Cell Death and Free Radical Injury Flashcards
Morphologic Hallmark of Cell death
Loss of Nucleus - Occurs via nuclear condensation (pyknosis) first, then fragmentation (Karyorrhexis), and finally dissolution (karyolysis)
Describe Coagulative Necrosis
- 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
When do you get coagulative necrosis? Notable exception?
-Characteristic of ischemic infarction of any organ except brain
Describe liquefactive necrosis
-Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction
When do you get liquefactive necrosis?
1) Brain infarction
2) Abscess
3) Pancreatitis
Describe gangrenous necrosis
Coagulative necrosis that resembles mummified tissue (dry gangrene). Characteristic if ischemia of lower limb and GI tract.
If dry gangrenous necrosis acquires a superimposed infection then what additional type of necrosis will ensue? What would we call the gangrenous necrosis now?
- Liquefactive necrosis
- “Wet gangrene”
Describe Caseous Necrosis
Soft, friable necrotic tissue with “cottage cheese-like” appearance. Characteristic of GRANULOMATOUS inflammation due to TB or fungal infection (histoplasmosis)
Describe Fat Necrosis
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.
Fat Necrosis is characteristic of what
Trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat
Compare dystrophic calcification to metastatic calcification
- 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
Saponification
-An example of dystrophic calcification in which calcium deposits on dead tissue
Describe Fibrinoid Necrosis
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.
In what setting would you see Fibrinoid necrosis?
-Malignant hypertension, vasculitis, preeclampsia (fibrinoid necrosis of placental vessels)
Give examples of apoptosis
- Endometrial shedding during menstrual cycle
- Removal of cells during embryogenesis
- CD8+ T cell-mediated killing of virally infected cells
Morphology of Apoptosis
1) Cell shrinks
2) Nucleus condenses and fragments
3 Apoptotic bodies fall from cell and are removed by macrophages; NOT followed by inflammation
What mediates apoptosis?
CASPASES
How do caspases mediate apoptosis?
Caspases activate proteases and endonucleases.
1) Proteases break down the cytoskeleton
2 Endonucleases break down DNA
How are caspases activated during apoptosis
1) Intrinsic mitochondrial pathway
2) Extrinsic receptor-ligand pathway
3) Cytotoxic Cd8+ T cell-mediated pathway
Describe intrinsic mitochondrial pathway in activation of caspases during apoptosis
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
Describe the extrinsic receptor-ligand pathway in activation of caspases during apoptosis
- FAS ligand binds FAS death receptor (CD95) on target cell –> activates caspases
- TNF binds TNF receptor on the target cell activating caspases
Describe cytotoxic CD8+ T cell-mediated pathway in activation of caspases involved in apoptosis
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.
Describe physiologic generation of free radicals
During oxidative phosphorylation, cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of oxygen yields superoxide, hydrogen peroxide, and hydroxyl radicals.
Causes of pathologic generation of free radicals
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
