10 - Cell Injury and Necrosis Flashcards

1
Q

Central axiom of Western medicine

A

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

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2
Q

Four aetiologies of necrosis

A

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

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3
Q

Most important cause of necrosis

A

Hypoxia/anoxia

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4
Q

Most-common cause of cell injury in medicine

A

Ischaemia

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5
Q

Infarction

A

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

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6
Q

Speed with which ischaemia can lead to cell death

A

20-30 minutes

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7
Q

Mechanism of acute myocardial infarction

A

Occlusion of one or both coronary artery branches.

Results in ischaemia, possible necrosis of cardiac tissue

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8
Q

Key event in cellular injury

A

Depletion of mitochondrial ATP production

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9
Q

Conceptual point at which cell death occurs

A

When mitochondrial ATP production stops

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10
Q

Two broad types of cellular injury

A

1) Reversible

2) Irreversible

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11
Q

Reversible stage of cellular injury

A

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

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12
Q
Stages of irreversible cell injury
1)
2)
3)
4)
5)
A

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

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13
Q

Five mechanisms of cell injury

A

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

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14
Q

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

A

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)

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15
Q

Effects of membrane damage
1)
2)
3)

A

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

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16
Q

Effect of DNA and protein damage

A

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

17
Q
How are membranes damaged in necrosis?
1)
2)
3)
4)
A

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

18
Q

Reperfusion injury

A

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

19
Q
Necrosis pathogenesis
1)
2)
3)
4)
A

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

20
Q
Coagulative necrosis
1)
2)
3)
4)
A

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

21
Q

Nuclear changes in necrosis
1)
2)
3)

A

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

22
Q

Histological features of coagulative necrosis
1)
2)
3)

A

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.

23
Q

Type of necrosis that occurs in the brain

A

Liquefactive necrosis (coagulative does not occur in brain)

24
Q

Features of liquefactive necrosis
1)
2)
3)

A

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

25
Q
Caseous necrosis features 
1)
2)
3)
4)
A

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

26
Q

Two main apoptosis pathways

A

1) Intrinsic (mitochondrial) pathway

2) Extrinsic (death receptor) pathway

27
Q

Features of apoptosis

A

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

28
Q
Mitochondrial apoptotic pathway
1)
2)
3)
4)
5)
6)
A

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

29
Q

Death receptor apoptotic pathway
1)
2)
3)

A

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

30
Q
Causes of apoptosis
1)
2)
3)
4)
A

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

31
Q

How does DNA damage lead to apoptosis?

A

p53 detects DNA damage, initiates intrinsic apoptotic pathway

32
Q

How does accumulation of misfolded proteins lead to apoptosis?

A

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

33
Q

How do immunological reactions lead to apoptosis?

A

Lymphocytes activate FAS receptor on infected cells.

34
Q

How do viral infections lead to apoptosis?

A

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

35
Q
Apoptosis morphology
1)
2)
3)
4)
A

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

36
Q

Difference in cells that phagocytose debris in necrosis and apoptosis

A

Neutrophils phagocytose necrotic cells.

Macrophages phagocytose apoptotic bodies