UNIT 1 UNTRODUCTION TO PATHOLOGY Page 4

) (General ):(Systemic
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- cell matrix- /
.
OVERVIEW: Cellular Responses to Stress and Noxious Stimuli Page 4
, homeostasis
. ,
,cellular adaptation " .
:

Hyperplasia

Hypertrophy

Atrophy

 , injurious agent
.cell injury , ' -
point of no return .
:
) ( .
Necrosis
' .
Apoptosis
.DNA
, .subcellular alterations
intracellular accumulations , .
) (.
.
TABLE 1-1 -- Cellular Responses to Injury
Nature and Severity of Injurious Stimulus

Cellular Response
Cellular adaptations:

Altered physiologic stimuli:

Hyperplasia, hypertrophy

Increased demand, increased trophic stimulation

)(e.g. growth factors, hormones

Atrophy

Decreased nutrients, stimulation

Metaplasia

) Chronic irritation (chemical or physical

Cell injury:

;Reduced oxygen supply; chemical injury

microbial infection

Acute reversible injury

Acute and self-limited

Irreversible injury cell death

) Progessive and severe (including DNA damage

Necrosis
Apoptosis
Subcellular alterations in various organelles

Mild chronic injury

Intracellular accumulations; calcifications

Metabolic alterations, genetic or acquired

Cellular aging

Prolonged life span with cumulative sublethal

injury

Cellular Adaptations of Growth and Differentiation Page 5

, ,
. ,
.Metaplasia
.
" . "
.
'
ECM .

Hyperplasia Page 6

Figure 1-2 The relationships between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation
depicted here is hypertrophy, and the type of cell death is ischemic necrosis. In reversibly injured myocardium, generally effects are
only functional, without any readily apparent gross or even microscopic changes. In the example of myocardial hypertrophy, the left
ventricular wall is more than 2 cm in thickness (normal is 1 to 1.5 cm). In the specimen showing necrosis, the transmural light area
in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections have been stained with
triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme
leakage after cell death.

Physiologic Hyperplasia
,
" .' ' .
DNA .
:
Hormonal Hyperplasia .1 .'
, .
Compensatory Hyperplasia .2 .'
, .
' ,lateral nephrectomy .
" ,
.
. GF
) (compensatory . "
.'
' . chronic hepatitis
.
Pathologic Hyperplasia
GF .
'
" , " 10-14
. .
, .
, .
, ,
3

 viral infections' papilloamviurses

.

Hypertrophy
. , .
. ,DNA
.
) ( .
, "
. ' ,bodybuilders
workload .
' " .
chronic hemodynamic overload
, .
' ,
. " )
( . .

Figure 1-3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid
)uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left
compared with large plump cells in gravid uterus (right).

, . ) (
" .
, ,
,
.
)(.
Mecahnisms of Hypertrophy
.
),(signal transduction pathways
.

Figure 1-4 Changes in the expression of selected genes and proteins during myocardial hypertrophy.

:
c-jun ,c-fos
TGF -fibroblast growth factor ,IFG1 insulin-like growth factor 1 ,
Vasoactive agents (angitensin2 ,endotelin1 ,adrenergic agonists
) (switch
'
, ,ATPase .
,'
' (atrial natriuretic factor) ANF ,
, . ,
) ANF ( ANF . ,
) ( , .hemodynamic load
:
mechanical triggers
.1
,IGF1 trophic triggers ,2 (Vasoactive agent) adrenergic agonists
.2
GF Vasoactive agents " nonmuscle cells " ,
.
" .
, .
. .
.
, ,
.

Atrophy
.
.
, ) (.
:
. notochord thrygossal duct
.
.
. .
5

 :
Decreased workload ,
.1
.
. ,
.
.
) (denervation atrophy

.2
.

)( .
.3
, ,
.atheroclerosis

Figure 1-5 A, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Atrophy of the brain is due to aging
and reduced blood supply. The meninges have been stripped. B, Normal brain of a 36-year-old male. Note that loss of brain
substance narrows the gyri and widens the sulci

.4

.5
.6
.7

, ).(marasmus
) .(cachexia
) (TNF
.cachexia
, '
.
, .
) (senile atrophy
.
.

. "
.

. ,
,ER " .
, . ,
. .
Mechanism of Atrophy
.
. .
' :
6

 )' ,(cathepsin
.
Ubiquitin-proteosome pathway
. " ' ubiquitin
.
- ,
) (.
TNF ) (.
.autophagic vacules
) .(ER , "
.
autophagic vacules " residual
body , sarcophagus.
- Lipofuscin granules ' .residual body
).(brown atrophy

Metaplasia
, ) ( " .
.
) ,(squamous
.
Figure 1-6 Metaplasia. A, Schematic diagram of columnar to
squamous metaplasia. B, Metaplastic transformation of esophageal
stratified squamous epithelium (left) to mature columnar epithelium
(so-called Barrett metaplasia).

, cilia
" .
' ,

.
(retinoic acid) A
.
A .

, .
.
, .,
) (.
.barrett esophagus
. )" glandular
.(carcinomas
.
' . .

Mechanisms of Metaplasia
.
.
" GF , ECM .
.
' TGF ,superfamiliy
. GF
. .
,A
.
cytostatic drugs DNA
.
Overview if cell injury and cell death
.
, .

Figure 1-7 Stages in the evolution of cell injury and death.

' :cell injury

Figure 1-8 Schematic
representation of a
normal cell and the
changes in reversible
and irreversible cell
injury. Depicted are
morphologic changes,
which are described in
the following pages and
shown in electron
micrographs in Figure 117 . Reversible injury is
characterized by
generalized swelling of
the cell and its
organelles; blebbing of
;the plasma membrane
detachment of
ribosomes from the
;endoplasmic reticulum
and clumping of nuclear
chromatin. Transition to
irreversible injury is
characterized by
increasing swelling of
the cell; swelling and
;disruption of lysosomes
presence of large
amorphous densities in
;swollen mitochondria
disruption of cellular
membranes; and
profound nuclear

changes. The latter include nuclear codensation (pyknosis), followed by fragmentation (karyorrhexis) and dissolution of the nucleus
(karyolysis). Laminated structures (myelin figures) derived from damaged membranes of organelles and the plasma membrane first
appear during the reversible stage and become more pronounced in irreversibly damaged cells. The mechanisms underlying these
changes are discussed in the text that follows.

: '
. / reversible cell injury.1
:

ATP

, irreversibly injury and cell death.2
-" lethal hit" . ,
' , , .
.( )
irreversibly injured cells invariably undergo morphologic changes .3
. : that are recognize as cell death
Figure 1-9 The
sequential
ultrastructural
changes seen
in necrosis (left)
and apoptosis
(right). In
apoptosis, the
initial changes
consist of
nuclear
chromatin
condensation
and
fragmentation,
followed by
cytoplasmic
budding and
phagocytosis of
the extruded
apoptotic
bodies. Signs
of cytoplasmic
blebs, and
digestion and
leakage of
cellular
components

TABLE 1-2 -- Features of Necrosis and Apoptosis

Feature

Necrosis

Apoptosis

Cell size

Enlarged (swelling)

Reduced (shrinkage)

Nucelus

Pyknosis karyorrhexis karyolysis Fragmentation into nucleosome size

fragments

Plasma membrane Disrupted

Intact; altered structure, especially

orientation of lipids

Cellular contents

Enzymatic digestion; may leak out of

cell

Intact; may be released in apoptotic

bodies

Adjacent
inflammation

Frequent

No

Physiologic or
pathologic role

Invariably pathologic (culmination of

irreversible cell injury)

Often physiologic, means of eliminating

unwanted cells; may be pathologic after
some forms of cell injury, especially DNA
damage

 , ,
.
DNA
.
.
.
' ,
.

Causes of Cell Injury

.
:
Oxygen Deprivation.1
. .
.
. ,
.
:
' .
) CO
( .
,.
' , ,
" ) ( ) (.
Physical agents .2 ,' ,,
.
Chemical Agents and Drugs .3
. , ,.
, , .
: , , '.
Infectious Agents.4 .
, , . .
Immunologic Reactions .5' .'
, ) (.
Genetic Reactions.6 )'
( ) S' ( .
.
Nutritional Imbalances.7 .
, .
) ( .
. , .
.

10

Mechanism of Cell Injury

. , '
:
.1 , . ,
,
,
.
.2 , .
, .
,
.
.

.3 .
!

Figure 1-10 Cellular and biochemical sites of damage in cell injury.

:
o ATP
o
o
o
o

Figure 1-11 Functional and morphologic

consequences of decreased intracellular
ATP during cell injury.

Depletion of ATP
ATP ATP"
.
ATP ,
,
.phospholipids turnover
ATP :
o oxidative
phosphorylation ADP
" .
Glycolytic pathway o ATP

.
11

 , , ATP
.
ATP 5%-10% ' ' :
.1 Na+K- . ' ,
. , ,
.ER
.2 . ,
, , oxidative
.phosphorylation
ATP AMP
. "
. -
. pH .
.3 Ca++ ,Ca++
.
.4 ATP , ,RER
. .
, ) . ,1-8(.
.5 , .
unfolded protein response .
,
" .

Mitochondrial Damage
. "
.
" :

Oxidative stress
" 2A

" ) ,(high conductance channels
.
,
-
, .
oxidative
,phosphorilation -
, .

C . C
,
.
Influx of intracellular calcium and Loss of
Calcium Homeostasis
.

) 0.1(

Figure 1-12 Mitochondrial

dysfunction in cell injury.

12

 " .ATPase Ca2+,Mg2+

' ,
.ER

.
'
. :
) ATPase o (ATP
o
o

o DNA

.
" )
( ,
.
Accumulation of oxygen-derived free radicals
)(oxidative stress
" .
.

