Apoptosis & Necrosis Flashcards
Define apoptosis
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.
Apoptosis is activated or prevented by…
Variety of intracellular and extracellular stimuli.
What does reduced apoptosis lead to?
Cell accumulation; i.e. neoplasia.
What does increased apoptosis lead to?
Atrophy
Characteristics of apoptosis
Energy-dependent
Biochemically specific
Enzymatic digestion of nuclear and cytoplasmic contents, followed by the phagocytosis of breakdown products. The cell membrane is still INTACT.
Necrosis
Unintended cell death in response to cellular injury.
What sort of cell death is seen in AIDS?
Apoptosis - HIV proteins may activate CD4 on uninfected T-helpers -> inducing apoptosis and immunodepletion.
Inhibitors of apoptosis
GFs, extracellular cell matrix, sex steroids, some viral proteins.
Inducers of apoptosis
GF withdrawal, loss of matrix attachment, glucocorticoids, some viruses, free radicals, ionising radiation, DNA damage, ligand-binding at death receptors.
Initiation of apoptosis
Extrinsic and intrinsic pathways, converge into a common effector pathways= activation of proteases and DNAses.
The intrinsic pathway of apoptosis.
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.
How does p53 work in apoptosis?
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.
The extrinsic pathway of apoptosis.
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).
The execution phase
Activation of caspases= proteases.
Normally present as pro-caspases.
- Initiator caspases activated: caspase 8.
- Activation of executioner caspases.
- Caspase 3 DNAses= nucleus shrinks (pyknosis) and fragments (karyorrhexis).
Apoptotic bodies: dead cell not phagocytosed fragment into smaller membrane bound organelles.
Why is there no inflammation to apoptosis?
Cell membrane is intact.
Apoptosis in development
- Interdigital cell death= separation of fingers. (syndactyly)
- Dorsal part of the neural tube during closure, required to reach continuity (spina bifida)
- Reproductive organ: Mullerian and Wolffian ducts.
Necrosis
Death of tissues following bioenergetic failure and loss of plasma membrane integrity.
Induces inflammation and repair.
Causes include: ischaemia, metabolic, trauma.
Coagulative necrosis
In most tissue, firm, pale area with ghost outline on microscopy.
Tissue texture is initially normal or firm, later becomes soft (digested by macrophages).
Colliquative necrosis
Liquify - seen in brain. lack of supporting stroma. Site is marked by a cyst.
Caseous necrosis
In TB - pale-yellow semi-solid material. Dead tissue is structureless.
Gangrene
Necrosis with putrefaction due to vascular occlusion. BLACK= iron sulphide degradation from degraded Hb.
Fibroid necrosis
Microscopic feature in arterioles in malignant hypertension.
Fat necrosis
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.
Ischeamia and cell death
Failure of ATP production -> plasma membrane ion pumps are ineffective -> loss of homeostasis, influx of water= lysis and cell death
