Mechanisms of Disease II - Cell Death and Cell Damage Flashcards
What is the function of necrosis
Removes damaged cells from an organism
Failure to do so may lead to chronic inflammation
Necrosis causes acute inflammation to clear cell debris via phagocytosis
What causes necrosis
Usually lack of blood supply as a result of:
- injury
- infection
- cancer
- infarction
- inflammation
Describe the step-by-step process of necrosis
- Result of an injurious agent or event.
- Initial events are reversible, later ones are not.
- Lack of oxygen prevents ATP production.
- Cells swell due to influx of water (ATP is required for ion pumps to work).
- Lysosomes rupture; enzymes degrade other organelles and nuclear material hapzardly
- Cellular debris released, triggering inflammation
What are the nuclear changes in necrosis
- Chromatin condensation/shrinkage.
- Fragmentation of nucleus.
- Dissolution of the chromatin by DNAse
What are the cytoplasmic changes in necrosis
- Opacification: protein denaturation & aggregation.
- Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis).
What are the biochemical changes in necrosis
- Release of enzymes such as creatine kinase or lactate dehydrogenase
- Release of other proteins such as myoglobin
These biochemical changes are useful in the clinic to measure the extent of tissue damage!
What is Apoptosis and what are its functions
Selective process for the deletion of superfluous, infected or transformed cells.
Involved in:
- Embryogenesis
- Metamorphosis
- Normal tissue turnover
- Endocrine-dependent tissue atrophy
- A variety of pathological conditions
Describe the step-by-step process of Apoptosis
- Programmed cell death of one or a few cells.
- Events are irreversible and energy (ATP) dependent.
- Cells shrink as the cytoskeleton is disassembled.
- Orderly packaging of organelles and nuclear fragments into membrane bound vesicles.
- New molecules are expressed on vesicle membranes that stimulate phagocytosis without an inflammatory response.
What are the cytoplasmic changes of Apoptosis
- Shrinkage of cell. Organelles packaged into membrane vesicles.
- Cell fragmentation. Membrane bound vesicles bud off.
- Phagocytosis of cell fragments by macrophage and adjacent cell.
- No leakage of cytosolic components.
What are the nuclear changes in Apoptosis
- Nuclear chromatin condenses on nuclear membrane.
- DNA cleavage.
What are the biochemical changes in Apoptosis
- Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)
- Protein cleavage by proteases, caspases
Describe how normal, apoptic and necrotic DNA would look like in DNA fragmentation
Normal - No banding
Apoptic - distinct bands visible
Necrotic - Smear like banding pattern
What are some examples of Apoptosis
Metamorphosis - Tadpole’s tail is lost
Interdigital web loss in mouse paw development
What are the two types of apoptosis
Intrinsic:
DNA damage – p53-dependent pathway
Interruption of the cell cycle
Inhibition of protein synthesis
Viral Infection
Change in redox state
Extrinsic:
Withdrawal of survival factors e.g. mitogens
Extracellular signals (e.g. TNF)
T cell or NK (Natural Killer) (e.g. Granzyme).
What are caspases
Caspases are cysteine protease
Caspases are the point of convergence for causes of apoptosis.
They form an activation cascade, where one cleaves and activates the next (analogous to kinase cascades)