Cell Adaptation, Injury, And Death

Front 1

Hyperplasia and hypertrophy

Back 1

a. Increase in stress
b. Leads to increase in organ size
c. Occurs via increase in size and/or number of cells
d. Usually occur together→ uterus during pregnancy

Front 2

Hypertrophy

Back 2

a. Involves gene activation
b. Protein synthesis
c. Production of organelles

Front 3

Phophoinositide 3-kinase/Akt pathway in hypertrophy

Back 3

1. Exercise-induced hypertrophy

Front 4

Signalin downstream of GPCR in hypertrophy

Back 4

1. Pathologic hypertrophy

Front 5

Barbiturates and hypertrophy

Back 5

i. Barbiturates cause hypertrophy of SER in hepatocytes
ii. Increases amount of P-450 able to detoxify drugs
iii. Alcohol also causes SER hypertrophy

Front 6

Hyperplasia

Back 6

a. Involves production of new cells
b. Benign process
c. Can be “premalignant”

Front 7

Physiologic hyperplasia

Back 7

i. Hormonal hyperplasia
Compensatory hyperplasia

Front 8

Hormonal hyperplasia

Back 8

1. Increases functional capacity of a tissue when needed

Front 9

Compensatory hyperplasia

Back 9

1. Increases tissue mass after damage or partial resection

Front 10

Permanent tissues

Back 10

a. Do not have stem cells
b. Cannot undergo hyperplasia→ only undergo hypertrophy
c. Cardiac myocytes, skeletal muscle, nerve tissue

Front 11

Hypertrophy in cardiac myocytes

Back 11

a. Thicker left ventricular wall

Front 12

Pathologic hyperplasia progression

Back 12

a. Usually caused by excesses of hormones or growth factors
b. Can progress to dysplasia and cancer

Front 13

Endometrial hyperplasia

Back 13

i. Long exposure to progesterone leads to carcinoma

Front 14

Benign hyperstatic hyperplasia and pathologic hyperplasia

Back 14

i. Does not lead to cancer
ii. No gene mutation in genes that regulate cell division

Front 15

Viral infections and hyperplasia

Back 15

i. Pathological hyperplasia is common response to certain viral infections
ii. HPV→ warts

Front 16

Mechanism of hyperplasia

Back 16

i. Growth-factor driven proliferation of mature cells
ii. Can be from tissue stem cells

Front 17

Atrophy

Back 17

a. Decrease in stress on organ leads to a decrease in organ size
b. Occurs via a decrease in the size of cells and organelles

Front 18

Common causes of atrophy

Back 18

i. Disuse
ii. Denervation
iii. Ischemia
iv. Malnutrition
v. Loss of endocrine stimulation
vi. Pressure

Front 19

Decrease in cell number in atrophy

Back 19

i. Occurs via apoptosis

Front 20

Ubiuitin-proteosome degradation of the cytoskeleton

Back 20

1. For cell to shrink, cytoskeleton must be broken down
2. Ubiquitin→ marks intermediate filaments of cytoskeleton, recognized by proteasome

Front 21

Autophagy of cellular components

Back 21

1. Consumption of own components in vacuoles
2. Vacuoles fuse with lysosomes
3. Lipofuscin granules→ residual bodies

Front 22

Metaplasia

Back 22

a. Change in stress on organ leads to change in cell type
b. Most commonly involves surface epithelium
c. Metaplastic cells are better able to handle new stress
d. Benign process

Front 23

Most common type of metaplasia

Back 23

i. Columnar→squamous

Front 24

Barrett esophagus

Back 24

a. Esophagus lined by squamous epithelium
b. Stomach lined by columnar epithelium
c. Reflux of acid from stomach to acid causes lower portion of esophagus to change epithelium to columnar epithelium

Front 25

Metaplasia occurs via

Back 25

a. Reprogramming of stem cells
b. Reversible with removal of the driving stressor
c. Seen in treatment of GERD

Front 26

Metaplasia can progress to cancer

Back 26

a. Example→ Barrett esophagus
b. Exception→ Apocrine metaplasia in breast

Front 27

Vitamin A deficiency can result in...

Back 27

a. Metaplasia
b. Vitamin A necessary for maturation of the immune system
c. Also necessary for maintenance of specialized epithelium in body

Front 28

Keratomalacia

Back 28

i. Thickening of conjunctiva of eye due to Vitamin A deficiency
ii. Change takes place due to metaplasia
iii. Specialized epithelium cannot be maintained

Front 29

Myositis ossificans

Back 29

i. Inflammation of skeletal muscle results in metaplastic reformation of bone
ii. Muscle converts to bone

Front 30

Factors determining the extent of cell injury

Back 30

a. Features of the injury
b. Features of the cell
c. Point of attack on cell

Front 31

Some causes of cell injury

Back 31

a. Hypoxia
b. Mechanical and physical agents
c. Chemical agents and drugs
d. Infectious agents
e. Immune reactions
f. Genetic derangements
g. Nutritional imbalances or deficiencies

Front 32

Hypoxia

Back 32

i. Oxygen deprivation
ii. Wastes do not accumulate
iii. Glycolytic substrates are delivered
iv. CO poisoning, lung disease, sever anemia

Front 33

Ischemia

Back 33

i. Reduced blood flow resulting in hypoxia
ii. Accumulation of wastes
iii. Lack of glycolytic substrates

Front 34

Mechanism of cell injury in ischemia or hypoxia

Back 34

a. Aerobic respiration is impaired
b. Impairment of the plasma membrane Na-K-ATPase pump leads to Na moving out of cell, causing cell swelling
c. Cell has to rely on inefficient glycolysis
d. Lactic acid is produced and acidosis develops
e. Ribosomes detach from ER→ slowing/stopping of protein synthesis
f. Cell function ceases

