostasis where is a%le to
handle nor"al physiologic de"ands) !tress can %ring a%out
cellular adaptation New altered steady state achieved2) !o
via%ility "aintained) &his is -daptation) If it cant adapt* or
the sti"ulus is Injurious in nature* Cell injury and death
results) -daptation would %e increased nu"%er of cells or
increase in si(e of cell) Hyperplasia and Hypertrophy)
-trophy is a decrease in the si(e and function of cells)
-trophy "ight %e fro" decreased nutrients or sti"ulation)
)
&al<ed of later Pg 1C
!trangulation
:ould re3uire cutting off air inta<e as well as the carotids
to prevent %lood flow to the %rain) $therwise would ta<e
too long with just cutting off air inta<e)
Plugged pipes
o -ne"ia
o C$ poisoning
&reat with H,P0RA-RIC o'ygen) Increased partial pressure) !o
can displace the C$) 0nough %eco"es dissolved in plas"a)
o Cyanide poisoning
o Pu"p failure
Nu"%er 1 <iller around the world)
o .ecreased %lood volu"e
Recall septic shoc< and IL1 and &N?
o Increased vascular space
Recall !eptic shoc< and IL1 and &N?

Local Hypo'ia
o :hat is the Aiggest Cause+
Ische"ia) :hat is Ische"ia+
Not getting enough AL$$.22) Is N$& sa"e as hypo'ia)
Is worse than Hypo'ia) Hypo'ic cell switches to -naero%ic
1lycolysis) Ische"ia dont get other nutrients plus
/eta%olites %uild up such as Lactate)
o -naero%ic ;-&PBglucose)
:hat are the different <inds of Ische"ia+
o -rterial $cclusion
Atherosclerosis
Thrombosis clot in a vessel.
Embolization gas, solid, liquid that moves from one site to another.
Terminal Cancer patients present with Pulmonar Emboli.
People with bro!en legs"#ed ridden ppl.
E$ternal pressure
o #enous $cclusion
Thrombosis
:hat are the effects of Ische"ia and Hypo'ia+
o $'idative phosphorylation goes down
o -&P dependent functions go down
o 1lycolysis goes 5P to co"pensate and therefore 1lycogen levels go down)
o pH decreases due to Increased glycolysis and Lactate for"ation)
o Ri%oso"e detach"ent decreased Protein)
$'ygen Related Injury
o Reperfusion injury
.og Hearts showed ti"es when infarct was %igger after returning %lood)
&his is just e'peri"ental* dont play it into clinical situations) -lways try to re
perfuse the tissue)
o ?ree Radicals
Have unpaired electron) $dd nu"%er of electrons e'ists)
0'tre"ely reactive
:hen react with another ato" or "olecule* usually results in -N$&H0R ?R00
R-.IC-L
I)e) ?ree electron "a<es it reactive and e'tracts electron fro" adjacent "olecule
leaving it with lone electron Results in another free radical)
:hy are free radicals i"portant+
o /odify cellular constituents)
o Initiate chain r'ns with those ato"s containing even nu"%er of electrons Product D $dd
nu"%er electron "olecule)
:hat are %iologically i"portant ?ree radicals and how are they "ade+
o -dding electrons to o'ygen 4R$!s64Reactive species of $'ygen6
Cells generate energy %y reducing $'ygen to :ater) &his is done in a se3uential
process) &his is Nor"al Respiration via addition of E electrons) .one %y en(y"es
in the 0R* Cytosol* /itochondria* Pero'iso"es* Lysoso"es)
o Leads to for"ation of F
!upero'ide
Hydrogen Pero'ide
/yelopero'idase converts this to Hypochlorous acid
Hydro'yl Ions
Can da"age lipids* proteins* .N-
Can cause LIPI. P0R$>I.-&I$N
o .efense syste"s e'ist)
I"%alance causes $'idative !tress)
Causes Cell death)
o Cytochro"e PEGH /echanis" 4go down for so"e e'a"ples 6
CClE and -ceta"inophen e'a"ples)
:hich of the a%ove three is "ost da"aging to the cell+
o Hydro'yl Ion
!upero'ide Hydrogen pero'ide 4via dis"utation6 Hydro'yl Radical
4Cu4;=6B?e4;=6 ?enten R'n Cycle6
Hydro'yl radical = /acro"olecules .-/-10
#ita"in C in the wrong conditions with Iron Present will actually P5!H this
reaction forward) Aecause #ita"in C 4-!C$RA-&06 pro"otes the conversion of
?e I 4ic6 to ?e ; 4ous6) &hen drives the ?enten reaction)
o PR$/$&0! ?0N&0N R>N 4conversion of Hydrogen pero'ide
hydro'yl radical)
:hat are the $'idant .efenses+
o !upero'ide .is"utase
1ets rid of supero'ide %ut price paid is that it "a<es hydrogen pero'ide)
?ound everywhere in the cell
o Catalase
&a<es care of Hydrogen Pero'ide water)
$ne pro%le"+ found only in P0R$>I!$/0!)