, . .reactive oxygen species '
.
' .oxidative stress
, , , " .
.
' ) : ,
, , , ' (.
, ' ,
.
' :

Figure 1-13 Sources and consequences of

increased cytosolic calcium in cell injury. ATP,
adenosine

Figure 1-14 The role of reactive

oxygen species in cell injury. O2 is
converted to superoxide (O2 -) by
oxidative enzymes in the
endoplasmic reticulum (ER),
mitochondria, plasma membrane,
peroxisomes, and cytosol. O2 - is
converted to H2 O2 by dismutation
and thence to OH by the Cu2+
/Fe2+ -catalyzed Fenton reaction.
H2 O2 is also derived directly from
oxidases in peroxisomes. Not
shown is another potentially
injurious radical, singlet oxygen.
Resultant free radical damage to
lipid (peroxidation), proteins, and
DNA leads to various forms of cell
injury. Note that superoxide
catalyzes the reduction of Fe3+ to
Fe2+ , thus enhancing OH
generation by the Fenton reaction.
The major antioxidant enzymes
are superoxide dismutase (SOD),
catalase, and glutathione
peroxidase

13

.1
.2
.3

.4

.5

) .(X-ray ,UV'
) (.
.' .(carbon tetrachloride) CCL4
- . ,
' " . "
,ER , , .
:
O2 - H2O2 - Hydrogen peroxide OH Hydroxyl ions PMN .
" .NADPH oxidase
, - )' (xanthine oxidase
.
' ,
)(Fenton
Fe2+ + H2O2 Fe3+ + OH + OH - ,(Fe3+) ferric
(Fe2+) ferrous ) . " (.
,(NO) Nitric Oxide " , ,
,
(ONOO-) highly reactive peroxynitrite anion NO2 .NO3-

, :
) (1-14
Lipid peroxidation of membrane .1
.
OH .
) ,(propagation
Termination . ,scavenger ,E .
Oxidative modification of proteins .2
, )' ( , .
. "
.
Lesions in DNA .3 " .
) .(7
.
. ,' ,
. ' - "" ) .(1-14
' :
Antioxidants .1 "" ) (scavenge
.
:
A
Eascorbic acid

.2 .
, .OH
:


14



.3 ) (hydrogen proxide .
:
(2H2O2 O2 + 2H2O) H2O2
Superoxide dismutase (O2- + 2H H2O2 + O2) H2O2
' manganese superoxide dismutase ,
copper-zink-superoxide dismutase
glutathione peroxidase " :
H2O2 + 2 GSH GSSG (glutathione homodimer)+2 H2O2
2OH + 2GSH GSSG + 2H2O
GSSG GSH , ""
.
, . ,
.

Defects in Membrane Permeability

.
, .
, ATP
" ) (.
" , ,
.
' :
Mitochondrial dysfunction .1
,

.
,
.
.ATP ,
.
.
:



Loss of membrane phospholipids .2
,
:
)
-(

ATP-dependent reacylation

Figure 1-15 Mechanisms of membrane damage in

cell injury. Decreased O2 and increased cytosolic
Ca2+ are typically seen in ischemia but may
accompany other forms of cell injury. Reactive
oxygen species, which are often produced on
reperfusion of ischemic tissues, also cause
membrane damage (not shown).

15

 Cytoskeleton abnormalities .3
. - , . ,
, .
-Reactive oxygen species .4 .
Lipid breakdown products .5 :
unesterified
)(acyl carnitine

, :
- ,
, .
: , , ,
. ribonucleic acid .ATP
, . RNases, DNases, :
.protease, phosphotases, glucoidases, cathepsins
, .

Reversible and Irreversible Cell Injury

:
ATP



DNA
, , ,
.
, , ' ) .
.(1-8 , , ) (
.ATP - -
.
, , , ribonucleic acids ,
ATP .hyperpermeable
:
.1
.2 , , ,
) (ripple effect
.3' -
.4
, .
-:
.1 ) , oxidative phosphorylation (ATP
.2 ) , " pH
(
- , .
, -
.
/ :
16

 , .
temperature-resistant -.

, " .
Morphology of Cell Injury and Necrosis
. ,
. time lag .

) .
.(1-16
,
,

.

,
.'

.

4-12
, -
20-60.
Figure 1-16 Timing of biochemical and morphologic changes
in cell injury.

Reversible Injury
:
.1 -
.
fatty change .2 , .
: .

Morphology
.
) (.
, .
, , .ER
) (hydropic change .vacular degeneration
.
- ) (ultrastructural changes ) :(1-17

17

Figure 1-17 Morphologic changes in

reversible and irreversible cell injury. A,
Electron micrograph of a normal epithelial
cell of the proximal kidney tubule. Note
abundant microvilli (mv), lining the lumen (L).
N, nucleus; V, apical vacuoles (which are
normal structures in this cell type). B,
Epithelial cell of the proximal tubule showing
reversible ischemic changes. The microvilli
(mv) are lost and have been incorporated in
apical cytoplasm; blebs have formed and are
extruded in the lumen (L). Mitochondria are
slightly dilated. (Compare with A.) C,
Proximal tubular cell showing irreversible
ischemic injury. Note the markedly swollen
mitochondria containing amorphous
densities, disrupted cell membranes, and
dense pyknotic nucleus

' Plasma membrane alterations

. )( blunting ,( ) blebbing
( ) myelin figures
-
small phospholipid-rich amorphous densities Mitochondrial changes
. , Dilation of ER
. Nuclear alterations

.1

.2
.3
.4

Necrosois
.-
. , ,
.
:
.autolysis , o
, o
,
. .
18

 4-12 ,
.

Morphology
eosinophilia:
o basophilia " RNA
o eosin ) . (1-18

Figure 1-18 Ischemic necrosis of the myocardium. A, Normal myocardium. B, Myocardium with
coagulation necrosis (upper two thirds of figure), showing strongly eosinophilic anucleate
myocardial fibers. Leukocytes in the interstitium are an early reaction to necrotic muscle. Compare
with A and with normal fibers in the lower part of the figure.

, .
, . , .
.myelin figures
" .
.calcium soaps , :
o
o
o myelin figures
o osmiophilic debris
o ) ,(fluffy ) (C1-17
, ) DNA 1-8
(C1-17
- Karyolysis .1 , .DNase
Pyknosis .2 ) ( . DNA
.
karyorrhexis .3 . .
, .
Coagulative necrosis - .
' ) .(A1-19 . ,
- , .
, , , . ,
" " .
Coagulative necrosis
.
19

 Liquefactive necrosis .
Liquefactive necrosis ,
) .(B1-19 , CNS .
, , .
" ,
.PUS

Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of
nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture.
B, A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells
and cellular debris, creating a renal abscess that obliterates the normal architecture.

Gangrenous necrosis " , .

, ,
. , " ) wet
(gangrene
- Caseous necrosis .
caseous )
.(1-20 ,

) granulomatous reaction .(2
, ,
.
Fat necrosis
.

Figure 1-20 A tuberculous lung with a large
. acute
area of caseous necrosis. The caseous
debris is yellow-white and cheesy.
.pancreatities
, triglyceride esters .
) ,(fat saponification
) .(1-21 , ,
.inflammatory reaction

Figure 1-21 Foci of fat necrosis with

saponification in the mesentery. The areas
of white chalky deposits represent calcium
soap formation at sites of lipid breakdown.

20

 , , "
" . ,
. .dystrophic calcification

21

)Examples of cell injury and necrosis (p. 23

, ,
, .
.
Ischemic and hypoxic injury
, , .
.
Hypoxia .
.
.
, Ischemia , ,
, .

" " .
.
: .
end artery .
. , ,

. , .
) (
) (reperfusion .
, .
.
) (reperfusion
.
.
.ischemia-reperfusion injury
) (.
: .1-22:
" .
" oxidative phosphorilation- ATP-
.
" ATP ,
.
" ) ( ) (.
: 60 .
. :
" :ATP- , ,
blebs .
" " -"myelin figures
. ,
.
" RER- ,
, .
.
.
:
" amorphous densities .

"
" .
30-40 .
) (reperfusion . "
) " -
(.

. "
" "myelin figures
calcification .calcium soaps

Ischemia- reperfusion injury

,
,
.
. .
reperfusion injury- ?
" " ,
.
" " oxidase- .
.
).(scavengers
" ) mitochondrial permeability transition-
( ATP- .
" "
. PMN
reperfusion ) .(2
) (
.
" " , Ischemia- reperfusion injury-
. IgM
reperfusion
. .

Chemical injury
, .9
2 :
.1 " .
mercuric chloride poisoning : sulfhydryl-

ATP . ,,
. '
. - cytochrome oxidase- ,
.oxidative phosphorilation-
.
.2
. " P450
SER- .
" , "
.
"
:
-(CCl4) carbon tetrachloride .
.
" P450
) (CCl3
) P450 ( .

SER- -
autooxidation .
lipid
peroxides .
,lipid peroxides-
.
CCl4-induced liver cell injury :
:
,
SER -
.RER


. fatty -
) liver of CCl4 poisoning .(1-24


. "

SER-
.

) .(1-23

 -Acetaminophen (Tylenol) . . -
" ,sulfation & glucoronidation
" " . P450 -
.GSH GSH ,
- . GSH

, 3-5 .
" ,
" .
)Apoptosis (p.26
"
DNA- .
.
.
, ) 1-9 .(1-2
.
Causes of apoptosis
1972" "" .
, ,
.
, DNA - . ,
.
:
. :
- , ,
. " "programmed cell death
.
.
- : ,
,
.
- crypt epithelia- ,
.
- acute -
.inflammatory response .
.GF
- .
" T -
.
: :
- :
DNA-
.
DNA- .
,

-
.
-
.
- .
" .
.

:
: ) ( EM- :
: , , .
: . ,
. 2- .
cytoplasmic blebs :apoptotic bodies- blebing

.
" :
,
.

" .
.
. .

.
H&E .
) .(1-26
"
, .
, , .

Biochemical features of apoptosis

)( , .
" - "
. -
. ,
. DNases DNA-.
.
" -DNA

DNA-
50-300
.kb


180-200 "


DNA ladder--
agarose gel
) electrophoresis
.(1-27



.
,


,
smear DNA


,
DNA
.

" -
.
" . annexin V ,
,thrombospondin ,
"
. "
. "
.
Mechanisms of apoptosis
"
.
.
C. elegance "
, ced
) (cell death abnormal . :-
" - .

: )" ( ) (
:

"
) "
( -


TNF-R
death domain

-

.

,

death domain

.

, TNFR1 :
.(CD95) fas
"

" :fas
cross linking"
) ( 3 fas
fas ) FADD death domain
FADD .(associated death domain " death domain-
.8 - ) 8 10 (

. "
FLIP - 8 .
" " fas.

.
" )( -
-
GF .
) bcl-2, bcl-x :bcl-2- B
c. elegance- .(ced9 20-
.
.
- ,bak, bax ,bim :
.
C . apaf-1
) apoptosis activating factor 1 (ced4- -
bcl-2) 9 bcl-x- ,
(. -
, (apoptosis inducing factor) AIF :
) ( .

 .
.
- : fas
- bcl- bid ,
.

: " ,
) .(ced-3- )
( 10- initiator (caspase 8 +9) & :
) executioner (caspase 3 +6 . ,
- , , " , "
, .-
execution caspases : )
( ,TF , .DNA 3
DNase"
.
:
, .
"
.
. ) (CD31
" .
.
Examples of apoptosis
: ,
. :
. :GF- ,
" ,
" - -.
. :DNA- "
.genotoxic stress P53 - tumor suppressor-
) ,
( P53 . TF bak, bax, apaf-1 :
.

