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Cellular adaptations, cell injury,and cell death
Monday Feb 7
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Terms
Etiology Pathogenesis
Morphologic changes Functional derangements and clinical
manifestations
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Hypertrophy
Figure removed for copyright reasons.Source: Figure 1.3 in [RC] Kumar, V., A. K. Abbas, and N. Fausto.
Robbins and Cotran Pathologic Basis of Disease. Philadelphia PA: Elsevier, 2005.ISBN: 0721601871.
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Hyperplasia
Photos removed for copyright reasons.
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Transmissible murine colonichyperplasia
Photo and diagram removed for copyright reasons.
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Photos removed for copyright reasons.Source: CD-ROM in [RC]. Control colon, H&E 200x
TMCH colon, H&E 200x TMCH colon, BrdU 200x
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Factors driving compensatoryhyperplasia
HGF from nonparenchymal cells acts via c-Metexpressed on hepatoctyes
TGF-alpha and EGF are also mitogenic forhepatocytes
IL-6 and TNF-alpha are produced early in hepaticregeneration, and are necessary for theproliferative response
A priming event is necessary for hepatocytes torespond to these cytokines and growth factors(degradation of ECM, release of norepinephrine,insulin, glucagon, etc.?)
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Resolution of compensatoryhyperplasia
TGF-beta is an important inhibitor,which is also produced bynonparenchymal cells in the liver
The adult stem cells of the liver donot appear to play an important rolein hyperplasia following partialhepatectomy
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Pathologic hyperplasia Hyperplasia constitutes a fertile soil in
which neoplasia may develop Hyperplasia in certain organs is a risk
factor for cancer But in tissues with a high turnover rate,hyperplasia may be a beneficial response
when mature cells are injured or killed,necessitating compensatory renewal
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Metaplasia
Figure removed for copyright reasons.
Source: Figure 1.6 in [RC].
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Reversible & irreversible injury
Figure by MIT OCW.
Normal CellNORM
AL
REVERSIBLECELLINJURY
IRREVERSIBLECELL
Injury
Necrosis
Clumping of
chromatin
Injury
Recovery
Death
Lysosome
rupture
Membraneblebs Swollen mitochondria
with amorphous densities
Swelling of endoplasmic
reticulum and loss of
ribosomes
Necrosis
Fragmentation of cell
membrane & nucleus
Nuclear
condensation
Myelin figures
Normal Cell
Swelling of endoplasmic
reticulum & mitochondria
N d
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Necrosis and apoptosis
NORMAL
Apoptotic
body
Phagocyte
Phagocytosis
of apoptotic cells
& fragments
Enzymatic digestion
& leakage of
cellular contents
NECROSIS
APOPTOSIS
Figure by MIT OCW.
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Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis,
karyorrhexis,karyolysis
Fragmentation into
nucleosome sizefragments
Plasma membrane disrupted Intact, alteredstructure
Cellular contents Enzymaticdigestion, leakage
Intact, release inapoptotic bodies
Adjacentinflammation Frequent No
Physiologic orpathologic role
Always pathologic Often, but notalways, physiologic
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Cellular and biochemical sites of damage
Figure by MIT OCW.
ATP
Loss of
energy-dependent
cellular functions
Cell deathProtein breakdown
DNA damage
Enzymatic digestion
of cellular components
Loss of cellular
contents
MitochondriaPlasma membrane
Lysosome
Membrane DamageIntracellular
Ca2+
O2H2O2OH
-
Reactive Oxygen
Species
Injurious Stimulus
Ca
Ca
Ca
C f ATP d l ti
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Consequences of ATP depletion
Ischemia
Mitochondrion
Oxidative phosphorylation
ATP
Na pump
Influx of Ca++
H2O, and Na+
Efflux of K+
Glycogen Detachment of
ribosomes, etc.
pH
Clumping of
nuclear chromatinProtein synthesis
Lipid deposition
ER swelling
Cellular swelling
Loss of microvilliBlebs
Anaerobic glycolysis Other effects
Figure by MIT OCW.
Mit h d i l d f ti
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Mitochondrial dysfunction
Cytochrome c
H+
Apoptosis
Mitochondrial
membrane
Cytochrome c, other
pro-apoptotic proteins
ATP
production
Mitochondrial
permeability transition (MPT)
Mitochondrial injury or dysfunction
(Increased cytosolic Ca2+, oxidative stress, lipid peroxidation)
Figure by MIT OCW.
C 2+ i ll i j
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Ca2+ in cell injury
Increased cytosolic
Ca2+
Extracellular
Ca2+
Injurious agent
Endoplasmic
reticulumMitochondrion
ATPase
Decreased
ATP
Membrane damage
Phospholipase
Decreased
phospholipids
ProteaseEndonuclease
Disruption of
membrane and
cytoskeletal proteins
Ca2+
Ca2+Ca2+
Nucleus
chromatin
damage
Ca2+
Figure by MIT OCW.
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ROS in cell injury
Figure removed for copyright reasons.Source: Figure 1.14 in [RC].
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Necrosis
Figure removed for copyright reasons.Source: Figure 1.19 in [RC].
h ll
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Ischemic cell injury
Figure by MIT OCW.
Ischemia
Oxidativephosphorylation
Other effects
Basophilia ( RNP)
Nuclear changesProtein digestion
Membrane
injury
Mitochondria
Reversible Injury Irreversible Injury(Cell death)
Leakage of
enzymes
(CK, LDH)
Ca2+influx
Loss of
phospholipids
Cytoskeletalalterations
Free radicals
Lipid breakdown
Others
Intracellular
release andactivation of
lysosomal
enzymes
ATP Glycolysis
Detachment
of ribosomes
Protein
synthesis
Lipid
deposition
Glycogen
pH
Clumping of
nuclear chromatin
Napump
Influx of Ca2+
H2O, and Na+
Efflux of K+
Cellular swelling
Loss of microvilli
Blebs
ER swellingMyelin figures
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CCl4
+O2
Microsomal polyenoic fatty acid
CCl3
Membrane Damage to RER
SER
Chemical Injury
Lipid Radicals
Polysome Detachment
Fatty Liver
LIPID PEROXIDATION
Apoprotein Synthesis
Release of Products of Lipid Peroxidation
Autocatalytic spreadalong microsomal
membrane
Damage to Plasma Membrane
Permeability to Na+
, H2O, Ca2+
Inactivation of Mitochondria, Cell Enzymes,
and Denaturation of Proteins
Massive Influx of Ca2+
Cell Swelling
Figure by MIT OCW.
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Mechanisms of apoptosis
Figure removed for copyright reasons.Source: Figure 1.28 in [RC].
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Extrinsic pathway of apoptosis
Figure removed for copyright reasons.Source: Figure 1.29 in [RC].
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Intrinsic pathway of apoptosis
Figure removed for copyright reasons.Source: Figure 1.30 in [RC].
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Reticulum cell sarcoma modelB cell lymphoma
Reticulum cell sarcoma (RCS)MMTV-encoded superantigen
Syngeneic CD4+ Vb16+ T cells
Produce B cell growth factorsReverse immune surveillance
Th1 cytokines
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Normal spleen
Capsule of Spleen
White Pulp
Venus Sinus
Red Pulp
Trabeculum
Figure by MIT OCW.
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Photos removed for copyright reasons.Source: CD-ROM in [RC]. Normal spleen, H&E 100x RcsX spleen, H&E 100x Normal spleen, H&E 200x
RcsX spleen, H&E 200x Normal spleen, H&E 400x RcsX spleen, H&E 400x RcsX spleen, iNOS 400x RcsX spleen, activated caspase-3 400x