N$& located in cytoplas" where "ost of the da"age occurs)
o 1lutathione Pero'idase
/ajor protector fro" Hydrogen Pero'ide in the C,&$PL-!/22 and everywhere else
e'cept the Pero'iso"e 4Catalase6
1lut 4reduced6 = H;$; 1lut 4o'idi(ed6 = :ater)
!$ ?$R 0>-/ &HI! I! &H0 /-@$R PR$&0C&$R -N. .0?0NC0 IN
&H0 C,&$PL-!/ -1-IN!& H,.R$10N P0R$>I.0)
o #I& 0
!cavenges radicals in C0LL /0/AR-N0
o #I& C
?e I= ?e ;=
o 5ric -cid
-ntio'idant in plas"a
-ni"als "a<ing this live longer)
/eta%olite of Purine
&oo "uch results in 1out)
o ?erritin* transferrin* lactoferrin* J ceruloplas"inF %ind ?e== J Cu== 4Kous "etals6
:0 .$N& H-#0 ?R00 C$PP0R $R IR$N IN A$., otherwise would cause death)
-ll iron in %ody either as the following for"sF -L:-,! %ound to so"ething "a<ing it in
a nonreactive state)
He"e
?erritin to store it
&ransferrin to "ove it around
:hat %inds copper+
Ciruloplas"in
:hat diseases result with deficiency+
He"ochro"atosis too "uch free Iron
:ilsons .isease)
Physical Injury
o 0lectricity
o Radiation ?ree Radicals 4Ioni(ing Radiation6
Area<s water Hydro'yl radicals)
Arain very resistant %ecause .$N& H-#0 .I#I.IN1 C0LL!)
Ische"ic tissue resistant %ecause less o'ygen to %egin with
.ose dependent da"age
IHH units will target the %one "arrow) /essing up the %lood cell for"ation and
i""une cells) !o get %leeding and infections .eath in I w<s
1HHH units goes deeper to "ess up epitheliu" death in ; w<s
;HHH units will start to affect %rain) Large dose re3d to get the %rain and radiation
resistant organs) .eath in 1 day
o &rau"a
o &e"perature
o IGL /agnu"
Che"ical Injury
o Corrosives
o &o'ins and Poisons 4free radicals6
o Carcinogens
o !ensiti(ers
o Can classify Che"ical injury as .IR0C& or IN.IR0C&
.irect Cyanide causes .irect da"age %y inhi%iting cytochro"e o'idase C
Indirect CClE and -ceta"inophen
CClE CClI radical
-ceta"inophen decreases 1!H22 ) 1!H depletion leads to Protein &hiol
o'idation causes cross lin<ing of "e"%rane proteins !&R5C&5R-L
-L&0R-&I$N $? PL-!/- /0/AR-N04+6 .eath4+6
o A$&H R0-C&I$N! -A$#0 C-&-L,M0. A, PEGH 4R0C-LL6
$'idation of protein thiols 4!H D &hiol group6
o Cystein residue in protein with !H groups !! %onds) Confor"ational change in protein
results en(y"e activity lost protein cross lin<ing
o Ca -&Pase pu"ps have thiol groups in active site* inactivated* Ca lea<s out of 0R and through
the plas"a "e"%rane increasing cytosolic Ca disregulated calciu" will activate proteases*
lipases* endonucleases* etc) -nd literally eat the cell alive)
1enetic Injury
o Injury "ay %e at different levels
Chro"oso"al Huge changes
/utationBdeletion "ore difficult to see
1enetic changes "ay %e inherited
I""une Injury
o Have various autoi""une diseases)
Reversi%le Cell Injury /orphology
o ?IR!& thing you see D !:0LLIN1 D Hydropic .egeneration2Bclouding swelling)
:hy do cells swell during Ische"ia+ &here are ; reasons
1) .ont have -&P* !o the pu"ps arent wor<ing* Cant pu"p out Na water
follows sodiu" Cell swells)
o Is the /-@$R cause
;) /olar concentration or tissue os"olality INCR0-!0!) &his is due to
Cata%olis" within the cell) &his happens later in ti"e as cell %egins to %rea< down
into s"aller pieces)
9idney &u%ules and Cell swelling
-re 0>&R0/0L,2 sensitive to H,P$>IC conditions)
.egeneration %egins very 3uic<ly22 in a%out N hr) ?ro" the ti"e the person
dies) Co"pare to !<eletal "uscle which degenerates after a%out 1 day or so)
o :hat part of 9idney /ost affected+ PR$>I/-L &5A5L0
o !ee ; things happening %elow
!ee the huge swollen cells
.ifference in !&-ININ1) Pin< %eco"es "ore .IL5&0. and stain
is lighter pin< due to the presence of :ater)
-t this point the change I! reversi%le
&he cells said to %e 7Cloudy swelling8 and C-N not
necessarily :ILL recover)

o /itochondrial swelling
/e"%rane aggregates)
o !"all dense %odies in "itochondria
o /e"%rane %le%%ing and swelling
o Intracellular accu"ulations 4e)g) lipid6
0') -ccu"ulation of fat) !ee fat accu"ulation in the liver)
Lipid -ccu"ulation /ainly occurs in H0P-&IC C0LL!)
