10 - Cell Injury and Necrosis

Question 1

Central axiom of Western medicine

Answer 1

All symptoms and signs of disease are caused by changes in the structure and function of cells and tissues

Question 2

Four aetiologies of necrosis

Answer 2

1) Hypoxia/anoxia
2) Microbial infection
3) Drug/toxin damage
4) Physical trauma

Question 3

Most important cause of necrosis

Answer 3

Hypoxia/anoxia

Question 4

Most-common cause of cell injury in medicine

Answer 4

Ischaemia

Question 5

Infarction

Answer 5

Hypoxia induced by reduced blood flow, often due to an occluded artery

Question 6

Speed with which ischaemia can lead to cell death

Answer 6

20-30 minutes

Question 7

Mechanism of acute myocardial infarction

Answer 7

Occlusion of one or both coronary artery branches.

Results in ischaemia, possible necrosis of cardiac tissue

Question 8

Key event in cellular injury

Answer 8

Depletion of mitochondrial ATP production

Question 9

Conceptual point at which cell death occurs

Answer 9

When mitochondrial ATP production stops

Question 10

Two broad types of cellular injury

Answer 10

1) Reversible

2) Irreversible

Question 11

Reversible stage of cellular injury

Answer 11

Depletion of mitochondrial ATP production leads to failure of membrane ion pumps, resulting in swelling of cell and organelles.

Question 12

Stages of irreversible cell injury
1)
2)
3)
4)
5)

Answer 12

1) Depletion of mitochondrial ATP production leads to failure of membrane ion pumps, resulting in swelling of cell and organelles.
2) Cell membrane breakdown
3) Protein synthesis stops (needs ATP)
4) Nuclear, cytoplasmic contents undergo dissolution
5) ROS production leads to lipid, protein, nucleic acid damage

Question 13

Five mechanisms of cell injury

Answer 13

1) ATP production depleted
2) Increase in ROS production
3) Uncontrolled Ca2+ entry into cell
4) Membrane damage
5) Protein misfolding, DNA damage

Question 14

Effects of uncontrolled Ca2+ entry into cell
1)
2)

Answer 14

1) Increase in mitochondrial permeability. Further reduces capacity to generate ATP
2) Activation of multiple intracellular enzymes (EG: phospholipases damage cell membranes, proteases disrupt membrane proteins)

Question 15

Effects of membrane damage
1)
2)
3)

Answer 15

1) Plasma membrane damage leads to influx of Ca2+, loss of organelles.
2) Lysosomal membrane damage leads to digestion of intracellular components
3) Organelle membrane damage reduces organelle capacity to work

Question 16

Effect of DNA and protein damage

Answer 16

Pro-apoptotic enzymes activated (EG: capsases by p53)

Question 17

How are membranes damaged in necrosis?
1)
2)
3)
4)

Answer 17

1) Ca2+ influx leads to phospholipase activity.
2) Loss of ATP generation by mitochondria leads to failure of phospholipid reacylation and synthesis
3) ROS leads to lipid peroxidation, which can damage phospholipids
4) Cytoskeleton damaged

Question 18

Reperfusion injury

Answer 18

When oxygen is supplied to ischamic tissues, there can be an increase in ROS production, which damages tissues.

Question 19

Necrosis pathogenesis
1)
2)
3)
4)

Answer 19

1) Loss of cell membrane integrity, leakage of enzymes, degradation/dissolution of cell
2) Cell swelling, nuclear swelling, membrane rupture
3) Cells digested by either lysosome degradation or leukocytes attracted by inflammation
4) Macrophage clean up dead cell debris

Question 20

Coagulative necrosis
1)
2)
3)
4)

Answer 20

1) Occurs in solid organs, except brain
2) Appears yellow macroscopically
3) If from infarction, clearly demarcated area of necrosis coinciding with occluded blood supply
4) Occurs when enzymatic degradation of tissues is relatively slow

Question 21

Nuclear changes in necrosis
1)
2)
3)

Answer 21

1) Pyknosis - nuclear basophilia, shrinkage
2) Karyorrhexis - Nuclear fragmentation
3) Complete dissolution of the nucleus

Question 22

Histological features of coagulative necrosis
1)
2)
3)

Answer 22

1) Increased eosinophilia -> Increased eosin binding to damaged proteins, loss of rRNA
2) Nuclear pyknosis, karyorrhexis
3) ‘Ghost’ outlines of dead cells - cellular and tissue architecture is preserved for a few days.

Question 23

Type of necrosis that occurs in the brain

Answer 23

Liquefactive necrosis (coagulative does not occur in brain)

Question 24

Features of liquefactive necrosis
1)
2)
3)

Answer 24

1) In brain, from infarction
2) When dead tissues are rapidly digested, resulting in liquid-filled cavity.
3) Inflammatory reaction is relatively mild

Question 25

Caseous necrosis features 
1)
2)
3)
4)

Answer 25

1) In lungs
2) Most often seen in necrotic granulomatous inflammation from TB infection
3) When enzymatic degradation of tissues is more advanced than coagulative, but less so than liquefactive
4) Histologically amorphous granular debris without distinct cell borders

Question 26

Two main apoptosis pathways

Answer 26

1) Intrinsic (mitochondrial) pathway

2) Extrinsic (death receptor) pathway

Question 27

Features of apoptosis

Answer 27

1) Minimal inflammation
2) ATP-dependent
3) Occurs in a single cell, or a small collection of cells, rather than large numbers like with necrosis

Question 28

Mitochondrial apoptotic pathway
1)
2)
3)
4)
5)
6)

Answer 28

1) Cell injury is detected by Bcl2 family sensors
2) Bcl2 family sensors activate Bcl2 effectors (EG: Bax, Bak)
3) Effectors can be inhibited by Bcl-2, Bcl-x
4) Mitochondria release Cytochrome-C, other pro-apoptotic protein
5) Caspases activated, endonuclease activity degrades DNA, cytoskeleton degraded.
6) Blebbing of apoptotic bodies, phagocytosed by macrophages

Question 29

Death receptor apoptotic pathway
1)
2)
3)

Answer 29

1) Fas receptor binds members of TNFa family
2) Caspases activated, endonuclease activity degrades DNA, cytoskeleton degraded.
3) Blebbing of apoptotic bodies, phagocytosed by macrophages

Question 30

Causes of apoptosis
1)
2)
3)
4)

Answer 30

1) DNA damage
2) Accumulation of misfolded proteins
3) Viral infection
4) Immunological reactions

Question 31

How does DNA damage lead to apoptosis?

Answer 31

p53 detects DNA damage, initiates intrinsic apoptotic pathway

Question 32

How does accumulation of misfolded proteins lead to apoptosis?

Answer 32

Accumulation of misfolded proteins in ER leads to ER stress. Results in intrinsic pathway

Question 33

How do immunological reactions lead to apoptosis?

Answer 33

Lymphocytes activate FAS receptor on infected cells.

Question 34

How do viral infections lead to apoptosis?

Answer 34

CD8+ T cells release granzymes, which activate apoptosis in target cell

Question 35

Apoptosis morphology
1)
2)
3)
4)

Answer 35

1) Cell shrinkage
2) Nuclear condensation
3) Blebbing of apoptotic bodies (membrane-bound, have organelles in them)
4) Phagocytosis of apoptotic bodies

Question 36

Difference in cells that phagocytose debris in necrosis and apoptosis

Answer 36

Neutrophils phagocytose necrotic cells.

Macrophages phagocytose apoptotic bodies