Mechanisms of Disease II Flashcards
Functions 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
Causes of Necrosis
• Usually lack of blood supply, e.g. – injury, – infection, – cancer, – infarction, – inflammation diagram
Necrosis step by step
- Result of an injurious agent or event.
(Whole groups of cells are affected.) - 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
diagram
Microscopic appearance of necrosis overview
Nuclear Changes
- Chromatin condensation/shrinkage.
- Fragmentation of nucleus.
- Dissolution of the chromatin by DNAse.
image
Microscopic appearance of necrosis in detail
Cytoplasmic Changes
- Opacification: protein denaturation & aggregation.
- Complete digestion of cells by enzymes causing cell to liquify (liquefactive necrosis).
Biochemical Changes
1. Release of enzymes such as creatine kinase or lactate dehydrogenase
2. Release of other proteins such as myoglobin
These biochemical changes are useful in the clinic to measure the extent of tissue damage!
ASTROCYTOMA
images of kidnesy normal vs necrotic
Functions of Apoptosis
• 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
Apoptosis step by step
- 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.
Microscopic appearance of Apoptosis 1
Cytoplasmic Changes
- 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.
Morphological features of apoptosis
images
Microscopic appearance of Apoptosis 2
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
DNA Fragmentation
images
Revision slide- e.g.’s of apoptosis
- Cell death in embryonic hand to form individual fingers.
- Apoptosis induced by growth factor deprivation (neuronal death from
lack of NGF). - DNA damage-mediated apoptosis. If DNA is damaged due to radiation or
chemo therapeutic agents, p53 (tumour suppressor gene product) accumulates.
This arrests the cell cycle enabling the cell to repair the damage. If repair
process fails, p53 triggers apoptosis. - Cell death in tumours causing regression.
- Cell death in viral diseases (ie viral hepatitis).
- Cell death induced by cytotoxic T cells (ie. Cellular immune rejection or vs. host disease).
- Death of neutrophils during an acute inflammatory response.
- Death of immune cells( both T and B lymphocytes) after depletion of cytokines
as well of death of autoreactive T cells in the developing thymus.
e.g. of metamorphosis
Tadpole’s tail lost by apoptosis - images
interdigital web loss, mouse paw development and humans (syndactyly)
Revision slide- 2 types of apoptosis
Intrinsic: • DNA damage – p53-dependent pathway • Interruption of the cell cycle • Inhibition of protein synthesis • Viral Infection - i.e. once virus is in the cell • Change in redox state
Extrinsic: - relative to the cell not the body
• Withdrawal of survival factors e.g. mitogens
• Extracellular signals (e.g. TNF)
• T cell or NK (Natural Killer) (e.g.Granzyme).
Caspases
• Caspases are the point of convergence for causes of apoptosis, e.g. extrinsic and intrinsic causes = caspases = apoptosis
• Caspases are cysteine proteases
(cysteine aspartate-specific proteases)
• Caspases form an activation cascade, where one cleaves and activates the next (analogous to kinase cascades)
Caspase activation
diagram
Caspase cascade
diagram
Death by a thousand cuts
• Hundreds of substrates for activated caspases
• Substrates fall into most classes of important genes
table
Effect of Caspase Activation
Caspase activation leads to characteristic morphological changes, such as shrinkage, chromatin condensation, DNA
fragmentation and plasma membrane blebbing. diagrams
Intrinsic and extrinsic cell death
- Extrinsic apoptosis (a little)
2. Intrinsic apoptosis (a lot)
How do we activate the initiator caspases?
Extrinsic and intrinsic causes = caspases = apoptosis
• Initiator caspases activate themselves when in close proximity
• Activation, therefore, means bringing initiator caspases together
Extrinsic Apoptosis
• Induced by ligand binding to receptors, causing receptor dimer- (or multimer-) isation
LIGAND-INDUCED
MULTIMERISATION: THE PLAYERS
diagrams
EXAMPLE: TNF - diagrams
Intrinsic Apoptosis
• Induced by cytochrome c released from
mitochondria
• Note: growth factor withdrawal (extrinsic
apoptosis) an exception that uses cytochrome c… (see later)
Cytochrome C
- Mitochondrial matrix protein
- Known for many years to be released in response to oxidative stress by a “permeability transition”
- Any inducers of the permeability transition also eventually induce apoptosis.
CYTOCHROME C-INDUCED
APOPTOSIS: THE PLAYERS
diagrams
CYTOCHROME C RELEASE
diagram
HOW IS THE RELEASE OF
CYTOCHROME C FROM THE
MITOCHONDRIA REGULATED?
diagrams
IF BCL-2 FAMILY PROTEINS REGULATE CYTOCHROME C RELEASE FROM MITOCHONDRIA, WHAT REGULATES BCL-2 PROTEINS?
diagrams