Is totally reversi%le D e'a"ple stop drin<ing
CIRRH$!I! is N$& reversi%le)
&his can %e due to "any reasonsF
o -lcohol 4ethanol6 D decreased Lipoprotein synthesis 4/$!& C$//$N6
-lso* In the "eta%olis" of alcohol* 1IP is a Ayproduct) &his is a
su%strate for &riglyceride synthesis
-lcohol "ay also* li<e hypo'ia* decrease %eta o'idation of ?-s
o Protein /alnutrition D decrease Lipoprotein synthesis
.ecreased protein can also cause decreased synth) $f -po A1HH
.ecreased -poA1HH also caused %y CClE)
o Hypo'ia D decreased ?atty acid o'idation
o !tarvation D increased fat li%eration fro" stores
Increased "o%ili(ation also caused %y alcohol
Irreversi%le Cell Injury Cell .eath) &he cell cant adapt to the Injury and cant recover) &his will %e
Necrosis and -poptosis)
o 1) Necrosis tissues loo< different when they die) 5se the following ter"s to descri%eF
4CC??L16)
/echanis" of Necrosis
-&P depletion
.ecrease pH
$'ygen radicals
Increased intracellular Ca== 222222222/$!& I/P$R&-N&2222222222
o %ecause its used In signal transduction) !o if its not regulated and you
increase its levels* you will start to activate stuff li<e -&Pases which is last
thing you want in an already -&P depleted cell222

Increased "e"%rane per"ea%ility
Irreversi%le "itochondrial da"age
Coagulative
22/0/AR-N0
.-/-1022
preservation of cell outlines of dead cells for a ti"e 2222
Characteristics of Coagulative Necrosis in !taining
o Hypereosinophilia
o Py<nosis 4also in apoptosis6
a !/-LL .-R9L, !&-IN0. N5CL05! "eans cell is dead
o 9aryorrhe'is
Nucleus Area<up
o 9aryolysis
Nucleus gone
o Large /itochondrial densities
o /yelin Aodies
o
,ou see Hypereosinophilia "eaning loo< at the stain in the cardiac "uscle
%elow) -nd see what is "issing) No nuclei and see no cross striations)
o Hypereosinophilia doesnt "ean "ore 0osinophils %ut rather cell protein
%ra<ing down so have "ore 0$!IN !&-IN %inding sites* stains dar<er)
/echanis"
o you are denaturing protein which accu"ulate due toF
Results fro" accu"ulate of Lactate or heavy "etals
4lead*"ercury6
0'posure of cells to Ioni(ing radiation
o ,ou da"age en(y"es that now prevents the autolysis of a da"aged cell)
Cell is dying %ut wont autolyse %ecause the cell is da"aged
Li3uefactive
!een in CN! 4infarct in %rain6 and L5N1 -A!C0!!0!
o -A!C0!!0! in %acterial infection
Hydrolytic en(y"es generated %y neutrophils li3uefy dead tissue
0') :et gangrene of toes of person with dia%etes "ellitus
due to -N-0R$AIC IN?0C&I$N 4Clostridiu"
Perfringens6

Caridac /uscle
Caridac /uscle
!ee P5!
Heart deprived of %lood to point where nucleus
dies
Caseous
green cheesy granulo"a for"ation)
o In the center of the granulo"a you seeF
-ctivated "acrophages* C.EHelper &cell* 1iant cells 4Langhan
type giant cell6
!o"e granulo"as dont show caseation e'a"ple
!-RC$I.$!I!)
/acrophages release &N? and IL1 too cause IN?L-//-&I$N
of the surrounding tissue D 1ranulo"atous Infla""ation) &his is
R0-C&I$N &$ IN@5R,) Not the &A that did it)
&hin< &A
o Caseous "aterial if for"ed %y the release of LIPI. fro" the cell walls of
/,C$A-C&0RI5/ &5A0RC5L$!I! and syste"ic ?5N1I 4eg)
Histoplas"a6 after destruction %y "acrophages)
?at
In adipose tissue located around an acutely infla"ed pancreas22
!een as chal<y yellowwhite deposits located in peripancreatic and o"ental2
adipose tissue
!ee this in Pancreatitis)22 4will %e 0NM,/0 "ediated6
o -cute Pancreatitis is a /edical 0"ergency
o Aelow see the fat cells dying off22
Can see it in &rau"atic fat necrosis such as fe"ale %reast fro" trau"a) Here dont
see it as 0NM,/0 /0.I-&0. %ut rather as result fro" trau"a)
/echanis" 40n(y"e "ediated6
o If you drin< too "uch alcohol activates Pancreas Lipase hydrolysis
of triglyceride in fat cells
o ?atty acids converted to soap 4saponification62
?ro" the co"%ination of ?- with C-LCI5/2

?i%rinoid
Pale outlines of fat cells
filled with %asophilic
staining calcified areas)
li"ited to s"all "uscular arteries* arterioles* venules* and glo"erular capillaries)
!ee protein in the wall and red ri")

1angrenous
gas for"ing infections

o -poptosis
Cell shrin!age %protein cleavage and cross&lin!ing'
(embrane blebs
)uclear shrin!age
P*+),-.- in a -/,00E) cell vs. a -123)4E) cell, pgnosis mean
5.66E2E)T T1.)+-77777
)uclear fragmentation
Phagoctosis b neighbor cells
-n apoptotic cell sends a strong signal to phagocytosing cells)
!enescent cells $ld cells
0"%ryologic develop"ent
0') Loss of /ullerian !tructures in a "ale fetus due to !ertoli cell synthesis of
/5LL0RI-N INHIAI&$R, ?-C&$R
I""une "ediated death
.eath of a tu"or cell or say virally infected cell %y C,&$&$>IC C.O & Cells
o !o"e viruses can prevent this) -denovirus and Hu"an Papillo"a virus)
o ,ou actually see a /I>0. R0!P$N!0222I/P222 "eaning that so"e