Front 35

Histologic signs of cell injury and necrosis

Back 35

a. Cell swelling
b. Pathological responses to injury
c. Mitochondrial damage
d. Rupture of lysosomal and plasma membranes

Front 36

Signs of cell injury and necrosis with irreversible injury

Back 36

a. Reduced oxidative phosphorylation
b. Mitochondria swell
c. Lysosomes leak enzymes into cytoplasm and all those “ases” begin to autodigest cell components
d. Membrane is permanently damaged

Front 37

Apoptosis

Back 37

a. Induced by tightly regulated suicide program
b. Cells destined to die activate enzymes that degrade the cells’ own DNA and nuclear/cytoplasmic proteins
c. Cell’s PM remains intact, but structure is altered such that cell is target for phagocytosis
d. Does not elicit inflammatory response from host

Front 38

Physiologic causes of apoptosis

Back 38

i. Programmed destruction of cells in embryogenesis
ii. Involution of hormone-dependent cells upon hormone withdrawal
iii. Cell loss in proliferating populations
iv. Elimination of self-reactive lymphocytes
v. Death of cells after their work is done

Front 39

Pathologic causes of apoptosis

Back 39

i. DNA damage from any cause
ii. Accumulation of misfolded proteins
iii. Cell death in certain infections
iv. Post-obstructive atrophy

Front 40

Biochemical features of apoptosis

Back 40

i. Activation of caspases
1. Cysteine protease+aspase for cleavage after aspartic acid residues
2. DNA and protein breakdown into large fragments, then into much smaller fragments
3. Membrane alterations and recognition by phagocytes

Front 41

Intrinsic pathway (mitochondrial) of apoptosis initiation

Back 41

1. Major mechanism of apoptosis in all mammalian cells
2. Result of increased mitochondrial permeability and release of pro-apoptotic molecules
3. Involves Bcl family of proteins

Front 42

Bcl family of proteins

Back 42

a. Reside in cytoplasm and in mitochondrial membranes
b. Control mitochondrial permeability
c. Prevent leakage of mitochondrial proteins that have the ability to trigger cell death

Front 43

Extrinsic pathway of apoptosis initiation

Back 43

1. Initiated by engagement of plasma membrane death receptors
2. Members of TNF family→ Fas ligand
3. May be many interconnections between the two pathways

Front 44

Execution phase of apoptosis

Back 44

1. Intrinsic and extrinsic pathways converge→ cascade of caspase activation→ mediates final phase
2. Endonuclease activation
3. Cytoskeletal breakdown
4. Membrane blebbing and formation of apoptotic bodies
5. DNA cleavage into nucleosomes
6. Phagocytosis of cell remnants
7. NO INFLAMMATION

Front 45

Morphologic changes in apoptosis

Back 45

1. Cell shrinkage
2. Chromatin condensation
3. Cytoplasmic blebs and apoptotic bodies
4. Phagocytosis usually by macrophages

Front 46

Apoptosis and cancer

Back 46

1. Some oncogenic mutations disrupt apoptosis leading to tumor initiation, progression or metastasis
2. Most cytotoxic anticancer agents induce apoptosis
a. B-cell leukemia
i. Lymphomas express high levels of Bcl-2
ii. Block apoptotic signals they may receive

Front 47

Necrosis

Back 47

a. Result of denaturation of intracellular proteins
b. Enzymatic digestion of lethally injured cells

Front 48

Necrosis and membrane integrity

Back 48

i. Necrotic cells cannot maintain membrane integrity
ii. Contents leak out
iii. Elicit inflammation in surrounding tissue

Front 49

Earliest histologic evidence of necrosis

Back 49

i. 4-12 hours
ii. Myocardial enzymes can be detected in blood 2 hours after injury

Front 50

Necrotic cell staining

Back 50

i. Eosinophilia in H&E
ii. Glassy homogeneous appearance

Front 51

Myelin figures

Back 51

i. Replace dead cells
ii. Large, whorled phospholipid masses

Front 52

Coagulation necrosis

Back 52

i. Architecture preserved but nuclei are gone
ii. Cells not lysed by enzymes initially
iii. Dead tissue will be removed by phagocytosis
iv. Usually result of ischemic injury→ infarct
v. “Ghost cells”

Front 53

Liquefactive necrosis

Back 53

i. Architecture is lost due to digestion of dead cells by enzymes released by leukocytes
ii. Characterized by purulence
iii. Usually the result of marked acute inflammation, characteristic of bacterial or fungal infections
iv. Often seen with CNS necrosis

Front 54

Gangrenous necrosis

Back 54

i. Not a specific pattern of necrosis. Used clinically
ii. Alternating areas of both coagulation and liquefactive necrosis
iii. Typical setting is in a limb with loss of blood flow and secondary acute inflammation of exposed dead tissue due to bacterial or fungal infection
iv. Dry v. wet gangrene.

Front 55

Caseous necrosis

Back 55

i. Most commonly seen in mycobacterial (TB) infection
ii. Cheese-like in appearance
iii. Collection of fragmented/lysed cells and amorphous, granular debris within a distinctive inflammatory border (granuloma)

Front 56

Fat necrosis

Back 56

i. Liquefactive necrosis in which the active enzymes are lipases and the matrix is fat
ii. Pancreatic enzymes liquefy membranes of fat cells in the peritoneum
iii. Grossly recognizable as little white spots with the consistency of soap
iv. Classic example is pancreatitis

Front 57

Fibrinoid necrosis

Back 57

i. Usually seen in immune reactions involving blood vessels
ii. Antigen-antibody complexes deposited in walls
iii. AA complexes with fibrin give amorphous, bright pink appearance to vessel walls on H&E stained sections