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Terms
• Etiology• Pathogenesis• Morphologic changes• Functional derangements and clinical
manifestations
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.
Photos removed for copyright reasons.Source: CD-ROM in [RC].• Control colon, H&E 200x• TMCH colon, H&E 200x• TMCH colon, BrdU 200x
Hepatic regeneration
• In normal adult liver, only 0.5 to 1.0% of cells are undergoing DNA replication
• After partial hepatectomy, the remaining cells proliferate to replace the lost tissue mass
• Hepatocytes begin to divide by 12 hours, and 1 to 2 days later 10% of the cells are synthesizing DNA
• Once liver mass is restored, some 1 to 2 weeks later, the rate of DNA synthesis decreases
Factors driving compensatory hyperplasia
• HGF from nonparenchymal cells acts via c-Met expressed on hepatoctyes
• TGF-alpha and EGF are also mitogenic for hepatocytes
• IL-6 and TNF-alpha are produced early in hepatic regeneration, and are necessary for the proliferative response
• A priming event is necessary for hepatocytes to respond to these cytokines and growth factors (degradation of ECM, release of norepinephrine, insulin, glucagon, etc.?)
Resolution of compensatory hyperplasia
• TGF-beta is an important inhibitor, which is also produced by nonparenchymal cells in the liver
• The adult stem cells of the liver do not appear to play an important role in hyperplasia following partial hepatectomy
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
Reversible & irreversible injury
Figure by MIT OCW.
Normal CellN
OR
MA
LR
EVER
SIB
LE C
ELL
INJU
RYIR
REV
ERSI
BLE
CEL
LIn
jury
Nec
rosi
s
Clumping of chromatin
Injury
Recovery
Death
Lysosome rupture
Membrane blebs Swollen mitochondria
with amorphous densities
Swelling of endoplasmicreticulum and loss of ribosomes
Necrosis
Fragmentation of cell membrane & nucleus
Nuclear condensation
Myelin figures
Normal Cell
Swelling of endoplasmicreticulum & mitochondria
Necrosis and apoptosis
NORMAL
Apoptotic body
Phagocyte
Phagocytosisof apoptotic cells
& fragments
Enzymatic digestion& leakage of
cellular contents
NECROSIS
APOPTOSIS
Figure by MIT OCW.
Feature Necrosis ApoptosisCell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis, karyorrhexis, karyolysis
Fragmentation into nucleosome size fragments
Plasma membrane disrupted Intact, altered structure
Cellular contents Enzymatic digestion, leakage
Intact, release in apoptotic bodies
Adjacent inflammation
Frequent No
Physiologic or pathologic role
Always pathologic Often, but not always, physiologic
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 DamageIntracellularCa2+
O2H2O2OH
-
Reactive OxygenSpecies
Injurious Stimulus
Ca
CaCa
Consequences of ATP depletionIschemia
Mitochondrion
Oxidative phosphorylation
ATP
Na pump
Influx of Ca++
H2O, and Na+
Efflux of K+
Glycogen Detachment of ribosomes, etc.
pH
Clumping of nuclear chromatin
Protein synthesis
Lipid deposition
ER swelling Cellular swelling Loss of microvilli
Blebs
Anaerobic glycolysis Other effects
Figure by MIT OCW.
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.
Ca2+ in cell injury
Increased cytosolic Ca2+
Extracellular Ca2+
Injurious agent
Endoplasmic reticulum
Mitochondrion
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.
Ischemic cell injury
Figure by MIT OCW.
Ischemia
Oxidative phosphorylation
Other effects
Basophilia ( RNP)Nuclear changesProtein digestion
Membrane injury
Mitochondria
Reversible Injury Irreversible Injury (Cell death)
Leakage ofenzymes(CK, LDH)
Ca2+ influx
Loss of phospholipidsCytoskeletalalterationsFree radicalsLipid breakdownOthers
Intracellular release andactivation of lysosomal enzymes
ATP Glycolysis
Detachment of ribosomes
Protein synthesis
Lipid deposition
Glycogen
pH
Clumping of nuclear chromatin
Na pump
Influx of Ca2+
H2O, and Na+
Efflux of K+
Cellular swellingLoss of microvilliBlebsER swellingMyelin figures
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.
Reticulum cell sarcoma modelB cell lymphomaReticulum cell sarcoma (RCS)MMTV-encoded superantigen
Syngeneic CD4+ Vb16+ T cellsProduce B cell growth factors“Reverse immune surveillance”
Th1 cytokines