of the cells %eing <illed %y the virus spilling out contents getting
infla""ation) -nd also see that these virally infected cells %eing <illed %y
I""une syste" via -poptosis) Aut with so"e viruses dont see fever or
anything) &he "ore stronger viruses will show "ore of a dual type of
response)
o -ids C.E & cells die %y apoptosis)
Corticosteroid destruction of ly"phocytes)
o ***Anti-inflammatory Steroids*** - inhibit inflammation via
APOPTOSIS
Hor"onal or cyto<ine withdrawal
0'a"ple 0ndo"etrial cell %rea<down after withdrawl22 of 0!&R$10N and
PR$10!&0R$N0 in the "enstrual cycle
Prostate 1landular 0pitheliu" re3uires constant hor"onal sti"ulation* after
C-!&R-&I$N* it dies of -poptosis)
Regression of lactating %reast after weaning of child 4child not dependent6
Cyto<ine such as IL; withdrawl) :hen culture & cells and re"ove IL; &
C0LL! .I0 A, -P$P&$!I!) /echanis" for deleting unnecessary & cells after
antigen Clearance222
:hat are so"e Pathological !tates of -poptosis+
o -utoi""une disease type E hypersensitivity
:hen we cant successfully re"ove autoreactive i""ature ly"phocytes %y -poptosis2
o -l(hei"ersBPar<insons
o Neoplasia
Loss of pGI) pGI IN.5C0! -poptosis 4upregulates A->6) !o no apoptosis
Neoplasia)
Co"pare and Contrast Necrosis and -poptosis
In necrosis first thing cell does it !:0LL* in apoptosis first thing cell does is get s"aller)
-poptosis can %e caused %y !-/0 !&I/5L5! that causes Necrosis* if the sti"ulus is
L0!! !0#0R022) 0') going over EI degrees you hurt it so "uch that Necrosis)
:ith Necrosis %unch of cells gone* -poptosis select cells*
Necrosis was fro" overwhel"ing stress and also generally has an IN?L-//-&$R,
R0!P$N!0) -poptosis is controlled %y specific 10N0!)
-dvantage+ if Necrosis happened every "onth in :o"ans 5terus* she would
have no 5terus after so"e ti"e) @ust spilling out intracellular contents openly)
&he Nuclear Chro"atin
/arginates in %oth)
In apoptosis it will C$N.0N!0 pic -
-poptosis .N- frag"ented sa"e ti"e its %eing condensed
In Necrosis* .N- frag"entation is late event)
.N- frag"ents rando" length in Necrosis !/0-R P-&&0RN IN 10L22
.N- frag"ents ;HH %p in -poptosis L-..0R -PP0-R-NC0 IN 10L
VERY IMPORTANT Nerosis has !enerali"ed #E$$ and N%#$E%S s&ellin'( So
EAR$Y S)E$$IN! and $ATE PY*NOSIS O+ N%#$E%S
/echanis" of -poptosis
o 0'trinsic
&R-IL! &u"or Necrosis ?actor Related -poptosis Inducing Ligands
0') ?-!* &N?
o Intrinsic 4"itochondrial6
Acl;* Aa'* pGI* inducing release of cytochro"e c* s"ac* .I-AL$
o &hese signals initiate -poptosis how+
-ctivating Caspases
0'trinsic pathway D O and 1H 4O for ?-! and &N?6
Intrinsic pathway D P*1; 4one for .N- other for Protein da"age6
C$//$N 0>0C5&I$N P-&H:-, fro" there on 8*C*L 40>0C5&I$N
C-!P-!0!
How do we study -poptosis+
o 1) 1enes in Ne"atodes controlling -poptosis
o ;) 5nderstanding that so"e "utations with "alignant tu"ors alter -poptosis
o I) !o"e virus genes Aloc< -poptosis)
-poptosis in Ne"atodes 4C) Elegans death6
o CedI and cedE death 4a%solutely re3d for -poptosis6) N$&0 nor"ally found in cells that
are N$& PR$1R-//0. &$ .I0 as well) 4so pro%a%ly a control "echanis" here6
o CedP Inhi%its -poptosis) Could %e lethal) If too "uch* "ight inhi%it develop"ental22
apoptosis) Loss is %ad %ecause "ight flip over to apoptosis too "uch)
-poptosis in Hu"ans and I"portant players
o Acl; gene fa"ily
Acl; protein is located on the outer "itochondrial "e"%rane22
-ntiapoptosis genes) Products of Acl; gene 4Acl; Protein6 class INHIAI& apoptosis)
/echanis"+
Prevent /itochondrial lea<age of cytochro"e c into the cytosol)
Acl; is regulated %y A->
:hat is the relationship %etween Acl; and A->+
o Acl; prevents apoptosis and A-> pro"otes it
o Aa' can for" heterodi"er with Acl; and ho"odi"er with another A->
o IT IS T,E -A$AN#E -ET)EEN T,ESE T)O &hih .ETERMINES T,E O%T#OME*
:hat is the hu"an analog to CedE+
o -paf1
o -paf1 conjunction with ctyochro"e c activates Caspase P
o -rgu"ent e'ists as to whether Acl; actually %inds to -paf1 and inhi%its it
:hat is a function of Aa'+
o Pro"ote release of cytochro"e c fro" outer "e"%rane of "itochondria
o Can %ind and inhi%it Acl; located in the outer "e"%rane)
:hat is analogous to cedI and cedE 4c) elegans6 in hu"ans+
o CedI Caspases
o CedE -paf1 4re"e"%er activates Caspase P6
:hat are caspases+
o &hey are group of cystein proteases that cleave proteins at -!P-R&IC -CI. R0!I.50
o 1roup of 1;
o Involved in apoptosis -N. infla""ation 4so"e6
o /ade as M,/$10N! 4inactive precursors6
How do caspases disasse"%le a cell+
o 1) inactivate inhi%itors of apoptosis e') Acl;
o ;) it can cleave !&R5C&5R-L protein
o I) deregulate proteins) How+ !eparate the regulatory and catalytic su%units)
0'trinsic pathway of -poptosis
o /ediated %y &R-IL Ligands) 0g) &N? and ?-!
