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CELL ADAPTATIONS CELL ADAPTATIONS CELL INJURY CELL INJURY CELL DEATH CELL DEATH

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Page 1: Ch1-Cell

CELL ADAPTATIONSCELL ADAPTATIONS

CELL INJURYCELL INJURY

CELL DEATHCELL DEATH

Page 2: Ch1-Cell

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

Page 3: Ch1-Cell

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

Page 4: Ch1-Cell

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

Page 8: Ch1-Cell

ETIOLOGY•Cause

vs.

•Risk Factors

Page 9: Ch1-Cell

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

Page 22: Ch1-Cell

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

Page 24: Ch1-Cell

METAPLASIA• A SUBSTITUTION of one NORMAL

CELL or TISSUE type, for ANOTHER– COLUMNAR SQUAMOUS (Cervix)– SQUAMOUS COLUMNAR

(Glandular) (Stomach)– FIBROUS BONE

–WHY?

Page 25: Ch1-Cell

CELL DEATH• APOPTOSIS vs. NECROSIS• What is DEATH? (What is LIFE?)

–DEATH is IRREVERSIBLE

Page 26: Ch1-Cell

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

Page 29: Ch1-Cell

REVERSIBLE = INJURY

IRREVERSIBLE = DEATH

SOME INJURIES CAN LEAD TO DEATH IF PROLONGED

and/or SEVERE enough

Page 30: Ch1-Cell

INJURY CAUSES (REVERSIBLE)

THE

USUAL

SUSPECTSBut…WHO

are the THREE

WORST?

Page 31: Ch1-Cell

INJURY CAUSES (REVERSIBLE)Hypoxia, (decreased O2)

PHYSICAL Agents

CHEMICAL Agents

INFECTIOUS Agents

Immunologic

Genetic

Nutritional

Page 32: Ch1-Cell

INJURY MECHANISMS (REVERSIBLE)DECREASED ATP

MITOCHONDRIAL DAMAGE

INCREASED INTRACELLULAR CALCIUM

INCREASED FREE RADICALS

INCREASED CELL MEMBRANE PERMEABILITY

Page 33: Ch1-Cell

What is Death?What is Life?

•DEATH is–IRREVERSIBLE MITOCHONDRIAL

DYSFUNCTION–PROFOUND MEMBRANE

DISTURBANCES

• LIFE is……..???

Page 34: Ch1-Cell

CONTINUUM• REVERSIBLE • IRREVERSIBLE• DEATH• EM• LIGHT MICROSCOPY• GROSS APPEARANCES

Page 35: Ch1-Cell

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

Page 43: Ch1-Cell

“DRY” GANGRENE

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EXAMPLES of Cell INJURY/NECROSIS

• Ischemic (Hypoxic)• Ischemia/Reperfusion• Chemical

Page 45: Ch1-Cell

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

Page 48: Ch1-Cell

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

Page 52: Ch1-Cell

SHRINKAGE/HYPERCHROMASIA

Page 53: Ch1-Cell

PHAGOCYTOSIS

Page 54: Ch1-Cell

APOPTOSIS BIOCHEMISTRY

• Protein Digestion (Caspases)

• DNA breakdown• Phagocytic Recognition

Page 55: Ch1-Cell

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)

Page 56: Ch1-Cell

INTRAcellular ACCUMULATIONS

• Lipids– Neutral Fat– Cholesterol

• “Hyaline” = any “proteinaceous” pink “glassy” substance

• Glycogen• Pigments (EX-ogenous, END-ogenous)• Calcium

Page 57: Ch1-Cell

LIPID LAW•ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically

Page 58: Ch1-Cell

FATTY LIVER

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FATTY LIVER

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Page 61: Ch1-Cell

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

Page 62: Ch1-Cell

TATTOO, MICROSCOPIC

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ANTHRACOSIS

Page 64: Ch1-Cell

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

Page 66: Ch1-Cell

CELL AGING parallels ORGANISMAL AGING

PROGRAMMED THEORY (80%)

vs.

WEAR AND TEAR THEORY (20%)