Cell Death and Free Radical Injury

Question 1

Morphologic Hallmark of Cell death

Answer 1

Loss of Nucleus - Occurs via nuclear condensation (pyknosis) first, then fragmentation (Karyorrhexis), and finally dissolution (karyolysis)

Question 2

Describe Coagulative Necrosis

Answer 2

• Necrotic tissue that remains firm due to preservation of the cell shape and organ structure by coagulation of cellular proteins. NUCLEUS disappears.
• Area of infarcted tissue is usually wedge-shaped and pale

Question 3

When do you get coagulative necrosis? Notable exception?

Answer 3

-Characteristic of ischemic infarction of any organ except brain

Question 4

Describe liquefactive necrosis

Answer 4

-Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction

Question 5

When do you get liquefactive necrosis?

Answer 5

1) Brain infarction
2) Abscess
3) Pancreatitis

Question 6

Describe gangrenous necrosis

Answer 6

Coagulative necrosis that resembles mummified tissue (dry gangrene). Characteristic if ischemia of lower limb and GI tract.

Question 7

If dry gangrenous necrosis acquires a superimposed infection then what additional type of necrosis will ensue? What would we call the gangrenous necrosis now?

Answer 7

• Liquefactive necrosis

- “Wet gangrene”

Question 8

Describe Caseous Necrosis

Answer 8

Soft, friable necrotic tissue with “cottage cheese-like” appearance. Characteristic of GRANULOMATOUS inflammation due to TB or fungal infection (histoplasmosis)

Question 9

Describe Fat Necrosis

Answer 9

Necrotic adipose tissue with chalky-white appearance due to deposition of calcium. Fatty acids released by trauma (ex. to breast) or lipase (pancreatitis) join with calcium via a process called saponification.

Question 10

Fat Necrosis is characteristic of what

Answer 10

Trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat

Question 11

Compare dystrophic calcification to metastatic calcification

Answer 11

• In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of NORMAL serum calcium and phosphate.
• Metastatic calcification occurs when HIGH serum calcium or phosphate levels lead to calcium deposition in normal tissues

Question 12

Saponification

Answer 12

-An example of dystrophic calcification in which calcium deposits on dead tissue

Question 13

Describe Fibrinoid Necrosis

Answer 13

Necrotic damage to blood vessel wall resulting in leakage of proteins (including fibrin) into vessel wall. Results in bright pink staining of the wall microscopically.

Question 14

In what setting would you see Fibrinoid necrosis?

Answer 14

-Malignant hypertension, vasculitis, preeclampsia (fibrinoid necrosis of placental vessels)

Question 15

Give examples of apoptosis

Answer 15

• Endometrial shedding during menstrual cycle
• Removal of cells during embryogenesis
• CD8+ T cell-mediated killing of virally infected cells

Question 16

Morphology of Apoptosis

Answer 16

1) Cell shrinks
2) Nucleus condenses and fragments
3 Apoptotic bodies fall from cell and are removed by macrophages; NOT followed by inflammation

Question 17

What mediates apoptosis?

Answer 17

CASPASES

Question 18

How do caspases mediate apoptosis?

Answer 18

Caspases activate proteases and endonucleases.
1) Proteases break down the cytoskeleton
2 Endonucleases break down DNA

Question 19

How are caspases activated during apoptosis

Answer 19

1) Intrinsic mitochondrial pathway
2) Extrinsic receptor-ligand pathway
3) Cytotoxic Cd8+ T cell-mediated pathway

Question 20

Describe intrinsic mitochondrial pathway in activation of caspases during apoptosis

Answer 20

Cellular injury –> DNA damage or decreased hormonal stimulation –> Decreased BCL2 (in charge of keeping cytochrome c within the mitochondria –> Cytochrome C is allowed to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases

Question 21

Describe the extrinsic receptor-ligand pathway in activation of caspases during apoptosis

Answer 21

• FAS ligand binds FAS death receptor (CD95) on target cell –> activates caspases
• TNF binds TNF receptor on the target cell activating caspases

Question 22

Describe cytotoxic CD8+ T cell-mediated pathway in activation of caspases involved in apoptosis

Answer 22

Perforins secreted by CD8+ T cell create pores in membrane of target cell. GRANZYME from CD8+ T cell enters pores and activates caspases. This is how CD8+ T-cells kill virally infected cells.

Question 23

Describe physiologic generation of free radicals

Answer 23

During oxidative phosphorylation, cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of oxygen yields superoxide, hydrogen peroxide, and hydroxyl radicals.

Question 24

Causes of pathologic generation of free radicals

Answer 24

1) Ionizing radiation
2) Inflammation - NADPH oxidase generates superoxide ions during oxygen dependent killing of neutrophils
3) Metals - copper and iron (Fenton reaction)
4) Drugs and Chemicals

Question 25

How do free radicals cause cellular injury

Answer 25

• Peroxidation of lipids

- Oxidation of DNA and proteins

Question 26

How do we eliminate free radicals

Answer 26

1) Enzymes: Superoxide dismutase (in mitochondria), Glutathione peroxidase (in mitochondria), catalase (in peroxisomes)
2) Antioxidants (glutathione, vitamins A, C, and E
3) Metal carrier proteins (ceruloplsmin, transferrin)