o /echanis"
0') ?-! ligand 4?-! L6 %inds to death receptor ?-! !ee the ?-! receptors
-11R01-&022 the ?-! receptor associated with a cytoplas"ic do"ain called
?-.. 4in this case64?-.. D ?-! associated .eath .o"ain6 %ind PR$ caspase O
induce pro'i"ity and autocatalytic activation of caspase O apoptosis
&R-.. would %e &N? receptor associated .eath .o"ain
#as/ase 0 and #as/ase 1
0') &N? has ; <inds of Receptors)
Note &N? Receptors Aind %oth ?-.. and &R-..
o &N?R1) !a"e "echanis" as ?-! A/o/tosis
o &N?R; ?-.. and &R-.. activate adaptor protein activate series
of 9inases N?<% Increase gene e'pression induce growth and
increase in collagen S2rvival) 4Helps in :$5N. H0-LIN16
o :ill see that &N? associated with L5N1 .I!0-!0)
&he Intrinsic Pathway
o /ediated "ainly %y lea<age of #YTO#,ROME #* SMA#* .IA-$O
o Regulated %y Acl; and pGI 4o&n 3 via -A46 1ene fa"ily)
o &his pathway is fired howQ+
1).irect injury to "itochondria
;).N- da"age
I)PR$&0IN222 da"age
E)&cell "ediated
:hat are !/-C and .I-AL$ doing+
o &hey are going to run around and eat up all the INHIAI&$R!
0') they inhi%it S%RVIVIN
:hat does Cytochro"e C do+
o It conjugates with -paf1) &hen goes on to activate Caspase P
:hat is pGI+
o &u"or suppressor gene
o Aefore cell enters ! phase* repair any da"aged .N-
; functions of pGI+
o 1) fi' da"aged .N-
o ;) 5pregulate A-> 4if too "uch da"age then A-> is upregulated6 -poptosis
:hat are the conse3uences of No pGI+
o Have L0!! radiation induced -poptosis
o 3suall with radiation, in normal and tumor cells ou are increasing p98 apoptosis
%chemotherap in case of tumor cells'
o In the case of !&0R$I. IN.5C0. apoptosis* pGI N$& re3uired)
:hen giving che"otherapy or radiation treat"ent* why dont you want it too %e too strong+
o Aecause not only does it increase pGI to induce -poptosis* it can induce N0CR$!I!)
How do we deal with da"aged protein+
o Not just wasted)
o Have Chaperones that are H0-& !H$C9 PR$&0IN! 0g. Hsp repair protein
:hat happens to protein that cant %e repaired+
o &ag with 5%i3uitin and send it off to Proteoso"e)
Can a cell %e sent into -poptosis just %ecause of Protein .a"age+
o ,0!) @ust li<e a cell with .N- da"age)
o &his is done #ia which Caspase+
#ASPASE 56 7*******8 Im/ortant)
RE#A$$ #ASPASE 1 &as ativated &ith .NA dama'e)

:hich "olecule or "echanis" %ypasses the e'trinsic and intrinsic pathways to directly affect the
0'ecution Caspases+
o 1R-NM,/0 A)
Released %y Cytoto'ic &cells22
1oes straight to e'ecution caspase I22
Perforin punches hole in "e"%rane for 1ran(y"e A
Inhi%ition of -poptosis
o 1) Have IAP 4Inhi%itor of -poptosis Proteins6
0') !urvivin
o ;) 7 .2mmy Ree/tors9 for TRAI$S)
Called du""y %ecause have no .eath .o"ains 4?-.. or &R-..6
o I) -+$IP
Inhi%its Procaspase O
2222!5//-R, 1R-PH2222
How is -poptosis .etected
o Have cell per"ea%ility la%eling .N- .yes)
o -poptosis doesnt want cell per"ea%ility* Necrosis cells have Per"ea%ility pro%le"s
&herefore Necrotic cells allow dye in222i"portant)
:hy is everything tal<ed a%out so far on -poptosis so i"portant+ !o"e -pplications)
o Cancer &reat"ent* can utili(e these pathways
o 1( TN+ and +AS$ are to:i( RE#OM-INANT TRAI$S* have /assed trials in non-h2man
/rimates(
TN+ If in;et into someone SEPTI# S,O#*(
Reo<s are 'ood bea2se they .ON<T need to interat &ith /=> or -l6 7!OO. +OR
--#E$$ $YMP,OMA8
o ;) Acl; -N&I!0N!0 "RN- will %ind sense and "a<e L0!! Acl; get -poptosis2
9ILL C-NC0R)
o I) Caspase Inhi%itor)
-daptation to Injury and !tress 222222N$&0! !H$5L. PR$A-AL, 1$ A0?$R0
IRR0#0R!IAL0 C0LL IN@5R,222222
o 1rowth -lterations
Hypertrophy
Hyperplasia
Aoth these result in AI1 organs* %ut in ; different ways)
-trophy
/etaplasia
.ysplasia
Hypertrophy
o Is the increase in !IM0 of cells)
o Can %e PH,!I$L$1IC 4uterus during pregnancy6 or P-&H$L$1IC 4Heart due to
Hypertension6
o !<eletal "uscle when lift weights22) &he stress on "uscles is :0I1H&!
