ch1-cell
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CELL ADAPTATIONSCELL ADAPTATIONS
CELL INJURYCELL INJURY
CELL DEATHCELL DEATH
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OBJECTIVESUnderstand the 3 main anatomic concepts of disease---Degenerative, Inflammatory,
Neoplastic
Understand the concepts of cellular growth adaptations---Hyperplasia, Hypertrophy, Atrophy, Metaplasia
Understand the factors of cell injury and death---O2, Physical, Chemical, Infection, Immunologic, Genetic, Nutritional
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OBJECTIVESUnderstand the pathologic mechanisms at
the SUB-cellular level---ATP, Mitochondria, Ca++, Free Radicals, Membranes
Understand and differentiate the concepts of APOPTOSIS and NECROSIS
Understand SUB-cellular responses to injury---Lysosomes, Smooth endoplasmic reticulum, Mitochondria, Cytoskeleton
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OBJECTIVESIdentify common INTRA-cellular
accumulations---Fat, Hyaline, CA++, Proteins, Glycogen, Pigments
Understand aging and differentiate the concepts of preprogrammed death versus wear and tear.
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PATHOLOGYPathos (suffering)
Logos
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PATHOLOGY•GENERAL•SYSTEMIC
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PATHOLOGY• ETIOLOGY (“Cause”)• PATHOGENESIS
(“Insidious development”)• MORPHOLOGY
(ABNORMAL ANATOMY)• CLINICAL EXPRESSION
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ETIOLOGY•Cause
vs.
•Risk Factors
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PATHOGENESIS“sequence of events from the initial stimulus to the ultimate expression of the disease”
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MORPHOLOGY• Abnormal Anatomy
–Gross–Microscopic–Radiologic–Molecular
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CLINICAL EXPRESSION• Ironically, even though “clinical
expression” is not often present in subclinical diseases, it is the “pathos” of pathology.
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Most long term students of pathology, like myself, will strongly agree that the very best way for most minds to remember, or identify, or understand a disease is to associate it with
a morphologic IMAGE.This can be gross, electron microscopic, light microscopic, radiologic, or molecular.
In MOST cases it is at the LIGHT MICROSCOPIC LEVEL.
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CLINICAL/FUNCTIONAL
Rudolph Virchow
1821-1902
The Father of Modern Pathology
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FUNCTIONAL DEFINITION OF DISEASE
HOMEOSTASIS
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CELL DEATH• APOPTOSIS (“normal”
death)• NECROSIS (“premature”
or “untimely” death due to “causes”
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The –plasia brothers• HYPER-• HYPO- (A-)• NORMO-
• META-
• DYS-• ANA-• “Frank” ANA-
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HYPER-PLASIAIN-CREASE IN NUMBER OF CELLS
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HYPO-PLASIADE-CREASE IN NUMBER OF CELLS
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The –trophy brothers• HYPER-• HYPO- (A-)
• DYS-
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HYPER-TROPHYIN-CREASE IN SIZE OF CELLS
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HYPO-TROPHY?DE-CREASE IN SIZE OF CELLS?
RARELY
USED
TERM
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A-TROPHY?DE-CREASE IN SIZE OF CELLS? YES
SHRINKAGE IN CELL SIZE DUE TO LOSS OF CELL
SUBSTANCE
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ATROPHY• DECREASED WORKLOAD• DENERVATION• DECREASED BLOOD FLOW• DECREASED NUTRITION• AGING (involution)• PRESSURE
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METAPLASIA• A SUBSTITUTION of one NORMAL
CELL or TISSUE type, for ANOTHER– COLUMNAR SQUAMOUS (Cervix)– SQUAMOUS COLUMNAR
(Glandular) (Stomach)– FIBROUS BONE
–WHY?
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CELL DEATH• APOPTOSIS vs. NECROSIS• What is DEATH? (What is LIFE?)
–DEATH is IRREVERSIBLE
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So the question is….
…NOT what is life or death, but what is REVERSIBLE or IRREVERSIBLE injury
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REVERSIBLE CHANGES
• REDUCED oxidative phosphorylation
• ATP depletion• Cellular “SWELLING”
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IRREVERSIBLE CHANGES
• MITOCHONDRIAL IRREVERSIBILITY
• IRREVERSIBLE MEMBRANE DEFECTS
• LYSOSOMAL DIGESTION
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REVERSIBLE = INJURY
IRREVERSIBLE = DEATH
SOME INJURIES CAN LEAD TO DEATH IF PROLONGED
and/or SEVERE enough
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INJURY CAUSES (REVERSIBLE)
THE
USUAL
SUSPECTSBut…WHO
are the THREE
WORST?
