PATH: Irreversible Cell Injury and Cellular Death

Question 1

What cellular damage must occur for irreversible damage to be inevitable?

Answer 1

Unrecoverable mitochondrial damage occurs with loss of ATP synthetic capacity and cell membrane damage of such severity that regulation of internal milieu is impossible

Question 2

Describe the feed-forward cycle of irreversible cell injury

Answer 2

Membrane dysfunction leads to influx of Ca++ which activates phospholipases, which further contribute to membranal damage and further influx of Ca++

Question 3

The detection of what hepatocyte enzymes are non-specific indicators of liver inflammation?

Answer 3

AST and ALT

Question 4

What pancreas proteins can be only detected in the serum in cases of pancreatitis?

Answer 4

Lipase and amylase

Question 5

What are the morphological changes of irreversible mitochondrial injury?

Answer 5

Marked swelling, dense body formation (calcium phosphate)

Question 6

What is karyolysis?

Answer 6

Marker of irreversible nuclear damage where the nucleus “fades away”

Question 7

What is pyknosis?

Answer 7

Marker of irreversible nuclear damage where the nucleus is hard and dark and becomes “clumped” and actually shrinks

Question 8

What is karyorrhexis?

Answer 8

Marker of irreversible nuclear damage where there is random breakup of nucleus into many fragments

Question 9

How long can it take for nuclear morphological signs of damage to be clinically observed?

Answer 9

6-12 hours

Question 10

What is reperfusion injury? What is thought to be the underlying mechanism of this damage?

Answer 10

Damage that occurs upon resumption of blood supply and reoxygenation of previously ischemic tissue; thought to be due to generation of ROS, including oxygen-derived free radicals

Question 11

What are three common examples of oxygen-derived free radicals?

Answer 11

Superoxide anion, hydrogen peroxide, and hydroxyl radical

Question 12

What are physiologic generators of ROS?

Answer 12

Oxidative phosphorylation, Neutrophilic respiratory burst, xanthine oxidase

Question 13

What types of damage can be induced by ROS?

Answer 13

Lipid peroxidation (form lipid peroxides); Protein-protein cross-linking; single-stranded DNA breaks

Question 14

What are the antioxidant mechanisms that protect from ROS?

Answer 14

Superoxide Dismutase (mitochondria) , Glutathione peroxidase and reductase (mitochondria), and catalase (peroxisomes)

Question 15

How does carbon tetrachloride cause cellular damage?

Answer 15

CCl4 is metabolized by cyP450 to form CCL3-, which is esp. damaging to the rER, inhibiting protein synthesis and export (esp. apoproteins), resulting in lipid accumulation within injured hepatocytes

Question 16

What vitamins serve as free radical scavengers?

Answer 16

Vit. E and A

Question 17

How does the cell regulate molecules that propagate free radical production?

Answer 17

Fe is bound by transferrin and/or ferritin; Cu is bound by ceruloplasmin

Question 18

After cell death via necrosis what two concurrent processes may be present in the cell?

Answer 18

Protein denaturation and enzymatic digestion of cell constituents

Question 19

What is the difference is autolysis and heterolysis?

Answer 19

Autolysis is enzymatic digestion of cellular contents by the cell’s own lysosome; Heterolysis is by inflammatory cells

Question 20

What cytoplasmic change can be observed following cell necrosis? Why does this happen?

Answer 20

Increased eosinophilia dueto loss of basophlic ribosomes and increased uptake of eosin dye by denatured proteins

Question 21

What is coagulation necrosis?

Answer 21

Cell necrosis in which denaturation (coagulation) of cellular proteins predominates, typically by autolysis

Question 22

What is an infarct? What is the difference between a pale/anemic infarct and hemorrhagic /red infarct?

Answer 22

An infarct is a circumscribed area of an organ undergoing coagulation necrosis due to ischemia; Pale infarcts are found in end organs (spleen, heart, kidney) which have no dual blood supply; Red infarcts happen in organs with dual blood supply (lung) or with large amounts of CT (gut)

Question 23

What kind of necrosis is gangrene? What is the cause?

Answer 23

A special type of coagulation necrosis caused by gradual ischemia of the distal extremities

Question 24

In which type of necrosis occurs in tissues in which the initial digestion of cells and tissue predominates, with resulting loss of tissue structure? What is the mechanism of this digestion?

Answer 24

Liquefactive necrosis; heterolysis

Question 25

In which organ is liquefactive necrosis seen following infarction rather than coagulation necrosis?

Answer 25

Brain

Question 26

What are the causes of caseous necrosis and what are the common characteristics they share?

Answer 26

Mycobacterial (TB) and some fungal infections; difficult for the body to eliminate, resulting in chronic inflammation

Question 27

What is the appearance of caseous necrotic tissue, grossly?

Answer 27

Necrotic tissue is walled off and transformed into focus of granular "cheesy" material, surrounded by granulomatous inflammation and fibrosis

Question 28

In which organ is fat necrosis likely to occur? What is the mechanism?

Answer 28

Pancreatic cells undergo necrosis and spill their hydrolytic enzymes, esp. lipases, which act on adjacent adipocytes to release fatty acids, which combine with calcium to undergo saponification

Question 29

Where does fibrinoid necrosis occur? When does it occur?

Answer 29

Arterial walls; Occurs in extreme hypertension or immune complex deposition in arterial walls

Question 30

True or False: Both Necrosis and Apoptosis are energy-requiring?

Answer 30

False- Apoptosis is energy-requiring but not necrosis

Question 31

What are the morphologic changes associated with apoptosis?

Answer 31

Cell shrinks and detaches from neighbors, blebbing, chromatin condensation, fragmentation into apoptotic bodies, little to no inflammatory response

Question 32

What class of proteins are caspases and what are their cellular functions? Which are initiators and which are effectors?

Answer 32

Cysteine proteases which cleave cytoskeletal proteins and cleave nuclear scaffolding; initiators are -2,-8, and -9; executioners are capases-3, -6, - and -7

Question 33

What is the function of Bcl-2 and where can it be found?

Answer 33

Bcl-2 is an anti-apoptotic protein normally found in the outer mitochondrial membrane, which stabilizes the membrane, prevents pore formation, prevents release of cytochrome c, binds to and sequesters Apaf-1

Question 34

What are the common pro-apoptotic members of the Bcl-2 family?

Answer 34

Bax and Bad

Question 35

What proteins form the apoptosome?

Answer 35

Apaf-1, cytochrome-c, and proCaspase 9

Question 36

What are the best known triggers of the extrinsic apoptotic pathway? What is the mechanism of activation?

Answer 36

Fas and TNFR1 receptors binding to their ligands (Fas-L or TNF-alpha); Interaction with the appropriate ligand results in trimerization, and trimerization of Fas interact with Fas Associated Death Domain which activates proCaspase 8 and triggers the cascade