 . " fas :TNFR ,fas-L

. TNF
)
" ( . TNF

) ? (:
" (TNF receptor associated death domain) TRADD FADD
. .
" (TNF receptor associated factors) TRAF's
(NF-kappa-B) nuclear factor kappa-B" .
.
. " T TCL :
graenzyme
B .
) execution
.(caspases CTL " fas fasL- .
) ( :
-1 -
. :
)( P53- : ,,
.
)( - -.
-2 - . :
)( neurodegradative diseases ,:
.
)( - .
)( .
)Subcellular responses to injury (p.32
.
, . :
-Lysosomal catabolism
acid :
.glucoronidases, sulfatases, ribonucleases ,collagenases ,phosphatases
,RER- ' , .
) /(
:
-hetrophagy . " )
, - (
.
. )
( .
-Autophagy . . autophagyic
vacuole "
.RER '

 , .
residual bodies-
.
.
.

.





.



.
chloroquine
pH-
.

"


.rheumatoid arthritis



.toxic myopathy-

)Induction (hyperthrophy) of smoth endoplasmic reticulum (SER

SER




.




SER

"
"
.P450-


: ,,
,eicosanoids , , , .
- .
) (
.
" .
" .SER
Mitochondrial alterations
.
, :
: )( .
: ) (megamitochondria-
alchoholic disease of the liver .
: ,
) mitochondrial
(myopathies


,
.crystalloids
:
,

)(


.

-Cytoskeletal abnormalities
. )20- :
(nm 25 ) (nm 6-8 : ) (nm 15 :
) (nm 10 .
, .
:
- , . " :
) cytocalasin B ( " ) phalloidin amanita -
phalloides ( .
- )(
) (bronchiectasis )= immotile
.(cilia syndrome
) colchicine ( gout
.urate
)(vinca alkaloids
.
-
. : )( ,
)( , )( , ) (
)( .
. (alcoholic hyalin) Mallory body : alcoholic liver
disease .'
Neurofibrillary tungle .

. ,myopathies :
.
: , .

.signal transduction- Wiskott Aldrich
) ( ,
, , .

)Intracellular accumulations (p.34

. 3-
:
) (1 ) , , ( .
) (2 - ) ( )
(.

) (3 - .
. )
( . ) ( .
3- :
.
.
fatty change of :
the liver
,



.
.

,
, ,
.






.
alpha1--
antitrypsin


ER-


.
.



.

.

.


.
,
,
.

Lipids
: , .
myelin figures- .
.
.
) :Steatosis (fatty change .
, , . : ,
, , , ) (anoxia
. .
,
, . " .
.



:

.
CCl4

.


.


.
fatty change

.
.

)

.(CCl4
.
steatohepatitis
fatty liver disease-


)( .

 fatty change : .
. ) (
.
H&E
) ( Sudan 4 Oil red O
- . periodic acid Schiff (PAS)-
.
.
fatty change : ,
3-6" , .
)( .ER-
, ,
.
.
: :gross-
) ( )(
) ( .triggered effect )
- ( -
.
:Cholesterol and cholesterol esters ) (5
.

:
.atherosclerosis .1 )
(
. ) .(foam cells
) .(atheromas
.11
.
.xanthomas .2 ) (
, ,
xantomas - .
-inflammation and necrosis .3
. ) ,
,( . myelin figures .
.
.cholesterosis .4

-
lamina propria
.
) . .(1-37
Niemann-Pick disease, .5
.type C



.

-Proteins
, ,
. EM- , . ,
amyloidosis .
:
. proximal tubule-
) .(proteinuria
, .proximal tubule-

) ( .
) .(1-38 , -
proteinuria .
.
)
( .ER-

, ,
.Russell bodies
.


.

"
alpha helix
,beta sheet
)
(
.
.
' , -
,ER' ) .(1-39 '
, " , ) heat shock
proteins (hsp70/90 " .
' )
(hsp " .
.
. :alpha1-antitrypsin -
deficiency
ER- .
CF- '
. familial hypercholesterolemia- LDL-
.
ER- " .
ER- .unfolded protein response
" ER- .

"
' . "

 .
.
.
. amyloidosis .
proteinopaphies : .protein-aggregation disease

:Hyaline change
hyaline ,
.H&E
. " .
) -Mallory , Russell bodies ,
Hyaline .(alcoholic hyaline ,
.
hyalinized-
.
:Glycogen
.
.
. ,
Best carmine- ,(PAS) periodic acid Schiff

 . ) diastase- (
Diabetes mellitus . .
proximal convoluted tubules
Henle's loop , .
" "
.glicogenoses
.
:Pigments
, )(
. ) (
) (.
:
.
.
) (anthracosis .
.coal worker's pneumoconiosis
. "
. .
: - ) wear and tear ,lipochrome :
.(ageing pigment ,pigment
.
. .
=Focus . ,
.
) .(1-40
cachexia . EM-
. .

) =melas :( - .
" ) dihydroxyphenylalanine- .(25
- ,
homogentisic acid -alkaptonuria
. , .ochronosis
) (hemosiderin ,
, . .13
" , . ,
, .

 , ) .(1-41
.
, ) (.
, .
" ) ( ,
, ,
. "
) ( "
. .
" ) - ( ,"
) ( .

hemosiderosis :
) (1 .
) (2
) (3
) (4 ) (.

: , , , .

. , , ,
, .
) ,, (
. Prussian blue-
" ferricferrocyanide- ) .(B1-41
.
hemochromatosis ,
, .
- . .
. .
) .(18
)Pathologic calcification (p.41
,
, .
: dystrophic calcification-
.

Dystrophic calcification
Dystrophic
calcification
) , (

.
,


) .(1-42
,

,
.

.
: H&E
. , , .
.
,
) psammoma bodies ( )
( .
) ( asbestos
.
:Pathogenesis Dystrophic calcification-
apatite hydroxyapatite- .
initiation (=nucleation) : ,propagation-
.
initiators . Dystrophic calcification
nm 200 , matrix vesicles
.
" :
) (1 .
) (2 .
) (3 .
) (4 -
. ) (PO4
, .connective tissue matrix proteins
Dystrophic calcification-
. .

Metastatic calcification
Metastatic calcification
. 4 :
)( PTH
PTH related protein .
)( : ),multiple myeloma
(, ) ( turnover , ) Paget
( .
)( :D) sacroidosis ,
,(D ) (
.D
)( .
: ) ( milk-alkali -
syndrome .
Metastatic calcification ,
, , .
.Metastatic calcification
, -.

. ) (nephrocalcinosis
.
)Cellular aging (p.42
7 , ,
,
.
.
, , .
" .
-
.


) .(1-43 :

: :
oxidative phosphorilation-" ,
,
, .TF ,

 .
:


ER
'
.
-Advanced glycation end products
cross linking , diabetes mellitus
,
.senile cataracts
) (.
:Replicative senescence


.

.

) .(1-44
,
) Werner syndrome

(
.



) .(cellular senescence

.
, ) cycline dependent
P21 kinase inhibitor genes( .
.
) (
. DNA ) (TTAGGG
,
.
, .
-
DNA . " "
" . RNA-
RNA- ) .(1-45
" ,
. "
. ,
, . ,
.
) ( .
, .

 : C. elegance-
. IGF-1/
. IGF-1 ,
.C. elegance- IGF-1-
.
" ,
.
: ,
"
."
" .
. reactive oxygen species -
oxidative phosphorilation .
.
. :
.1
" .
.2 SOD :
.
, "
.

 , ) glutation ,E
(peroxidase .
,
.DNA- DNA- " ,
. DNA- .
, -DNA helicase
, DNA , .DNA-
.

. ataxia telangiectasia :
.DNA- budding yeast- C. elegance-
DNA- . ,
. "
.
DNA .
,
.
, :
, , ,
" , , :
.
.

 Inflammation 2

, / .
, =
- :
- , , , " - "
, " .
, .
= .
. ,
.
.

= , .
, ) ,(
) ( . , ,
.
, :
:
) Rheumatoid arthritis (
) Atherosclerosis (
Lung Fibrosis
, .
:

.

.
:2-
.1
.2
" " ,
. , ,
.
/ .MI

Figure 2-1 The components of acute and chronic inflammatory responses: circulating cells and proteins, cells of blood vessels,
and cells and proteins of the extracellular matrix.

:2-1
: circulating









: :
, , tenascin ,nonfibrillar.

Basement Membrane .

 :
) ( , , .
) (EDEMA ,
.
- , ,
.
, . -
.

,Celsus ,
:
Rubor Tumor , Calor , Dolor ,.
Virchow .
,1793 ,' .
, Edema
.
,1880s ,' ,
.
, , , ,
.

.
3 :
.1 .
.2 - ) (microvasculature
.
.3 ,
. .2-2

Figure 2-2 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood
flow (causing erythema and warmth), (2) extravasation and deposition of plasma fluid and proteins (edema), and (3) leukocyte
emigration and accumulation in the site of injury.

:
= Exudation , .
= Exudate , , , gravity ,1.020
.
= Transduate ) ( gravity .1.012

.
= Edema Transduate
.Exudate
exudate = Pus ) ( , .


) , ,( .
) (
)' : , ,frosebites ,
.

) , ,(
)(hypersensitivity

, .
,
.

.
:
Vasodilation . ,
.1
Vasodilation .
.
. "
.NO
,
.2
.Vascular Leakage = .
Stasis ,
.3
. stasis 15 30
, , .
Stasis , ,
.4
.
.
Vascular Leakage
, exudates .
, ,
. ,
= .Edema
:2-3

Figure 2-3 Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation. A, Normal hydrostatic
pressure (red arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid
osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Although
fluid tends to leave the precapillary arteriole, it is returned in equal amounts via the postcapillary venule, so that the net flow (black
arrows) in or out is zero. B, Acute inflammation. Arteriole pressure is increased to 50 mm Hg, the mean capillary pressure is
increased because of arteriolar dilation, and the venous pressure increases to approximately 30 mm Hg. At the same time,
osmotic pressure is reduced (averaging 20 mm Hg) because of protein leakage across the venule. The net result is an excess of
extravasated fluid.

. " 12 = , " 32 =
.0 = . . " 25 =
, " 50 ,
. " 30 ,
. , . " 20
:" "
, , , :
. ,P ,
.( 30 15)
.Immediate transient response
. , 60 20 ,
,
.


