Removal Examination: Crash Course

Cellular Responses to Stress & Toxic Insults: Adaptation, Injury & Death

Pathology: General & Systemic

4 Aspects
a. Etiology:
- Genetic
- Acquired
b. Pathogenesis
c. Molecular & morphologic changes
d. Clinical manifestations

ADAPTATION
HYPERTROPHY – ↑ trophy (size); non-dividing cells ATROPHY

Steps: Causes
1. I-ntergrated Actions (cell surface) - Atrophy of disuse/denervation atrophy
a. Mechanical sensors - ↓ blood supply
b. Growth Factors - ↓ nutrition
c. Vasoactive amines - no endocrine stimulation
2. S-ignal Transduction Pathways (cytoplasm) - pressure
a. PI3K/AKT (physiologic)
b. G-protein-coupled receptors (pathologic) Mechanism
3. T-ranscription Factors (nucleus) - ↓ CHON synthesis
- ↑ CHON degradation
Mechanism - ↑ proteolysis-ubiquitin proteosome pathway
S-witch of fetal to fetal CHONs
I-nduction of genes Evidence
M-echanical/trophic triggers - Autophagic vacuoles
- Residual bodies
Limited by
V-ascular supply PHYSIOLOGIC PATHOLOGIC
O-xidative capabilites a. Embryogenesis a. Loss of muscle mass
C-ytoskeletal alterations - Notochord - Denervation
A-ltered CHON synthesis/degradation - Thyroglossal duct - Disuse
b. Brain; heart atrophy
b. Uterus - Senile atrophy
PHYSIOLOGIC PATHOLOGIC
- Post-partum c. Cachexia
a. Hormonal a. Heart
- Uterus (pregnancy) - Hypertension d. Menopause
- Breast (lactation) - Faulty Heart valves e. Pressure

b. Functional Atrophy – From normal size to smaller

- Skeletal muscle Involution – From hyperplasia/hypertrophy to smaller size
(exercise)
Metaplasia/Hyperplasia – pre-cancerous
HYPERPLASIA – ↑ production; METAPLASIA

Mechanism
EPITHELIAL CONNECTIVE
- ↑ Growth factor (mature and stem cells)
a. Squamous metaplasia a. Muscle to bone
- ↑ Growth Factor receptors
- Smoking/Vit. A - - Myositis ossificans
- Activation of intracellular signal pathways
respiratory
- Production of transcription factors
- Stones: exocrine gland
and ducts

PHYSIOLOGIC PATHOLOGIC b. Columnar metaplasia

a. Hormonal (↑ in function) a. ↑↑↑ Hormones - Barrett’s
- Uterus (pregnancy) - Endometrium esophagus
- Breast (puberty/pregnancy) - BPH

b. Compensatory (↑ tissue mass) b. ↑↑↑ Growth Factors

- Hepatectomy - Warts
- Keloid

INJURY
1. REVERSIBLE INJURY
HALLMARKS
- ↓ Oxygen phosphorylation (ATP)
- Cellular swelling

FEATURES
- Cellular swelling/Vacuolar degradation/hydrophic change
- Steatosis

CHANGES
- Plasma membrane alteration (bleb, blunt, loss of microvilli)
- Mitochondrial changes (swell)
- Dilation of endoplasmic reticulum (detached polysomes; intracytoplasmic myelination)
- Nuclear alterations (granular and fibrillar disaggregation); ↑ eosinophilia

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2. IRREVERSIBLE INJURY

NECROSIS APOPTOSIS
1. ↑ Eosinophilia 1. Cells shrink
2. Glassy homogenous appearance 2. Chromatin: condensed
3. Cytoplasm: vacuolated 3. Cytoplasmic blebs; apoptotic bodies
- Moth-eaten appearance 4. Macrophages phagocytose apoptotic cells/bodies
4. Myelin figures
5. Calcification of fatty acid residues PHYSIOLOGIC PATHOLOGIC
a. Embryogenesis a. Cell death in tumor
TYPES b. Hypoglossal duct involution b. Misfolded proteins
1. Coagulative c. Deletion of cell proliferative c. Viral infection
- Preserved architecture population d. Atrophy in duct
- Firm texture d. Served purpose obstruction
- Blocked denaturation proteolysis e. Self-reactive lymphocytes
- Eosinophilic f. Cytotoxic T-cells
- Anucleated
APOPTOSIS
- INFARCT EXCEPT THE BRAIN
- Tightly regulated
2. Liquefactive
- Intact membrane
- CNS Hypoxia
- Altered structure
3. Gangrenous
- Target for phagocytes
- DM
- Cleared rapidly
4. Caseous
- No inflammatory reaction
- Lysed cell
- Amorphous granular debris within MECHANISMS
inflammation border
1. Initiation – caspases (activated) via:
- TB; granuloma
a. Intrinsic (mitochondrial) major pathway
5. Fat
- BAD, BIM, BIM – sensors
- Lipase (pancreas; perintoneal)
- BAK, BAX – pro apoptosis
6. Fibrinoid
- BCL 2 - anti
- Blood vessel; immune reaction
b. Estrinsic (receptor-mediated)
- TNF
NUCLEAR CHANGES
- FRL
1. Karyolysis (light nucleus)
- FAS
- Faded basophilia
- DDR
- Loss of DNA – degradation by
2. Execution – caspases act to cause cell death
endonucleases

