Apoptosis & Necrosis

Question 1

Define apoptosis

Answer 1

Individual cell deletion in physiological growth control and in disease. Programmed sequence of intracellular event without the release of products harmful to the surrounding cells.

Question 2

Apoptosis is activated or prevented by…

Answer 2

Variety of intracellular and extracellular stimuli.

Question 3

What does reduced apoptosis lead to?

Answer 3

Cell accumulation; i.e. neoplasia.

Question 4

What does increased apoptosis lead to?

Answer 4

Atrophy

Question 5

Characteristics of apoptosis

Answer 5

Energy-dependent

Biochemically specific

Enzymatic digestion of nuclear and cytoplasmic contents, followed by the phagocytosis of breakdown products. The cell membrane is still INTACT.

Question 6

Necrosis

Answer 6

Unintended cell death in response to cellular injury.

Question 7

What sort of cell death is seen in AIDS?

Answer 7

Apoptosis - HIV proteins may activate CD4 on uninfected T-helpers -> inducing apoptosis and immunodepletion.

Question 8

Inhibitors of apoptosis

Answer 8

GFs, extracellular cell matrix, sex steroids, some viral proteins.

Question 9

Inducers of apoptosis

Answer 9

GF withdrawal, loss of matrix attachment, glucocorticoids, some viruses, free radicals, ionising radiation, DNA damage, ligand-binding at death receptors.

Question 10

Initiation of apoptosis

Answer 10

Extrinsic and intrinsic pathways, converge into a common effector pathways= activation of proteases and DNAses.

Question 11

The intrinsic pathway of apoptosis.

Answer 11

Integration of multiple pro- and anti-apoptotic members of the Bcl-2 family.

Bcl-2: inhibit factors that induce apoptosis.
Bax-bax dimer: enhances apoptotic stimuli.
Thus Bcl-2 Bax ration determines susceptibility.

Question 12

How does p53 work in apoptosis?

Answer 12

responds to DNA damage by stabilising the protein product of p53 gene.
P53 protein is multifunctional - induces cell cycle arrest and initiates DNA damage repair.

If unsuccessful, induces apoptosis via activation of Bcl-2.

Question 13

The extrinsic pathway of apoptosis.

Answer 13

Ligand binding by death-receptors.

Tumour necrosis factor receptors: TNFR1, Fas.

Binding promotes clustering of a signal transduction cascade= activates caspases. (Immune system eliminates lymphocytes that have self-antigens).

Question 14

The execution phase

Answer 14

Activation of caspases= proteases.

Normally present as pro-caspases.

1. Initiator caspases activated: caspase 8.
2. Activation of executioner caspases.
3. Caspase 3 DNAses= nucleus shrinks (pyknosis) and fragments (karyorrhexis).

Apoptotic bodies: dead cell not phagocytosed fragment into smaller membrane bound organelles.

Question 15

Why is there no inflammation to apoptosis?

Answer 15

Cell membrane is intact.

Question 16

Apoptosis in development

Answer 16

1. Interdigital cell death= separation of fingers. (syndactyly)
2. Dorsal part of the neural tube during closure, required to reach continuity (spina bifida)
3. Reproductive organ: Mullerian and Wolffian ducts.

Question 17

Necrosis

Answer 17

Death of tissues following bioenergetic failure and loss of plasma membrane integrity.

Induces inflammation and repair.

Causes include: ischaemia, metabolic, trauma.

Question 18

Coagulative necrosis

Answer 18

In most tissue, firm, pale area with ghost outline on microscopy.

Tissue texture is initially normal or firm, later becomes soft (digested by macrophages).

Question 19

Colliquative necrosis

Answer 19

Liquify - seen in brain. lack of supporting stroma. Site is marked by a cyst.

Question 20

Caseous necrosis

Answer 20

In TB - pale-yellow semi-solid material. Dead tissue is structureless.

Question 21

Gangrene

Answer 21

Necrosis with putrefaction due to vascular occlusion. BLACK= iron sulphide degradation from degraded Hb.

Question 22

Fibroid necrosis

Answer 22

Microscopic feature in arterioles in malignant hypertension.

Question 23

Fat necrosis

Answer 23

Trauma - cause a mass, or after pancreatitis as multiple white spots (due to lipases).

In the latter - pancreatic lipase= fat cells have their stores split into FAs + Ca2+= white soaps. HYPOCALCAEMIA can occur.

Question 24

Ischeamia and cell death

Answer 24

Failure of ATP production -> plasma membrane ion pumps are ineffective -> loss of homeostasis, influx of water= lysis and cell death

Question 25

Anaerobic conditions

Answer 25

Leads to acidosis -> promoting Ca2+ inflow.

Uptake by mitochondria exceeds the capacity for storage= disruption of the inner membrane. ATP production ceases and contents leak into the cytosol.

Question 26

How does reperfusion contributes to cell death?

Answer 26

Burst of ROS production.

Question 27

Proliferating cells and PARP

Answer 27

These cells are dependent on glycolysis -> leads to NAD depletion = ATP depletion, consequently necrosis.

Question 28

Calcium and cell death

Answer 28

Falling ATP levels - death channel-mediated calcium uptake - large increase= activation of calcium-dependent proteases/mitochondrial permeability transition.

Free radical damage to ER = calcium stores leak into the cytosol -> smaller rise = apoptosis.

Question 29

How do free radicals cause cell death?

Answer 29

Damage to lysosomal membranes -> proteases released (cathepsins) = damages other membranes.

Question 30

All these pathways lead to…

Answer 30

Rupture of plasma membrane -> spillage of contents = provoke an inflammatory response. (HSPs + purine metabolites).