<- .
:2-5

Figure 2-5 Vascular leakage induced by chemical mediators. A, This is a fixed and cleared preparation of a rat cremaster muscle
examined unstained by transillumination. One hour before sacrifice, bradykinin was injected over this muscle, and colloidal carbon
was given intravenously. Plasma, loaded with carbon, escaped, but most of the carbon particles were retained by the basement
membrane of the leaking vessels, with the result that these became "labeled" black. Note that not all the vessels leakonly the
venules. In B, a higher power, the capillary network is faintly visible in the background. (Courtesy of Dr. Guido Majno, University of
)Massachusetts Medical School, Worcester, MA.

,IF-Gama ,TNF ,IL-1 "

.
4-6 , , 24 , .

: ,
. .
, ,
.
.Immediate sustained response.
: , ,.
.

: 2 12 ,
.
.
" , X UV .
.
" ,
.

" : ,

.

 , ,
.

Transcytosis :
, ,Vesiculovacuolar organelle .
VEGF " .
.

: , =
.angiogenesis ""
.
, VEGF .
,VEGF ,Subtance P ,
.

 2-4 ":
Figure 2-4 Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation (see text).

, . , ,
" , , " ,
.
.
, , :
immediate transient response.1 30 , " .
delayed response .2 8 ," , ' .
.3 , .

 : Cellular Events
.
, .
.
:EXTRAVASATION,
, , , :
.1 ,margination
.
:Margination ,
. , , ) wall shear
,(stress . =
.margination
: .
: . "
= .pavamenting
Transmigration .2 ) (diapedesis -

basement membrane , .
.3 " .

Figure 2-6 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first
roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement
membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles
in different steps of this processselectins in rolling; chemokines in activating the neutrophils to increase avidity of integrins (in
green); integrins in firm adhesion; and CD31 (PECAM-1) in transmigration.

 transmigration
" .
) (chemoattractants .
, , .

3 ,
.
N domain .C-type lectins
) C ( . ,
, -
.
" .Sialylated Olligosaccharides
.(GlyCAM-1,PSGL-1,ESL-1,CD34) mucin-like glycoproteins
(CD62E) E Selectin " .
= . Lewis X Lewis A : , , T .
T , . " . " .E-selectin (CD62P) P Selectin .
.Weibel-palade bodies
P-Selectin , .
, T. " .E-Selectin (CD62L) L Selectin .
" .HEV " . . GlyCAM-1 : HEV MadCAM-1 MALT.
CD34 .
.
: L-Selectin .T
E-Selectin : P-Selectin
.
P : E .
P .E

2 Immunoglobulin family .VCAM-1 ,ICAM-1 :

.

30 -
-.
, ,
. .
,,
.
: , , .
) Arg-Gly-Asp (RGD . ),,,- ,(.
3 . 5. 1 Very Late Activation) VLA ( .
.CD49a-hCD29
8 1 .8
1
1 "
.
) VLA-4 :(4
" .VCAM-1 .
2 .CD11a-cCD18
2 3
CD11aCD18 LFA1
, ,APC .
(Mac-1,CR3)CD11bCD18 (CR4) CD11cCD18
CD11bCD18 .
iC3b .
,
.

Mucin-like glycoproteins heparin sulfate .CD44

.

.2-1
TABLE 2-1 -- Endothelial/Leukocyte Adhesion Molecules
Major Role
)Rolling (neutrophils, monocytes, lymphocytes

Leukocyte
Receptor
Sialyl-Lewis X

Endothelial
Molecule
P-selectin

PSGL-1
Rolling, adhesion to activated endothelium

Sialyl-Lewis X

E-selectin

TABLE 2-1 -- Endothelial/Leukocyte Adhesion Molecules

Endothelial
Molecule

Leukocyte
Receptor

Major Role
(neutrophils, monocytes, T cells)

ICAM-1

CD11/CD18
(integrins)

Adhesion, arrest, transmigration (all leukocytes)

(LFA-1, Mac-1)
VCAM-1

41 (VLA4)
(integrins)

Adhesion (eosinophils, monocytes, lymphocytes)

47 (LPAM-1)
GlyCam-1

L-selection

Lymphocyte homing to high endothelial venules

CD31 (PECAM)

CD31

Leukocyte migration through endothelium

*ICAM-1, VCAM-1, and CD31 belong to the immunoglobulin family of proteins; PSGL-1, Pselectin glycoprotein ligand 1.

Figure 2-7 Regulation of endothelial and leukocyte adhesion molecules. A, Redistribution of P-selectin. B, Cytokine activation of
endothelium. C, Increased binding avidity of integrins

.2-7 :
weibel ) P-Selectin PAF , .A
. ( palade bodies

 .B , , "
TNF IL-1.
TNF IL-1 :
1-2 .E-Selectin , ,
, , .
" .
TNF IL-1 : VCAM-1 ,VLA-4
ICAM-1 LFA-1 .Mac-1
.
.C , , heparin sulfate
glycosaminoglycans .
.
, , .
, ,
. ,
.
:Diapedesis/Transmigration

, /.
) ( , .
) (
. PECAM-1 .CD31
, ,basement membrane
, " . .
, " 1
CD44 . .
::
(Leuukocyte adhesion deficiency type 1) LAD1
,2 LFA-1 .Mac-1
LAD2 ,.LEWIS X E-Selectin
) Fucosyl transferase (.
.
:
:
6-24 :.
24-48 :.
:
. ,
) P .(E
. , 24 48
.

Figure 2-8 Schematic and histologic sequence of events following acute injury. The photomicrographs are representative of the
early (neutrophilic) (left) and later (mononuclear) cellular infiltrates (right) of infarcted myocardium. The kinetics of edema and
cellular infiltration are approximations. For sake of simplicity, edema is shown as an acute transient response, although secondary
waves of delayed edema and neutrophil infiltration can also occur.

:
, - Pseudomonas 2 4.
, . ,hypersensitivity .
, =
.
,
.
endogenous exogenous .
. N-formyl-
.methionine .
: . , .C5a
. , .B4
. , , .IL-8
) G-protein 7 ( .
PLC , ,PI3K ) .(3
PLC PI3K ) (IP
GTPases Rac/Rho/cdc42 .
GTPases . "
.

Figure 2-9 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail.

.
,
cross-linking .
,gelsolin , ,
.

, , , ,
= .
" ,
PKC .A2
" :
" A2.
- .Oxidative Burst
.
, .
, ,
, .
:
) Toll-Like Receptors (TLR ,TOLL
. ,10
.
TLR LPS ,
CpG , RNA " .
microbicidal substances
.
GPCR .
7 -.

 , .
: ,N-formyl-methionine ,
,C5a ,PAF : .LTB ,E
,
,N-Formyl-Methionine
.
, G-Protein .GDP
,G-Protein GDP ,GTP ,
PLC ,IP .PKC

microbicidial substances .respiratory burst
.
, " NK ,INNATE" T
.ADAPTIVE .
.
, , .
:
.1 IgG .
" RI Fc .
.2 C3 ,
) (
) ( .
.
CR1
.C3
.3 ), fibrinectin,Mannose Binding Lectin (MBL
C-Reactive protein ,fibrinogen "
.
C1q .MBL
.fibrinogen

Figure 2-10 Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli. The
receptors initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details).

"
. 3-:
.1 "
) (
,
" 2 :
Mannose Receptors ,
. ,
.N-acetyl-galactosamine
.
Scavenger Receptors LDL
.LDL
.LDL
* (Cd11b/Cd18) Mac-1 .
" ,
.MBL
- Engulfment.2 . , engulfment
) (pseudopods
" . ,
. -.
,
.
, .

 Receptor-mediated-endocytosis
.
.3 .
. ,,
" hexose-monophosphate shunt ) ROIs
(.
ROI " ,NADPH Oxidase NADPH
- .O2-
NADPH Oxidase 7 .
, . ,
,
) .(2-11 B ROI
, . NO
.
H2O2" .
" , ,
HOCL MPO .MPO
.
, ) halogenation
. ( .
H2O2-MPO-Halide
MPO ) (.

.OH ,
" Catalse/ ) .Glutathione Oxidase
.(!1

," .
,BPI = Bactericidal Permeability Increasing protein
,
.
muramic-acid-N-acetyl-glucoamine
.
, .
,Major Basic Protein
.
,Defensins , ,Arg ,
) (.
, , .
, pH 4-5 ,
.

Figure 2-11 A, Phagocytosis of a particle (e.g., bacterium) involves attachment and binding of Fc and C3b to receptors on the
leukocyte membrane, engulfment, and fusion of lysosomes with phagocytic vacuoles, followed by destruction of ingested particles
within the phagolysosomes. Note that during phagocytosis, granule contents may be released into extracellular tissues. B,
Production of microbicidal reactive oxygen intermediates within phagocytic vesicles.

, microbicial
:
ROI . !
.

:

TABLE 2-2 -- Clinical Examples of Leukocyte-Induced Injury

Acute

Chronic
Arthritis

Acute respiratory distress syndrome

Asthma

Acute transplant rejection

Atherosclerosis

Asthma

Chronic lung disease

Glomerulonephritis

Chronic rejection

Reperfusion injury
Septic shock
Vasculitis

.
" :
= Regurgitation During Feeding . = Frustrated Phagocytosis , , ,
.
= Cytotoxic Release , Urate Crystals .
)( . , " .

, , :
LAD1 :
.
LAD2 ,
.
Chediak-Higashi Syndrome :
.
,
) (,
,
.
" Blood
.Smears




T.

 Chronic Granulomatous Disease :microbicidal

.
.NADPH Oxidase
X-Linked
).(gp91phox
2
) p47phox .(p67phox
: , .
,
.
TABLE 2-3 -- Defects in Leukocyte Functions
Disease

Defect

Genetic
chain of CD11/CD18 integrins

Leukocyte adhesion deficiency 1

Fucosyl transferase required for synthesis of

)sialylated oligosaccharide (receptor for selectin

Leukocyte adhesion deficiency 2

Decreased oxidative burst

Chronic granulomatous disease

NADPH oxidase (membrane

X-linked

NADPH oxidase (cytoplasmic

Autosomal recessive

Absent MPO-H2 O2 system

Myeloperoxidase deficiency

Protein involved in organelle membrane docking

and fusion

Chdiak-Higashi syndrome

)component
)components

Acquired
Thermal injury, diabetes, malignancy, sepsis, Chemotaxis
immunodeficiencies
Adhesion

Hemodialysis, diabetes mellitus

Phagocytosis and microbicidal activity

Leukemia, anemia, sepsis, diabetes,

neonates, malnutrition

:
, ' , ,.
, , ) TNF, IL-1(
.

. .

, ,
.
, , .
:
- , - .
TGF-Beta " .

)" ( TNF.
" )
, (.