o In hypertension* the stress on the heart is due to PR0!!5R0
o Hypertensive patient has %igger heart relative to a /arathon runner
o Hypertrophied heart can get as high as 1HHH gra"s) Nor"al for G1H "ale is a%out IPHEHH
gra"s
:hat causes Hypertrophy+ List I)
o 1) !o"e "echanical sti"ulation such as Pressure or Pulling due to lifting of weights 4"eans
INCR0-!0. :$R9L$-.6
Left #entricular Hyptrophy
:eight training
!"ooth "uscle hypertrophy of urinary %ladder due to prostates 1*PE2P0A-.A2
o%structing 5rinary passage through the urethra22)
Re"oval of one <idney increases wor< load of other
o ;) 0ndocrine influence
0') 1H sti"ulation
0strogen222 sti"ulating 5&0R5! !"ooth "uscle !"ooth "uscle hypertrophy
o Increase in .0/-N. of that cell 4functional de"and6)
0') Lose one <idney) .e"and on other one goes up) /onths later you see it gets
AI110R 4Hypertrophy6
/yocardial Hypertrophy) :hat is seen+ :hat are I things that happen+
o 1) In a hypertrophied heart* see over e'pression of -trial Natiuretic ?actor 4-N?6) -L!$* see
-N? "ade in #0N&RICL0!)
o ;) Cfos* jun* 01R? %eco"e e'pressed in these hypertrophied cells)
o I) Change in contractile protein)
/yosin
Aeta "yosin 4fetal for"6 replaces -lpha /yosin)
o :hy would this happenQQ+ 22222
Aecause Aeta "yosin uses L0!! -&P and is "ore efficient than
-lpha "yosin) !o then why rid this in the 1
st
placeQQ+22222
Aecause Price is paid for having "ore efficient) Has less
-&P at rest %ut :H0N N00.0. such as in 0>0RCI!0
C$N.I&I$N! etc* it %eco"es difficult to 5P &H0 C$
4Cardiac $utput6) -lpha /yosin is good here) 22
Hyperplasia
o Increase in N5/A0R of cells
o Can %e Physiological or Pathological)
Physiological 0'a"ple Lactating Areast
Pathological 0'a"ple PR$!&-&022 enlarge"ent)
:hat are so"e causes of Hyperplasia+
o 1? sti"ulation endocrine or stress induced
0ndo"etriu" proliferation each "onth of "enstrual cycle
Callus for"ation
0rythroid hyperplasia under chronic hypo'ic conditions
o #iral induced
HP# loves the s3ua"ous epitheliu" :arts
Partial hepatecto"y
o Re"ove part of the liver* the re"aining lo%es of the liver will undergo H,P0RPL-!I- to re
esta%lish the liver "ass)
-trophy
o 5ecrease in size, and often function, of cells, generall associated with a decrease in
size and"or function of a tissue or organ
o It can %e physiological lift weights then stop) 7.ont use it* you lose it8
o /ost of the ti"e* tal<ing of a pathological process)
:hat are so"e causes of -trophy+ List L)
o 1) .isuse* voluntary or denervation "uscles use it or lose it
o ;) decreased %lood supply
Aenign Prostatic Hyperplasia
cere%ral atrophy due to atherosclerosis of the carotid artery
o I) decreased nutrients
total calorie deprivation in "aras"us
o E) loss of endocrine sti"ulation 4hor"one sti"ulation6
o G) Loss of 1?s)
o C) -ging
1ood to do strength training as we age)
o L) Pressure
.ue to Increased Alood Pressure)
0') -trophy of the renal corte'22 and "edulla in Hydronephrosis22241oljan6
.ue to N-RR$:IN1 of R0N-L -R&0R,)
2220>-/222 on e'a" if see this and 3uestions says what is the /$!&
LI90L, !I1N -N. !,/P&$/ $A!0R#0. IN &HI! P-&I0N& with a chronic
Ische"ic <idney 1?R goes down ReninB-N1 syste" <ic<s in AP 1$0!