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INJURY CAUSES (REVERSIBLE)Hypoxia, (decreased O2)
PHYSICAL Agents
CHEMICAL Agents
INFECTIOUS Agents
Immunologic
Genetic
Nutritional
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INJURY MECHANISMS (REVERSIBLE)DECREASED ATP
MITOCHONDRIAL DAMAGE
INCREASED INTRACELLULAR CALCIUM
INCREASED FREE RADICALS
INCREASED CELL MEMBRANE PERMEABILITY
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What is Death?What is Life?
•DEATH is–IRREVERSIBLE MITOCHONDRIAL
DYSFUNCTION–PROFOUND MEMBRANE
DISTURBANCES
• LIFE is……..???
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CONTINUUM• REVERSIBLE • IRREVERSIBLE• DEATH• EM• LIGHT MICROSCOPY• GROSS APPEARANCES
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DEATH:ELECTRON MICROSCOPY
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DEATH:LIGHT MICROSCOPY
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NECROSIS BROTHERS:• Liquefactive (Brain)• Gangrenous (Extremities, Bowel, non-specific)
– WET– DRY
• Fibrinoid (Rheumatoid, non-specific)• Caseous (cheese) (Tuberculosis)• Fat (Breast, any fat)• Ischemic (non-specific)• Avascular (aseptic), radiation, organ specific,
papillary• OneLook lists 153 terms preceding the word
“necrosis”: http://www.onelook.com/?w=*necrosis&ls=a
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LIQUEFACTIVE NECROSIS, BRAIN
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MORE LIQUID MORE WATER MORE PROTONS
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CASEOUS NECROSIS, TB
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FIBRINOID NECROSIS
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“WET” GANGRENE
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“DRY” GANGRENE
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EXAMPLES of Cell INJURY/NECROSIS
• Ischemic (Hypoxic)• Ischemia/Reperfusion• Chemical
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ISCHEMIC INJURY•REVERSIBLE IRREVERSIBLE
•DEATH (INFARCT)
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ISCHEMIA/RE-PERFUSION INJURY
NEW Damage “Theory”
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CHEMICAL INJURY• “Toxic” Chemicals, e.g CCl4 • Drugs, e.g tylenol• Dose Relationship• Free radicals, organelle, DNA
damage
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APOPTOSIS•NORMAL (preprogrammed)
•PATHOLOGIC (associated with Necrosis)
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“NORMAL” APOPTOSIS• Embryogenesis • Hormonal “Involution”• Cell population control, e.g.,
“crypts”• Post Inflammatory “Clean-up”• Elimination of “HARMFUL” cells• Cytotoxic T-Cells cleaning up
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“PATHOLOGIC” APOPTOSIS
• “Toxic” effect on cells, e.g., chemicals, pathogens
• Duct obstruction• Tumor cells• Apoptosis/Necrosis spectrum
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APOPTOSIS MORPHOLOGY
• DE-crease in cell size, i.e., shrinkage• IN-crease in chromatin concentration,
i.e., hyperchromasia, pyknosis karyorhexis karyolysis
• IN-crease in membrane “blebs”• Phagocytosis
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SHRINKAGE/HYPERCHROMASIA
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PHAGOCYTOSIS
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APOPTOSIS BIOCHEMISTRY
• Protein Digestion (Caspases)
• DNA breakdown• Phagocytic Recognition
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SUB-Cellular Responses to Injury(APOPTOSIS/NECROSIS)
• Lysosomal Auto-Digestion• Smooth Endoplasmic Reticulum (SER)
activation• Mitochondrial “SWELLING”• Cytoskeleton Breakdown
– Thin Filaments (actin, myosin)– Microtubules– Intermediate Filaments (keratin, desmin,
vimentin, neurofilaments, glial filaments)
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INTRAcellular ACCUMULATIONS
• Lipids– Neutral Fat– Cholesterol
• “Hyaline” = any “proteinaceous” pink “glassy” substance
• Glycogen• Pigments (EX-ogenous, END-ogenous)• Calcium
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LIPID LAW•ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically
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FATTY LIVER
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FATTY LIVER
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PIGMENTSEX-ogenous--- (tattoo, Anthracosis)
END-ogenous--- they all look the same, (e.g., hemosiderin, melanin, lipofucsin, bile), in that they are all golden yellowish brown on “routine” Hematoxylin & Eosin (H&E) stains
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TATTOO, MICROSCOPIC
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ANTHRACOSIS
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Hemosiderin/Melanin/etc.
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CALCIFICATION• DYSTROPHIC (LOCAL
CAUSES) (often with FIBROSIS)• METASTATIC (SYSTEMIC
CAUSES)–HYPERPARATHYROIDISM–“METASTATIC*” Disease
*NOT to be confused with “metastatic” calcification
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CELL AGING parallels ORGANISMAL AGING
PROGRAMMED THEORY (80%)
vs.
WEAR AND TEAR THEORY (20%)