2. Pyknosis (nucleus shrink)

- ↑ basophilia

3. Karyorrhexis (pyknotic nucleus)

- Fragmentation

NECROPTOSIS
ü Morphology: same with necrosis – ruptured membrane
ü Mechanically: same with apoptosis – genetically programmed
ü NO CASPASE ACTIVATION

NECROSIS APOPTOSIS
Enlarged/swelling Cell Size Reduced/shrink
Pyknosis→karyorrhexis→karyolysis Nucleus Nucleosome – size fragments
Disrupted Plasma Membrane Altered structure; intact
Enymatic digestion: leak out Cell Contents Intact; released in apoptotic bodies
✓ Inflammation 𝗫
Variably pathologic Role Physiologic

ISCHEMIA HYPOXIA
↓ blood flow Definition ↓ oxygen availability
Mechanical obstruction (artery-vein system) Cause ↓ hemoglobin amount/saturation
Compromised delivery of substrate for Energy source Glycolytic energy
glycolysis → faster injury to tissue

Ischemia-Reperfusion Injury
ü Blood restoration can promote recovery or cause cell death via:
a) Oxidative stress
b) Calcium Overload
c) Inflammation
d) Complement system activation

Chemical Injury
ü Direct: critical component + organelle
ü Indirect: convert component and it will act on organelles

CELL INJURY MECHANISM

a. ATP depletion d. Loss of calcium hemostasis
b. Mitochondrial damage e. Defects in membrane permeability
c. Oxidative stress f. Damage to DNA and proteins

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 AUTOPHAGY
ü Cytoplasmic materials going to the lysosome
ü In many physiological states

TYPES:
a. Chaperone mediated – direct translocation; with chaperone proteins
b. MICROautophagy – inward invagination
c. MACROautophagy – major form: sequestration and transport of cytosol portions to autophagic vacuoles

STEPS:
1. Formation of isolation membrane (derived from ER) and nucleation
2. Elongation of vesicle
3. Maturation of autophagosome
4. Fusion with lysosome
5. Degradation of contents

INTRACELLULAR ACCUMULATION
1. Normal – water, lipids, proteins, carbohydrates
2. Abnormal – EXOgenous (Products of infectious agents); ENDOgenous (products of abnormal synthesis)

PATHWAYS
1. Abnormal metabolism – Fatty liver
2. Defect in protein folding transport – accumulation of abnormal proteins
3. Lack of enzyme – lysosome storage disease; accumulation of endogenous materials; genetic diseases
4. Ingestion of materials – accumulation of endogenous products

LIPIDS PROTEINS HYALINE CHANGE

Triglyceride
ü Fatty change/steatosis
ü Liver, kidney, heart, muscle
Cholesterol (foam cells)
ü Cholesterolosis
ü Atherosclerosis
ü Neimann-Pick Disease Type C
ü Xanthomas
ü Rounded eosinophilic droplets ü Odd proteins
ü CKD- reabsorbed droplets ü Homogenous glassy pink
ü Immune disease- Russel bodies substances
ü Proteinopathy – amyloid ** Hyaline change is a description
ü Alzheimer’s Disease – and not a morphology
neurofibrillary tangles

Glycogen
- Inside the cell; energy source
- ↑↑↑ in metabolic diseases (diabetes and glycogenoses
- Stains with PAS (best with Carmine stain)

PIGMENTS
1. Exogenous:
- Anthracosis
- Tattoo
2. Exogenous
- Lipofuscin: wear and tear/brown atrophy in aging cell (around nucleus of cardia muscles)
- Melanin: nevus; mole
- Homogentisic Acid: Alkaptonuria; ochronosis
- Hemosiderin: product of hemoglobin; seen in hemosiderosis and hemochromatosis

PATHOLOGIC CALCIFICATION

DYSTROPHIC METASTATIC
ü Necrosis only ü Hypercalcemia
ü Atheromas § ↑ PTH
ü Aging or damaged heart valves § Bone tissue destruction
ü Calcium salts appear as: § Vit. D related disorder
- Fine § Renal failure
- White granular/clumps ü Affects
- Felt as gritty § Gastric mucosa
ü Tuberculous lymph node converted to stone § Kidneys
(hard/tubercle) § Lungs
§ Systemic arteritis
§ Pulmonary veins

“Study like you’ve never prayed.

Pray like you’ve never studied.”

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