5P) !o AP goes up)
o ,ou R0/$#0 &H0 -&R$PHI0. 9I.N0, and the AP goes %ac< up22
:hat is the "echanis" of -trophy+
o 1) Increased Cata%olis" of Cell organelles and reduction in cytosol
see $rganelles and cytosol for"ing autophagic vacuoles fuse with pri"ary lysoso"e
en(y"atic degredation
5ndigested lipids stored as residual %odies
AR$:N -&R$PH, is a tissue discoloration that results fro" Lysoso"al
accu"ulation of LIP$?5!CIN 47wear and tear pig"ent86) Lipofuscin is an
indigesti%le LIPI. derived fro" Lipid Pero'idation22 of cell "e"%ranes* which
"ay occur in atrophy and free radical da"age of tissue)
o Loss of Cells %y -poptosis) 4goljan6
/etaplasia
o Replace"ent of fully differentiated cell type %y another
o !ee there is an INCR0-!0. RI!9 $? C-NC0R with /etaplasia)
&he cells that are su%stituted :hy+
Aecause are less sensitive to a particular stress) List ; 0'a"ples)
o #lassi E:am/le TRA#,EA S?( Meta/lasia) :hat is the epitheliu"+
Colu"nar 0pitheliu" with Cilia) Nor"ally N$ s3ua"ous
0pitheliu" in the Lung) Aut N$&0 ;GR of Lung cancers are of
!S) C0LL 0PI&H0LI5/ C-RCIN$/-!) How+ Cig) !"o<e
is to'ic* !3) epitheliu" is tough and protective)
o #lassial E:am/le #ol2mnar 'astri meta/lasia of distal eso/ha'2s
in !ER. 7barrets eso/ha'2s6 going fro" !3) in the esophagus which
"a<es sense) Its protective) &he sto"ach nor"ally has "ucous secreting
Colu"nar) :hy+ to protect against -CI.) ***S?( EPIT,E$I%M
!o"e !3ua"ous
epitheliu" still
re"ains
#ANT PROTE#T A!AINST A#I. IN !ER.) #O$%MNAR #AN
bea2se IT ,AS A M%#O%S $ATER22222 Aarrets 0sophagus
Note there is no such thing as changing2 fro" one differentiated cell to another
differentiated cell 4its the R0PL-C0/0N&6
Its STEM #E$$S that alter their path of differentiation to slowly do the
replace"ent)
!o saw ; e'a"ples here) ?ro" 1landular !3ua"ous and !3ua"ous 1landular) Can also have
fro" 1landular to other for" of 1landular 4called Intestinal "etaplasia in Pylorus and -ntru" in
response to H) Pylori6
.ysplasia $?&0N &0!&0. -N. /I!!0.222222222222
o .isordered cell growth
o C-N progress to Cancer) 22
o Cells lose ; things
5nifor"ity
-rchitectural organi(ation
:hat are the ris< factors for .ysplasia+
o Hyperplasia
o /etaplasia
o Infection
Hu"an Papillo"avirus type 1C !3ua"ous .ysplasia of the Cervi'
!3ua"ous .ysplasia of the Cervi' is a Precursor for !3ua"ous Cell
Carcino"a) Lac< of orientation of the s3ua"ous cells in 5PP0R ;BIs of
epitheliu") P-10 1G 1$L@-N NIC0 PIC
o P-P !"ear
&he nor"al organi(ation fro" Aase"ent "e"%rane up should %e
1) Progenitor ;) differentiating I) s3ua"ous)
In dysplasia have less "ature s3ua"ous cells in the surface)
-ngry loo<ing nuclei in cells of pap s"ear
o Che"icals
o 5#
:hat is -naplasia+
o &his is C-NC0R) Co"plete loss of "orphological differentiation)
o In vast "ajority of Cancers this is the case)
o N$& all cancers are -naplastic) Ie) ,ou can have :0LL differentiated cancers where the cancer
cells loo< li<e the Nor"al cells)
o Cells loo< nothing li<e their parents* and have no idea where they ca"e fro"22222
o IN .,!PL-!I- you see differentiated cells and you <now where they ca"e fro"22
:hat is Neoplasia+
o -utono"ous new growth)
(eaning somehow cell escape ),2(A0 C,)2,0 (EC1A).-()
o New growth* %ut now add so"ething &5/$R!
o Neoplasia doesnt "ean /alignancy
o Neoplasia C-N %e "alignant 4carcino"a6 or %enign 4fi%rinoid6)
Cellular -ccu"ulations
o 0ipids %fats and cholesterol'
Pic to the right shows accu"ulation of
Cholesterol in arterial wall in -therolsclerosis)
Note the Crystalin srtucture
o Proteins
o 1aline change
N$& a real !5A!&-NC022
o +lcogen
-ssociated with Po"pes .isease) Rare.
Pic in class slide ;HP showing Po"pes in Heart)
o Pigments
-nthracotic Pig"ent222 an e'ogenous accu"ulations
Coal :or<ers pneu"oconiosisF phagocytosis of %lac< anthracotic pig"ent 4coal
dust6 %y alveolar "acrophages 47.5!& C0LL!86
Nor"al ppl dont have nice pin< lungs) :e are in society with environ"ental
pollution so we have it in our lungs) !o no real difference fro" !/$90R!) Cant
"a<e the differentiation
SO E4AM ****#ANT %SE T,IS AS .IA!NOSTI# O+ SMO*IN!(
TR%E )AY O+ TE$$IN! I+ IT<S A SMO*ERS $%N! OR NOT to he@
and see ,O) A%I#*$Y IT #AN -E #$EARE.***
Aut a &R5L, AL-C9 L5N1 diagnostic of Coal :or<ers .isease)
Suestion &0!& ; ly"ph nodes got "i'ed up* how to tell difference+
How can -lcohol affect the Liver) :hat are the changes that occur+
Changes here are !5AL0&H-L ,ou stop drin<ing* you fi' the pro%le"* Aut if cirrhosis* your done*
cant reverse it)
o 6att Change
If 3uit drin<ing* the fat will go away) !LI.0 ;H1 and 1oljan Page P 42226
o Alcoholic 1aline (A00,2* #,5.E-777.(P,2TA)T
/allory Aodies are .-/-10. 4u%i3uinated6 Cyto<eratin IN&0R/0.I-&0
?IL-/0N&! inside hepatocytes in alcohol liver disease
5%i3uitin %inds to da"aged inter"ediate fila"ents
-nd "ar<s the" for degredation in proteoso"e)
!tains glassy red appearance in hepatocytes)
N$& diagnostic of -lcoholis"
-lcohol is the C$//$N C-5!0 %ut not the only cause)222 2
o (egamitochondria
o (itochondrial Crstals
o Proliferation of endoplasmic reticulum
Protein -ccu"ulation Refer to .) LI&& N$&0! ;
nd
last page)
He"osiderin -ccu"ulations
o Is a ?0RRI&IN degradation product)
-n insolu%le product of ferritin degradation in lysoso"es)
o Iron $verdose He"ochro"atosis
0'cesss He"osiderin deposition in parenchy"al cells* leading to free radical da"age and
organ dysfunction 4eg) Cirrhosis6)
Heart failure cells) %ut %ecause its %rown in the cell* is not diagnostic of
he"osiderin)
&o deter"ine if its He"osiderin IR$N !&-IN 4Prussian Alue6 &5RN!