:
.1 ) (kinins ,
" .
) (
- ) ,( .
: , ,/, .
) , ,( .
.2 "
,Kinins , .
.3 .
) ( ) ROI .(NO
.4 " .
.
.
.5 ,
.
.6 , - . )
( " ) kininase (bradykinin
"" ) "" ( )
(.
.7 .

Figure 2-12 Chemical mediators of inflammation. EC, endothelial cells.

Vasoactive amines

.
.
.
.
:
.1 , ,.
.2 ) .(6
Anaphylatoxins .3 C3a .C5a
.4 .
.5 ).(Subtance P
.6 .IL-1,IL-8
. !
Immediate transient phase
.
" .H1

Figure 2-13 A flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue. Stained with
metachromatic stain to identify the mast cell granules (dark blue or purple). The red structures are fat globules stained with fat
)stain. (Courtesy of Dr. G. Majno, University of Massachusetts Medical School, Worcester, MA.

. )(5-hydroxytryptamine
.
, ,enterochromaffin .
,,ADP ,
-.
" PAF .IgE ,
.
PAF .


.
20 .
INNATE ADAPTIVE .
, ,
.
.C1-C9
.
C3 3
:
C1 ) IgM (IgG , C2 C4
C4b2b .C3 Convertase
" )' ,(LPS ,
, . C3 " C3b
.Bb B C3bBb .C3 Convertase
) (
.C1 .
3 C3 Convertase C3 :
C3a C3b /.
:
C3b ) (C3 Convertase C5 Convertase
C5 C5a , C5b .C6-C9 C9
,MAC
.
!Error

 " ,MAC :
.1

.2
.3

C3a :Vacular Phenomena C5a C4a

. ) Anaphylatoxins
C5a .(anaphylaxis

.
C5a : ,
, .
C3b : ) iC3b ( , ,
.

C3 C5 "
Exudate . .
: ,
...
!Error

Figure 2-14 The activation and functions of the complement system. Activation of complement by different pathways leads to
cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement
proteins, and by the membrane attack complex (MAC). The steps in the activation and regulation of complement are described in
Box 2-2 .


" ,
, .
:
C3 Convertase :C5 Convertase
DAF C3b .I
" : , "
(C1INH) C1 Inhibitor .C1
MAC CD59 Membrane Inhibitor of
.Reactive lysis

:
C3 .
.
C2 C4 , ,Systemic Lupus Erythematosus
-.
MAC
, .Neisseria
, :
Paroxysmal Nocturnal Hemoglobinuria
- .
IP , DAF CD59
.
.
C1INH Hereditary Angioneurotic Edema
, " . ,
C1 C4 .C2 C2 Kinin = C2
. C1NH , ,kallikrein
12 .
.
Vasoactive ,Kininogens"
.Kallikreins
,Bradykinin
, . .
:
.1 ) Hageman 12 ( "
.basement membrane
.2 .(prekallikrein activator / factor 12a) 12
.3 prekallikrein .kallikrein

 . ) Hageman (1
. . . C5
.C5a
kallikrein .4 kininogen
/ ) 12 - (1
.bradykinin
bradykinin "
.kininase " angiotensin converting
.(ACE) enzyme

" ) Hageman (12
basement membrane
) ( . 12
.12a
. 2 :
. , ,
. ) (2a
) (2" .4
.
)) Protease Activated Receptors (PAR
, ( . GPCR
, , .
, , PAR-1
:
P Selectin

.
2
PAF NO

.

fibrolytic system/ 12a "

, .
Vascular Phenomena :
Plasminogen Activator " , ,
, .
Fibrin Split Products
.
C3 .C3

Hageman
.

, :
C5a ,C3a ,
C5a .
.

C3a C5a .1 : ) (.
.2 .
Kallikrein ,Plasmin .3 .

12a = Hageman Factor , 4 :

. Kinin .vasoactive kinins
, kallikrein" Hageman factor
.
. , , X .
Fibrinolytic system . .
. .
" .
, " .

Figure 2-15 Interrelationships between the four plasma mediator systems triggered by activation of factor XII
(Hageman factor). Note that thrombin induces inflammation by binding to protease-activated receptors (principally
PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.

 ,Robbins ) 68-86 (:
Arachidonic acid metabolites: prostaglandins, leukotrienes and lipoxins
" , " ,
-- , .
- autocoids , "
.
) - (AA . - , 20 , . .
, :
(1 , , ).(C5a
(2 - ) Ca2+
(.
(3- -
.
(4 AA- :
- eicosanoids o " )
( . G-proteins
. , -
) NSAID (COX-2 .
) lipoxygenases o (.

- cyclooxygenase pathway ) COX-1 ( ) COX-2-

( .AA- :
- PGE2 o : ,hyperalgesic
,
.
-.
- PGD2 o ,mast -.
- PGF2 o -.
- (prostacyclin) PGI2 o prostacyclin synthetase
,PGI2 PGI2 .PGF1 - ,
.
- (thromboxane) TxA2 o

thromboxane

,synthetase - TxA2 :

- . TxB2-
.
.
COX-2 , "" , COX-1-
, ) ,
(.

- lipoxygenase pathway 3-
. - (5-LO) 5-lipoxygenase : 5-
- HETE .
. " ) CysLT1--
(1 .CysLT2- .
- LTB4 o
.
LTD4 ,LTC4 o) LTE4- ( - -
,- )
, - ,
(.
- lipoxins AA- - )
( : , , ,
.
.
) LXB4 ,LXA4 o A4 - (B4- " 12-lipoxygenase
LTA4 .
: ) (
. ,
.

- resolvins .AA- :
" . ,
, resolvin-.

TABLE 2-4 - Inflammatory Actions of Eicosanoids

Action

Metabolite

Vasoconstriction

Thromboxane A2 , leukotrienes C4 , D4 ,
E4

Vasodilation

PGI2 , PGE1 , PGE2 , PGD2

Increased vascular permeability

Leukotrienes C4 , D4 , E4

Chemotaxis, leukocyte adhesion

Leukotriene B4 , HETE, lipoxins

 - :eicosanoid pathways-

- .
o - ) (acetylating .
- COX-2 inhibitors o , COX-2-
. COX-1 -
.inhibitors
o - ) ,(NSAIDs .indomethacin

5-LO - ,NSAIDs- .
o .
o ) CysLT1.(CysLT2-

- Broad-spectrum inhibitors :glucocorticoids

o down-regulation , -
,COX-2 ,A2 - ) (TNF ,IL-1NO ) iNOS-
.(synthase
o up-regulation - ,lipocortin 1
AA- " .

- .
" " .

)platelet-activating factor (PAF

PAF - .
, " IgE .
.
:- . . ,A . B
-.
PAF .G-protein " ' inactivating PAF
.acetylhydrolases PAF- :
, ) ,(mast- , / .
- :

-.

-.

:- , ) 100-1000
(.

)" (.

-.

.oxidative burst

eicosanoids" .

: PAF
) (.
cytokines and chemokines
" , " ,
. .
. .
TNF :IL-1- . " .
lymphotoxin " T ) : TNF TNF TNF-
IL-1 .(lymphotoxin " .
" - , , ,
.
:

- ) (endothelial activation
, ,eicosanoids ,GF ,
,NO- , priming ,
.

) acute-phase reactions (IL-6 ,

, , ,slow-wave ,
corticotropin ) septic shock ,hypotension :(TNF
, pH- TNF .
" .
TNF ,cachexia- anorexia-
.

chemokines
) 8-10-(
. 40 20- . cys-
:

) CXC - ( chemokines : )
( , ,IL-8 : " ,
IL-1-.TNF-

) CC - ( chemokines : cys- . monocyte

macrophase inflammatory protein ,eotaxin ,(MCP-1) chemoattractant protein
(MIP-1) 1.(regulated and normal T cell expressed and secreted) RANTES-
, , , .
, eotaxin .

) C - ( chemokines : cys- ,:
.lymphotactin .

- CX3C ,fractalkine :
- "

 ;T - , "
.
: .G-protein ,
.
CXCR-4 CCR-5- co-receptors-- ,HIV-1-
.
:

" .ECM-

NO
) , , -
( . , - "
) .(endothelial-derived relaxing factor :
.
- ) , (
" ,GMP - ,
.
NO L-arginine-" .(nitric oxide synthase) NOS 3
:

) eNOS() nNOS ,( -
, ,
.NO

- (inducible) iNOS "

) (IFN- ,TNF.

NO NO : -
, ,
mast .
NO- "rolling"- .postcapillary venules-
NO .
NO ,atherosclerosis- -
.hypertension
NO , . :
(1 NO- -.
(2 NO -
.
(3 NO .
(4 iNOS ) ( .
, NO , .
lysosomal constituents of leukocytes
. .
:

) - (secondary , , ,',
,- , -.

) - (primary , ,
) ,( , ),
,G , .(3

- .
) ( - ,
.
:

- - , pH-
.

- - :,

basement

,membrane , , .
C3 C5- , anaphylatoxins
- .
o - .
o , , , - -
.
, ,
. "
antiprotease , - 1-antitrypsin :
.2-macroglobulin
) .(1-antitrypsin deficiency-

oxygen-derived free radicals

- ,
.
.NADPH
- ) ,(SO ) (H2O2 ) (OH .
NO . -
) ,(IL-8
" . . ,
. -
.
:

- .
:
o .
o ,xanthine oxidation -
.

- antiprotease .a1-antitrypsin
.ECM-

) ,(.

-
:

- ceruloplasmin .

- transferring .

- superoxide dismutase .

- catalase - -.

- glutathione peroxidase - -.

" .
neuropeptides
, vasoactive amines- ,eicosanoids-
. substance Pneurokinin A-
,tachykinin neuropeptides- CNS-.PNS-
substance P ' substance P .
, , "
.
- ,
.
other mediators
, , ,
.
:
(1 - , .
" ,hypoxia-induced factor 1
,VEGF .

 (2 - .
- uric acid : " ,
- . .
) - (gout
) (.
summary of chemical mediators of acute inflammation
) (.
, . ,
.in vivo

- , , , .NO-

C3a) anaphylatoxins ,,(C5a-

, D ,C PAF ,E-.substance P-

C5a , ) (LTB4.

- , , .

IL-1 TNF- - acute

.phase reactants

NO - .

