Mechanisms of disease - cell damage and cell death Flashcards
What is necrosis?
Exists to removes damaged cells from an organisms
Failure to do so, may lead to chronic inflammation
- necrosis will cause acute inflammation to clear the cell debris
What are the causes of necrosis?
Lack of blood supply…
- Following injury
- Following infection
- Cancer
- Infarction
- inflammation
What is the process of necrosis?
- Result of 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 (as no ATP to work ion pumps)
- Lysosomes rupture - enzymes degrade other organelles and nuclear material hapzadly
- Cellular debris released, triggering inflammation
What are the changes which happens during necrosis?
Nuclear changes:
- Chromatin condenses/shrinks
- Fragmentation of nucleus
- Dissolution of chromatin by DNAs
Cytoplasmic changes
- Opacification - protein denaturation and aggregation (opaque to white)
- Complete digestion of cells by enzymes causing cell to liquify
Biochemical changes
- Release of enzymes such as creatine kinase or lactate dehydrogenase
- Release of other proteins such as myoglobin
What is apoptosis?
Selective process for the deletion of superfluous, infected or transformed cells
Involved in:
- Embryogenesis
- Metamorphosis
- Normal tissue turnover
- Endocrine-dependent tissue atrophy
What are some key points about apoptosis?
- Programmed cell death of one or few cells - very selective
- Events are irreversible and energy 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 different changes that happen during apoptosis?
Cytoplasmic changes:
- Shrinkage of cell, organelles packaged into membrane vesicles
- Cell fragmentation, membrane bound vesicles bud off
- Phagocytosis of cell fragments by macrophages and adjacent cells
- No leakage of cytosolic components
Nuclear changes
- Nuclear chromatin condenses on nuclear membrane
- DNA cleavage
Biochemical changes
- Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)
- Protein cleavage by proteases, caspases
What are some examples of apoptosis?
- Cell death in embryonic hand to form individual fingers
- Apoptosis induced by growth factor deprivation
- DNA damage-mediated apoptosis - TP53 will accumulate enabaling the cell to repair itself, of if this fails triggers apoptosis
- Cell death in viral diseases
- Cell death in tumours causing regression
- Death of neutrophils during an acute inflammatory response
What are the 2 types of apoptosis?
Intrinsic
- DNA damage
- interruption of the cell cycle
- inhibition of protein synthesis
- vrial infection (once the virus is in the cell)
- change in redox state
Extrinsic (of the cell, not body)
- withdrwal of survival factors like mitogens
- extracellular signals like TNF
- T cell or NK
What are caspases?
They are a family of cysteine proteases that serve as primary effectors during apoptosis to dismantle cellular sturctures
What is the activation cascade of caspases?
They form an activation cascade, where each one cleaves and activates the next
Initiator caspase activate themselves when in close proximity
Activation, therefore, means bringing initiator caspase together
What is the result of caspase activation?
Caspase activation leads to shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing
What happens during extrinsic apoptosis?
- Induced by ligand binding to receptors - which causes receptor dimerization
- Death-inducing signalling complex (DISC) is assembled from procaspase-8, FADD, and the tumour necrosis factor receptor and the tumour necrosis factor itself
- TNF is bound to the receptor, which has brought together death domains into close proximity which creates a environment which dimerization is favoured
- High concentration of FADD, which then recruit procaspase-8
Autoproteolysis leads to activation of procaspases –> caspase 8
What happens during intrinsic apoptosis?
Induced by cytochrome c released from mitochondria
Cytochrome C = mitochondrial matrix protein
- Released in response to oxidative stress by a permeability transition
- Anything that induces permeability transition of mitochondria will induce apoptosis
How is the release of cytochrome C from the mitochondria regulated?
BCL-2 family proteins form the pore through which cytochrome C is released
Can either be:
- anti-apoptotic
- Repress cytochrome c release
- pro-apoptotic
- Facilitate cytochrome c release
What regulates BCL-2 proteins?
Gene expression