NIC0 AL50
Liver suffering fro" He"ochro"atosis Note the R5!&, C$L$R) Color is
indication here)
o &reat"ent+ !i"ple Alood Letting
Polari(a%le foreign %ody
o 0g) &alc) How did this get into %lood strea" of patient in the hospitalQ+
!houldnt %e there in the %lood) Not in nor"al circulation
Injected* .rug a%users) .rug dealer put it in the crac<)
&alc filters out at Lungs222 fi%rosis Interstitial ?i%rosis22 .0-&H
?oreign %ody giant cells
o /acrophages surround foreign %odies in atte"pt to digest
o Ruptured silicon %reast i"plant
Lipofuscin
o Arownish yellow intracellular pig"ent)
+rom li/id and /rotein a2m2lation from $IPI.
PERO4I.ATION of +A<s in s2bell2lar membranes(
o -ccu"ulates in non dividing or slow dividing cells
Neurons* cardiac "yocites22* hepatocytes
o Hard to distinguish fro" H0/$!I.0RIN)
o In L$N1 LI#0. C0LL! accu"ulates with age)
o !lide ;;I see heart "uscle) -nd Lipofuscin) Could it %e He"osiderin+ It could %e) Recall
saw pic) !o <eep it in the differential for heart disease)
o !ee a N$R/-L H0-R& aging* and see Lipofuscin)
.ifferent types of CalcificationF
.ystro/hi #alifiation - ****IMPORTANT****
o -ccu"ulation of calciu" salts at sites of chronic stress and injury22
o Hardening of an artery is C-LCI?IC-&I$N 4the chronic infla""atory response6 following
-thelerosclerosis)
Can actually s3uee(e the" and hear that crunch22222
!o"e get it and so"e dont)
:e dont <now why it happens222
Calciu" seen easily on >R-,
Is the N%M-ER ONE TIP O++ IN A MAMO!RAM(
o IMPORTANT IN EAR$Y -REAST #AR#INOMAB there are small
MI#RO #A$#I+I#ATIONS 7&e don<t @no& &hy8( Easier to see this
than a small t2mor(
So &hen bio/sy ta@en MI#RO#A$#I+I#ATION %SE.**
/etastatic Calcification
o /eta%olic pro%le" with calciu"
Parathyroid tu"or
Renal disease
Iatrogenic ta<ing calciu" supple"ents)
o Hypercalce"ia -LL $#0R &H0 A$.,) /ore glo%al)
:uestion Can ou visualize 5strophic Calcification in a )ormal ,rgan; (etastatic
calcification;
o N$) Aecause in dystrophic calcification* the calciu" is there due to deathBdisease)
o ,0! for /etastatic calcification can visuali(e in a nor"al organ)
Hyaline Change)
o !aw /allory Aody 4the na"e of Hyalin in liver6 in Liver of -lcoholics
1aline is .)TE2(E5.ATE 6.0A(E)T- < 3biquitin
o -nother e'a"ple H,-LIN0 /0/AR-N0 in the Lungs surrounding the -lveoli22
1aline is 6.#2.)
3sed to onl see in premature children. )ow see it in adults.
o A530T 2E-P.2AT,2* 5.-T2E-- -*)52,(E
The capillar lea! out fibrin in the lung and in this case forms
haline surrounding alveoli.
o -o see 1aline isn=t a -ubstance, can be from different things eg. 6ibrin, .6=s. .snt
particulate stuff. Can var.
o /.00 -EE T1AT Amloid is same thing.
Aging
o 0'peri"ental evidence suggests there is a cloc<
o $ne thing that decreases with age Population dou%ling level
&elo"erase activity decreases with age
Protein that co"es and elongates the telo"eres)
&u"or cells reactivate &elo"erase)
.ou%ling ti"e of tu"or cells Never run out or %eco"e senescent)
Cells li<e ste" cells that have replicating a%ility High a"ounts of &elo"erase)
.ou%ling level of 1HH year old less than new %orn and person with :erner has less than
1HH year old)
o $ther factors affecting Cellular Longevity+
1enes influencing cell life
222insulinBinsulin li<e 1? Receptor cells die less+
Coloric restriction diets "ight pro"ote longevity
0ven overuse of o'ygen li<e calories can put %urden onto cell) !o %urning22 "ore
o'ygen can increase longevity of cell
.N- da"age
o :erners they have pro%le" with .NA ,E$I#ASE22
- .N- H0LIC-!0 !,N.R$/022
o -ta'ia&elanactasia .N- %rea<s22