:
TABLE 2-5 - Summary of Mediators of Acute Inflammation
Action
Chemotaxis

Vascular
Leakage

Histamine and Mast cells,

serotonin
platelets

Pain

Plasma substrate

Bradykinin

Opsonic fragment
)(C3b

Plasma protein
via liver

C3a

Leukocyte adhesion,
activation

Macrophages

C5a

Vasodilation, pain,
fever

Other

Potentiate
other
mediators

Source

Mediator

Prostaglandins Mast cells, from

membrane
phospholipids

TABLE 2-5 - Summary of Mediators of Acute Inflammation

Action
Mediator

Source

Vascular
Leakage

Chemotaxis

Other

Leukotriene
B4

Leukocytes

Leukocyte adhesion,
activation

Leukotriene
C4 , D4 , E4

Leukocytes, mast
cells

Bronchoconstriction,
vasoconstriction

Oxygen
metabolites

Leukocytes

Endothelial damage,
tissue damage

PAF

Leukocytes, mast
cells

Bronchoconstriction,
leukocyte priming

IL-1 and TNF Macrophages,

other

Acute-phase reactions,
endothelial activation

Chemokines

Leukocytes,
others

Leukocyte activation

Nitric oxide

Macrophages,
endothelium

Vasodilation,
cytotoxicity

TABLE 2-6 - Role of Mediators in Different Reactions of Inflammation

Vasodilation

Prostaglandins
Nitric oxide
Histamine

Increased vascular permeability

Vasoactive amines
C3a and C5a (through liberating amines)
Bradykinin
Leukotrienes C4 , D4 , E4
PAF
Substance P

Chemotaxis, leukocyte recruitment and

activation

C5a
Leukotriene B4
Chemokines
IL-1, TNF
Bacterial products

Fever

IL-1, TNF
Prostaglandins

Prostaglandins

Pain

Bradykinin
Neutrophil and macrophage lysosomal
enzymes

Tissue damage

Oxygen metabolites
Nitric oxide

outcomes of acute inflammation

. ,
, . ,
, , .
3 :
(1 ) - (complete resolution .
, ,
. ,
, ,
) ( , ,
lymphatics .
)(.
(2 ) - (healing by connective tissue replacement
,

 . ),pleura
(peritoneum , ,
.organization
. .
(3
o - ,

. (*) :
) ,(pneumonia
, (*) .
.
)(.
o ) (.

morphologic patterns of acute inflammation

, ,
.
serous inflammation

, ) .(effusion
.

fibrinous inflammation
, ,
, -.
) (
) (exudate . ,meninges :
. "
" .
- .
, ) (resolution ,
.
) (organization
) strands
( .

suppurative or purulent inflammation

,
, .
) (staphylococci ) pyogenic
( . .acute appendicitis
, ,
. pyogenic.
:
o .
o .
o ,
.
" ) :(.

ulcers
, ,
ulceration . .
:
o , , .
o - , .
.
PMN - .
, ,
.

summary of acute inflammation

:

, ,
.

, "
lipid messangers , ) (.

. " "
.

, - .
, .

"
) (:

-
" , . -
, ) .(exudate
junctions- .
) ,(rubor ) (calor ) (tumor .

- ) ( "
, .
" "
, .
, ).(dolor

chronic inflammation
. ) ( ,
.

- ," . ,
tuberculosis ,atherosclerosis ,rheumatoid arthritis .
causes of chronic inflammation
:

- ,tubercle bacilli
) treponema pallidum ( , .
.delayed type hypersensitivity
) granulomatous reaction(.

) ( -
o - particulate silica - -
.silicosis
o - atherosclerosis
" .

-- .
rheumatoid arthritis :.lupus erythematosus-

morphologic features
, ,
, :

- , .

-" .

" -"
)( .

mononuclear cell infiltration

.
: ) reticuloendothelial
.(system , tissue -
.macrophages ) (,
, ) (sinus histiocytes ) .(alveolar macrophages
.
, tissue macrophage . tissue -
macrophage " , ,
.

 . 48
. " ) ,
( .
- . ":

) (IFN- T.NK-

- .

, ,
.

,
.
- ) / (
. " :

-
. ) ( .
:
o , ) MCP-
.(1 .delayed-hypersensitivity
.C5a o
) GF o platelet derived - PDGF.(TGF--
o .
o-.

- .
.atheromatous plaques

-" .

)(.

) , ( -
) ECM(.

) , (.

, ).(GF

, , .
.
:
" , , -
,fibrinolytic
uric acid . T .
, , .
(A) : : , )
- ( , )( (B) .
: , (.

other cells in chronic inflammation

- , -
.
o ) (
.
o ) (IL-1 ,TNF
.

 - , :
T co-stimulators
) IL-12( , .T T
) ,(IFN- . B,
.
APC ,
.germinal centers ,lymphoid organogenesis ,
.rheumatoid arthritis

- IgE .
.
.eotaxin ,major basic protein
- ,
.

- mast .
Fc- .(FcRI) IgE
o - IgE- mast- -
.AA

 , / .
. , .
o - mast- .

- ,
) .(osteomyelitis
: "
.T
.

granulomatous inflammation
,
, ) .(epithelioid -
, ) (.
: ),cat-scratch disease ,sarcoidosis ,(tuberculosis

lymphogranuloma

,syphilis ,brucellosis ,leprosy ,inguinale berylliosis ,mycotic

.
: - , ,
(.

, .
, ,
- , , ,
.
- epithelioid-
, "" .
, , .
. epithelioid giant cells
) ,(40-50 m 20 ,
) ( )
.(foreign body-type .

:
, : ,- " - foreign-body granuloma

" ,
giant cells- epithelioid .
.( , )
, - immune granuloma

.
.
IL-2 , . ,T
.giant cells- epithelioid IFN-- T
tubercle .
, .-
. .
:
acid-fast " )o
.(
.( ) o
.( ) o
.sarcoidosis-

TABLE 2-7 -- Examples of Diseases with Granulomatous Inflammations

Disease

Cause

Tissue Reaction

Tuberculosis Mycobacterium
tuberculosis

Noncaseating tubercle (granuloma prototype): a

focus of epithelioid cells, rimmed by fibroblasts,
lymphocytes, histiocytes, occasional Langhans giant
cell; caseating tubercle: central amorphous granular
debris, loss of all cellular detail; acid-fast bacilli

Leprosy

Mycobacterium
leprae

Acid-fast bacilli in macrophages; non-caseating

granulomas

Syphilis

Treponema
pallidum

Gumma: microscopic to grossly visible lesion,

enclosing wall of histiocytes; plasma cell infiltrate;
central cells are necrotic without loss of cellular
outline

Cat-scratch
disease

Gram-negative
bacillus

Rounded or stellate granuloma containing central

granular debris and recognizable neutrophils; giant
cells uncommon

lymphatics in inflammation
- .
,
.
) (lymphatics , .
junctions basement membrane , )
(.
- . -
junctions " - . ,
.
, .
, .

) (lymphangitis ) .(lymphadenitis ,
-
. hyperplasia- ) (follicles-
hyperplasia .
,reactive .lymphadenitis
,
.bacteremia- ,
. , ,
,meninges , . ,meningitis ,endocarditis
.septic arthritis-
systemic effects of inflammation
acute phase response

systemic

.(SIRS) inflammatory response "

LPS .
:acute phase response-

- 4 , .
pyrogen , "
- . :
(exogenous pyrogens) LPS IL-1
,(endogenous pyrogens) TNF-
AA . , ,PGE2

 ,cAMP set-point-
,NSAIDs . , "
- .
. ,
heat shock- .

- acute-phase proteins , ,
. ,(C-reactive protein) CRP :
.(SAA) serum amyloid A protein- " "
, ) IL-6 ( IL-1-) TNF- (.
CRP o SAA- .
, .
o SAA ,acute-phase response ,apolipoprotein A
. ,
,
.
o ) ,(rouleaux
. erythrocyte sedimentation ) ESR
(rate .LPS
acute-phase proteins- ,
) (SAA:
o amyloidosis- .
o CRP- myocardial -
infarction . atherosclerosis
CRP) infarction-
, ( . , -
.myocardial infarction-

- , . " -
15,000-20,000 , 40,000-100,000-
)=( . leukemoid reactions
) ( . :
o postmitotic reserve pool- )
IL-1 .(TNF- -
) (.

 o ,
.CSF
.
- neutrophilia .
. ) mumps ,infectious mononucleosis-
(German measles
) .(lymphocytosis ),hay fever ,bronchial asthma
(parasitic infestations ,
.eosinophilia ) ,typhoid fever ,rickettsiae ,
protozoa , (
).(leucopenia

o .
o , ,
.
o ).(rigors
o ) (chills .
o.
o.
o ) (malaise .

- sepsis ) (sepsis LPS-

, TNF .IL-1-
. TNF
- ) .(DIC :
LPS o TNF- (TF) tissue factor" , .
o - "
(TFPI) tissue factor thrombomodulin- .
,
gluconeogenesis- .
, NO "
, . -DIC
- .setptic chock
- . LPS

 , )
( .
o (ARDS) adult respiratory distress sybdrome -
" , .
o . .
consequences of defective or excessive inflammation
:
o - / .
.innate immunity-
,
.
o - - -
- .
:,
,atherosclerosis - .,
,
, "."silent killer
, .
, .ECM

) (MPS ,
)(.
, -
. ground substance - .
MPS- dermatan sulfate, heparan sulfate
.keratan sulfate, and chondroitin sulfate

. ,
,
, .
,MPS 1- .7
. MPS-
, , x-linked .
) MPS 1 -1-( -
. ,
- .
MPS , ,
, , . " ," ,cornea-
.
.
: ,
, ) ( .
, , , ,
.
, ,
, - . " ,

,PAS-positive , .
, MPS .CNS-,
" - ,
.niemann-pick ) ( , ,
- - -
.MPS-
-
. - , .
7 , . ,hurler
,MPS 1 H -1- .
.MPS ,
6-24 . ,
.MPS " 6
10 , - . , ,MPS 2
hurler- ) ,(x-linked cornea-
.

 )(
.
,
.
,
, - ,
.

) .(5-17 , .
-6- "
)( . , -6- -1-,
- )-UDP( .
) 100( , 10,000
-1,4- . "
. ,
-1- 4-
, .
. debranching enzyme- ,
" . ,
" .

Figure 5-17 Pathways of glycogen metabolism. Asterisks mark the enzyme deficiencies associated
with glycogen storage diseases. Roman numerals indicate the type of glycogen storage disease
associated with the given enzyme deficiency. Types V and VI result from deficiencies of muscle and
liver phosphorylases, respectively. (Modified from Hers H, et al: Glycogen storage diseases. In Scriver
CR, et al [eds]: The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, p.
425.)

,
. , 12-
. ,
: - ,
. , :
,

.
, , ,
) .(5-18 -6-
) ,von gierke (1
- ) .(5-7
,debranching enzyme-
. "
, .
) ( : , ,
, .
,
- . : )(
) ' ,(5 ) (pfk )
(7 .
,
.

Figure 5-18 Top, Simplified schema of normal glycogen metabolism in the liver and skeletal muscles.
Middle, Effects of an inherited deficiency of hepatic enzymes involved in glycogen metabolism.
Bottom, Consequences of a genetic deficiency in the enzymes that metabolize glycogen in skeletal
muscles.

 ) ( -
branching enzyme-
. .
,
, ( , 2 )
)'( 4 .( )
, , ,
.

Figure 5-19 Pompe disease (glycogen storage disease type II). A, Normal myocardium with
abundant eosinophilic cytoplasm. B, Patient with Pompe disease (same magnification) showing the
myocardial fibers full of glycogen seen as clear spaces. (Courtesy of Dr. Trace Worrell,
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

. -
TABLE 5-7 -- Principal Subgroups of Glycogenoses
Clinicopathologic
Category Specific Type
Hepatic Type Hepatorenal
von Gierke
disease (type I)

Enzyme
Deficiency

Morphologic
Changes

Clinical
Features

Glucose-6- Hepatomegaly
In untreated
phosphatase intracytoplasmic patients: failure
accumulations of to thrive, stunted
growth,
glycogen and
hepatomegaly,
small amounts of
lipid; and renomegaly.
Hypoglycemia
intranuclear
glycogen due to failure of
glucose
Renomegaly
mobilization,
intracytoplasmic
accumulations of often leading to
convulsions.
glycogen in
cortical tubular Hyperlipidemia
and
epithelial cells
hyperuricemia
resulting from
deranged glucose

TABLE 5-7 -- Principal Subgroups of Glycogenoses

Clinicopathologic
Category Specific Type

Enzyme
Deficiency

Morphologic
Changes

Clinical
Features
metabolism;
many patients
develop gout and
skin xanthomas.
Bleeding
tendency due to
platelet
dysfunction.
With treatment
most survive and
develop late
complications,
e.g., hepatic
adenomas

Myopathic Type

McArdle
Muscle Skeletal muscle
Painful cramps
syndrome phosphorylase
only associated with
(type V)
accumulations of
strenuous
glycogen
exercise.
predominant in
Myoglobinuria
subsarcolemmal occurs in 50% of
location
cases. Onset in
adulthood (>20
years). Muscular
exercise fails to
raise lactate level
in venous blood.
Serum creatine
kinase always
elevated.
Compatible with
normal longevity

Mild
Generalized
Lysosomal
Massive
Miscellaneous
glucosidase hepatomegaly
cardiomegaly,
Types glycogenosis
Pompe disease (acid maltase)
ballooning of
muscle
lysosomes with
(type II)
hypotonia, and
glycogen, cardiorespiratory
creating lacy failure within 2
cytoplasmic years. A milder
pattern adult form with
only skeletal
Cardiomegaly
muscle
glycogen within
involvement,
sarcoplasm as
presenting
with
well as
chronic
membranemyopathy

TABLE 5-7 -- Principal Subgroups of Glycogenoses

Clinical
Features

Morphologic
Changes

Enzyme
Deficiency

Clinicopathologic
Category Specific Type

bound
Skeletal
musclesimilar
to changes in
heart
)(ochronosis
, , " .
,
. ,
. ,
.
: , ,
- , .

. ,
.
,-
. -
, , .
" .
, "
.30- ,
.
,
.

" : -
,tumor suppressors .
. ,
- , -
5% .
,
. .
12 -
, 100,000 " . 1 -
, 2 .
, .
1 1 .3000- 3 :
.1 )(

 .2 , - ) ???(
.3 )( , .lisch
.
-
, -.
: ,
, , .
3 1 ,- -.
,
. -
, " . -
" , -
20" .
- ,
. " - .
.
, " .
,
, .
. -
. -
) ( .
, 5%-
.1
. ) -(
.
, , 90% -.
- -,
" . ,
. , 6
1.5-" , .1
) lisch ( 94%- 6
. , .
, ) 30%-
50%( , :
, , ,
, .
1 2 4 ,
) ( , ) (,
) ," ( , ,-
) (.
.
IQ , .
, .
- .
- ,
. (NF-1)1
, down-regulation
,p21 .tumor suppressors -

 2
, ) ( -
. , , .
- ,
)( , )
( , ) -
," ( . -,
lisch . ,1 1-
40 50.
,NF-2 , .tumor suppressor , ,
, - .
.
.
' ) 187
, (:

DNA- .
probes , DNA
, . ,
:
,
)(
,

, HIV
)( )( ,
.
,
, , , . ,15
P-450- .
,
. , ,
-
. -
, , .

.

) ( . ,
: .
.karyotyping
-
- . -

) amniocentesis ( , .
) (:
) (+34
,
) - ,
(

) x-linked
(.
- " .:


) (
- ) -(
) (
x-
- ) (
)
(.
-
.karyotyping
) ( ,
) ( . DNA-
. DNA
- :
. DNA-
100,000- , PCR-
DNA RNA , 100-
.
DNA .PCR-
DNA
) ( .
,DNA- -
.
- ,
,
.
DNA :
, -.

' , , "
" . .DNA-
, ,PCR DNA
. RNA- ,

 cDNA .PCR-
.RT-PCR

DNA- .5
) ,(4 5
. 10
.Mnl1 G A-
. , -
'3 '5- . DNA-
, .
.Mnl1 3
) 37 ,67 163- ( ,
2 - 200
.67 " ' ,"
" -.
) DNA- (
" .PCR , x-
3 . 5-38 PCR
.
. ,
DNA- -
. "
" ' . PCR-
, southern blot-
.
PCR
" " ) (DNA-
. ,"
PCR-
. - ""
) (beacon" ." probes
- ) (hairpin
) DNA( . mismatch ,
.

Figure 5-37 Direct gene diagnosis: detection of coagulation factor V mutation by polymerase chain
reaction (PCR) analysis. A GA substitution in an exon destroys one of the two Mnl1 restriction sites.
The mutant allele therefore gives rise to two, rather than three, fragments by PCR analysis.

Figure 5-38 Diagnostic application of PCR and Southern blot analysis in fragile-X syndrome. With
PCR, the differences in the size of CGG repeat between normal and premutation give rise to products
of different sizes and mobility. With a full mutation, the region between the primers is too large to be
amplified by conventional PCR. In Southern blot analysis the DNA is cut by enzymes that flank the
CGG repeat region, and is then probed with a complementary DNA that binds to the affected part of

the gene. A single small band is seen in normal males, a higher-molecular-weight band in males with
premutation, and a very large (usually diffuse) band in those with the full mutation.

DNA :
,
. , ,
. , ,
. -
) ( - .
.
" .DNA-
.
.RFLP DNA
, 200 500 .
, ,
. probes-
,
DNA- .southern blot,
RFLP .
, RFLP- . 5-39
. ,
, . ) (A
,Kb 7.6 B
, .
, . DNA
probe
, ,Kb 7.6
.Kb 6.8 -
.southern blot
, .
PCR ,RFLP
PCR-.
DNA : - .
,
.
- . " Kb-
2 6 . ) 1 3
,(Kb " 15 70 .
" ,
) .(5-40A
5-40B
) .(PKD
, C PCR- A ,B
. C .
,
.

Figure 5-39 Schematic illustration of the principles underlying restriction fragment length
polymorphism analysis in the diagnosis of genetic diseases.

Figure 5-40 Schematic diagram of DNA polymorphisms resulting from a variable number of CA
repeats. The three alleles produce PCR products of different sizes, thus identifying their origins from
specific chromosomes. In the example depicted, allele C is linked to a mutation responsible for
autosomal dominant polycystic kidney disease (PKD). Application of this to detect progeny carrying
the disease gene is illustrated in one hypothetical pedigree.

) (SNP .
SNP , .
) , ( .
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5%- 25
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30,000 .26,000 2% ,
30,000 . " alternative splicing
100,000- . ,
.
99.9%- .
.single nucleotide polymorphism (SNP)- SNP- " -
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):(single-gene Mendelian disorders
- .
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. , ,
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single-gene ) .(5-4
. :
.1 .
.2 .
.3 , .
.4 .
TABLE 5-4 -- Biochemical and Molecular Basis of Some Mendelian Disorders
Disease

Molecular Lesion

Example

Phenylketonuria

Splice site mutation:

reduced amount

Phenylalanine
hydroxylase

Tay-Sachs disease

Splice site mutation or

Hexosaminidase

Protein
Type/Function
Enzyme

TABLE 5-4 -- Biochemical and Molecular Basis of Some Mendelian Disorders

Protein
Type/Function

Example

Molecular Lesion

Disease

frameshift mutation with

stop codon: reduced
amount
Adenosine Point mutations: abnormal
deaminase
protein with reduced
activity
Enzyme
Inhibitor
Receptor

1 -Antitrypsin

Missense mutations:
impaired secretion from
liver to serum

Severe combined
immunodeficiency
Emphysema and
liver disease

Low-density
Deletions, point
Familial
lipoprotein
mutations: reduction of hypercholesterolemia
receptor synthesis, transport to cell
surface, or binding to lowdensity lipoprotein
Vitamin D Point mutations: failure of
receptor
normal signaling

Vitamin D-resistant
rickets

Hemoglobin Deletions: reduced amount

-Thalassemia

Defective mRNA
processing: reduced
amount

-Thalassemia

Point mutations: abnormal

structure

Sickle cell anemia

Cystic fibrosis
transmembrane
conductance
regulator

Deletions and other

mutations

Cystic fibrosis

Collagen

Deletions or point
mutations cause reduced
amount of normal collagen
or normal amounts of
mutant collagen

Osteogenesis
imperfecta; EhlersDanlos syndromes

Fibrillin

Missense mutations

Marfan syndrome

Dystrophin

Deletion with reduced

synthesis

Duchenne/Becker
muscular dystrophy

Spectrin, ankyrin,
or protein 4.1

Heterogeneous

Hereditary
spherocytosis

Factor VIII

Deletions, insertions,

Hemophilia A

Transport
Oxygen

Ions

Structural
Extracellular

Cell membrane

Hemostasis

TABLE 5-4 -- Biochemical and Molecular Basis of Some Mendelian Disorders

Disease

Molecular Lesion

Example

Protein
Type/Function

nonsense mutations, and

others: reduced synthesis
or abnormal factor VIII
Hereditary
retinoblastoma

Deletions

Rb protein

Neurofibromatosis
type 1

Heterogeneous

Neurofibromin

Growth
Regulation

. , . 5-7
" ) (1,2,3 1 .2-
.1 M1 M2- .
:
.1 - , .
2 . M1- .M2-
M1 M2- . , ,
.
.
.2
. , . .
,
, .
.3 '
-1- . - .
.

Figure 5-7 Scheme of a possible

metabolic pathway in which a substrate
is converted to an end product by a
series of enzyme reactions. M1, M2,
products of a minor pathway.


. "
" . familial hypercholesterolemia-
,LDL- LDL
. CF-
.
,

, . ,
, . , , ,
" .

.
. G6PD- .
. "
.
)" "(.

):(structural proteins
.5-4
. .Marfan's and Etlers-Danols Syndromes-

Marfan's Syndrome
' 154
, , '
. ,1:5000- 70%-85%
. .
: - .1-
- .
. , ,
. .
1- 2- " FBN1FBN2-
15q21 5q3- . FBN1- , -
FBN2 . 500-
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.

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.
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, .1

)Etlers-Danols Syndromes (EDS

' 155
EDS
. .
" .
.3
6 EDS . 5-5
. :
: , . ,
.
: )( . EDS
.
: ) EDS( ,
) EDS( , ) EDS(.
)TABLE 5-5 -- Classification of Ehlers-Danlos Syndromes (EDS
Gene Defects

Inheritance

Clinical Findings

EDS Type

COL5A1,
COL5A2

Autosomal
dominant

Skin and joint hypermobility,

atrophic scars, easy bruising

)Classical (I/II

Unknown

Autosomal
dominant

Joint hypermobility, pain,

dislocations

Hypermobility
)(III

COL3A1

Autosomal
dominant

Thin skin, arterial or uterine

rupture, bruising, small joint
hyperextensibility

)Vascular (IV

Lysylhydroxylase

Autosomal
recessive

Hypotonia, joint laxity,

congenital scoliosis, ocular
fragility

Kyphoscoliosis
)(VI

COL1A1,
COL1A2

Autosomal
dominant

Severe joint hypermobility,

skin changes mild, scoliosis,
bruising

Arthrochalasia
)(VIIa,b

Procollagen Npeptidase

Autosomal
recessive

Severe skin fragility, cutis

laxa, bruising

Dermatosparaxsis
)(VIIc

EDS
, .
.
.
.III 3
) III ( . ,

 , ,III ,
.
arthrochalasia dermatosparaxis- I .I
I . arthrochalasia I
) ( , dermatosparaxis
. .
30-50%- V .
.
EDS , , ,
,
.

:
)Familial Hypercholesterolemia (FH
' 156
FH " " ,LDL-
. ,
)(MI
. ) (1:500
,
. 5-6 .
, MI .
.20 3-6%- MI- .FH
7% 70% , " ,
LDL- . ,LDL-
.
Figure 5-8 Schematic
illustration of low-density
)lipoprotein (LDL
metabolism and the role of
the liver in its synthesis
and clearance. Lipolysis of
very-low-density
lipoprotein (VLDL) by
lipoprotein lipase in the
capillaries releases
triglycerides, which are
then stored in fat cells and
used as a source of energy
in skeletal muscles.

 FH- 50% - LDL-

. LDL
. LDL-" ,
. , -
.LDL ) LDL- .(5-8 ,IDL
LDL , LDL ) (Apo B-100 and E receptors
. ,FH- IDL- .LDL
LDL scavenger receptors .
LDL- ) (.
.LDL- ,FH- ,
LDL ,
. ) (xanthomas
.
LDL- .19 ) :(5-10
Class I ,
Class II , ER- '
Class III , LDL
Class IV , ,LDL .
Class V LDL- , .LDL-
.
Figure 5-10 Classification of LDL
receptor mutations based on abnormal
function of the mutant protein. These
mutations disrupt the receptor's
synthesis in the endoplasmic
reticulum, transport to the Golgi
complex, binding of apoprotein
ligands, clustering in coated pits, and
recycling in endosomes. Each class is
heterogeneous at the DNA level.
(Modified with permission from Hobbs
HH, et al: The LDL receptor locus in
familial hypercholesterolemia:
mutational analysis of a membrane
protein. Annu Rev Genet 24:133170,
)1990. 1990 by Annual Reviews.

. LDL- HMG CoA

Reductase" .LDL-
gene therapy .FH-



.
(1 :
(2

.
'
) 5-
.(11

.
) (autophagy ) .(heterophagy
.

) .(5-12
:
.1
.
.2
.
Figure 5-11 Synthesis and
.3 ) -
intracellular transport of lysosomal
-6 (.
enzymes.
.4 .
.5/ .
.6 .
, .
Figure 5-12 Schematic diagram
illustrating the pathogenesis of
lysosomal storage diseases. In the
example shown, a complex
substrate is normally degraded by a
series of lysosomal enzymes (A, B,
and C) into soluble end products. If
there is a deficiency or malfunction
of one of the enzymes (e.g., B),
catabolism is incomplete and
insoluble intermediates accumulate
in the lysosomes.

) .(5-6
(1) : ) (2

GM2- GM1 , , ."

.
.
,
.
- ,
glycogenoses, sphingolipidoses, mucopolysacharidoses (MPS) and :
glycogenoses- .mucolipidoses
. .
TABLE 5-6 -- Lysosomal Storage Diseases
Disease

Major Accumulating
Metabolites

Enzyme Deficiency

Glycogenosis
Type 2Pompe disease

-1,4-Glucosidase (lysosomal
glucosidase)

Glycogen
Sphingolipidoses

GM1 gangliosidosis

GM1 ganglioside galactosidase

GM1 ganglioside,
galactose-containing
oligosaccharides

Tay-Sachs disease

Hexosaminidase- subunit

GM2 ganglioside

Sandhoff disease

Hexosaminidase- subunit

GM2 ganglioside,
globoside

Ganglioside activator protein

GM2 ganglioside

Type 1infantile,
generalized
Type 2juvenile
GM2 gangliosidosis

GM

gangliosidosis,
variant AB

Sulfatidoses
Metachromatic
leukodystrophy

Arylsulfatase A

Sulfatide

Multiple sulfatase Arylsulfatases A, B, C; steroid

deficiency sulfatase; iduronate sulfatase;
heparan N-sulfatase

Sulfatide, steroid sulfate,

heparan sulfate, dermatan
sulfate

Krabbe disease

Galactosylceramidase

Galactocerebroside

Fabry disease

-Galactosidase A

Ceramide trihexoside

Gaucher disease

Glucocerebrosidase

Glucocerebroside

Niemann-Pick disease:
types A and B

Sphingomyelinase

Sphingomyelin

Mucopolysaccharidoses (MPS)

TABLE 5-6 -- Lysosomal Storage Diseases

Disease

Enzyme Deficiency

MPS I H (Hurler)
MPS II (Hunter)

Major Accumulating
Metabolites

-L-Iduronidase Dermatan sulfate, heparan

sulfate
-Iduronosulfate sulfatase

Mucolipidoses (ML)
I-cell disease (ML II) Deficiency of phosphorylating
and pseudo-Hurler
enzymes essential for the
polydystrophy
formation of mannose-6phosphate recognition marker;
acid hydrolases lacking the
recognition marker cannot be
targeted to the lysosomes but
are secreted extracellularly

Mucopolysaccharide,
glycolipid

Other Diseases of Complex Carbohydrates

Fucosidosis

-Fucosidase

Fucose-containing
sphingolipids and
glycoprotein fragments

Mannosidosis

-Mannosidase

Mannose-containing
oligosaccharides

Aspartylglycosaminuria

Aspartylglycosamine amide
hydrolase

Aspartyl-2-deoxy-2acetamido-glycosylamine

Other Lysosomal Storage Diseases

Wolman disease

Acid lipase

Cholesterol esters,
triglycerides

Acid phosphate
deficiency

Lysosomal acid phosphatase

Phosphate esters

(GM2 Gangliosidosis: Hexoaminosidase -subunit deficiency) -

160 '
GM2 gangliosidoses
. " , 3 .GM2 gangliosides
.GM2
- , , .
.A - 15
.1:30
GM2 , A :
. ,
, ,
. oil red O- .
, .
. , ,

 , , , ' .
GM2 .
cherry red spot -
.macular choroid
.
- ,
. 6.
, ,
, . cherry red spot- .
.2-3
GM2- ) (5-13
. Sandhoff Disease - GM2 activator -
.deficiency

Figure 5-13 The three-gene system required for hexosaminidase A activity and the diseases that
result from defects in each of the genes. The function of the activator protein is to bind the
ganglioside substrate and present it to the enzyme. (Modified from Sandhoff K, et al: The GM2
gangliosidoses. In Scriver CR, et al [eds]: The Metabolic Basis of Inherited Disease, 6th ed. New
)York, McGraw-Hill, 1989, p. 1824.

Figure 5-14 Ganglion cells in Tay-Sachs disease. A, Under the light microscope, a large neuron has
obvious lipid vacuolation. (Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of
Texas Southwestern Medical Center, Dallas.) B, A portion of a neuron under the electron microscope
shows prominent lysosomes with whorled configurations. Part of the nucleus is shown above. (Electron
micrograph courtesy of Dr. Joe Rutledge, University of Texas Southwestern Medical Center, Dallas,
)TX.

- ) :(Niemann-Pick AB-
' 163
- A B-
. ,C .
A , ,
.3 B ) organomegaly ( '
. " . - .
: A missense .
) ( .
.
90m ,
. ) .(5-15
.
.
.zebra bodies
, , , ,' .
10 , .
.
: gyri- sulci- . '
. , Cherry red spot .
." .
6 .
. , , lymphadenopathy ,
. .
" .
, .

- (NPC) C

 A- B- . NPC-1
. , . NPC-1
.
NPC . . )(hydrops fetalis
, .
: ,supranuclear palsy , , .

Figure 5-15 Niemann-Pick disease in

liver. The hepatocytes and Kupffer cells
have a foamy, vacuolated appearance
owing to deposition of lipids. (Courtesy
of Dr. Arthur Weinberg, Department of
Pathology, University of Texas
Southwestern Medical Center, Dallas,
)TX.

)(Gaucher Disease
' 163

. .
. , ,
' .
. - :
) - chronic non-neuronopathic form (type I , 99%- .
.
. . I
. .
) Acute neuronopathic (type II .
. .
. , , '
.
Type III . "
I II -
.
.
:
. Gaucher Cells , ,
, , , , .peyer's patches-
.
) .(5-16
100m / . PAS
. ,
- . . I
10" . .
lymphadenopathy .


. -
. , . ,
.

Figure 5-16 Gaucher disease involving the bone marrow. A, Gaucher cells with abundant lipid-laden
granular cytoplasm. B, Electron micrograph of Gaucher cells with elongated distended lysosomes.
(Courtesy of Dr. Matthew Fries, Department of Pathology, University of Texas Southwestern Medical
)Center, Dallas, TX.

:
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