Cell Damage and Cell Death Flashcards
What are the genetic causes/mechanisms of cell death
Abnormal number chromosomes (aneuploidy)
Abnormal chromosomes (deletions/translocations)
Increased fragility (Fanconi’s anaemia)
Failure of repair (Xeroderma pigmentosa)
Inborn errors (Storage disorders ie. Tay Sachs disease)
What are the inflammatory causes/mech of cell death
Trauma
Thrombo-embolism
Atherosclerosis
Vasculitis
What are the physical causes/mech of cell death
Irradiation
Heat
Cold
Barotrauma
What are the chemical causes/mech of cell death
Acids/corrosives
Specific actions e.g. enzymes
Interference with metabolism e.g. alcohol
What are the causes/mech of infection on cell death
Toxic agents
Competition for nutrients
Intracellular replication
- viruses/mycobacteria provoking
an immune responseWhat are the causes/mech of traumatic damage on cell damage
Interruption of blood supply
Direct rupture of cells
Entry of foreign agents
What is barotrauma
Increased air/water pressure
What is metamorphosis
Process by which an animal physically develops after birth or hatching
What is necrosis and when does it occur
Cell injury which results in the premature death of cells in living tissue by autolysis
Occurs after stresses such as ischemia, trauma, chemical injury
What is apoptosis and what is it’s purpose
Programmed cell death.
Eliminates unwanted host cells by activation of a co-ordinated, internally programmed series of events effected by a dedicated set of gene products
What is autophagic cell death
Degradation of normal proteins in cellular remodeling (metamorphosis, aging + differentiation)
Digestion/removal of abnormal proteins ( if not = accumulate following toxin exposure, cancer, or disease)
Causes of necrosis
Usually caused by a lack of blood supply to cells/tissues Injury Infection Cancer Infarction Inflammation
Relationship between pH, pO2 and distance from vessel
As distance from vessel increases, the pH decreases and pO2 decreases (0 after around 200mm)
Describe 7 properties of necrosis
Whole of group of cells affected
Result of an injurious agent or event
Reversible events proceed irreversible
Energy deprivation causes changes (No ATP as no O2)
Cells swell due to influx of water (ATP required for ion transport)
Haphazard destruction of organelles + nuclear material by enzymes from ruptured lysosomes
Cellular debris stims inflammatory response
Describe nuclear changes in necrosis
Chromatin condensation/shrinkage
Fragmentation of nucleus
Dissolution of chromatin by DNAse
Describe the cytoplasmic changes in necrosis
Opacification: denaturation of proteins with 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 proteins such as myoglobin
Why are biochemical changes useful
These biochemical changes are useful in the clinic to measure the extent of tissue damage!
What is an astrocytoma - describe it’s spread
Brain tumour in cerebrum glial cells = astroycytes
Doesn’t spread out brain/spinal cord + does not usually effect other organs
What is the function of necrosis and what does a failure in this lead to
Removes damaged cells from an organism
Failure = may lead to chronic inflammation
Apoptosis - define and list what it’s involved in
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
Give 8 examples of apoptosis
Cell death in embryonic hand to form individual fingers
Apoptosis induced by growth factor deprivation
DNA damage-mediated apoptosis
Cell death in tumours causing regression
Cell death in viral diseases
Cell death induced by cytotoxic T cells
Death of neutrophils during an acute inflammatory response
Death of immune cells after depletion of CKs + autoreactive T cells in thymus
Survival due to
Growth factors
Cytokines
Cell-cell and/or cell-matrix contacts
Apoptosis due to
Death domain ligands
DNA damaging agents
Lack of growth factors
Disruption of c-c and/or c-m contacts
Describe intrinsic apoptosis
DNA damage – p53-dependent pathway Interruption of the cell cycle Inhibition of protein synthesis Viral Infection Change in redox state
Describe extrinsic apoptosis
Withdrawal of growth factors (e.g. IL-3)
Extracellular signals (e.g. TNF)
T cell or NK (Natural Killer) (e.g. Granzyme)
What are caspases
Cysteine Aspartate-specific Proteases
Role = initiation of apoptosis
Describe the intracellular proteolytic cascade
Active caspase X activates PC Y
Cleaves sites close to amine/carboxyl terminal domain
2 parts now form a dimer
AC Y formed
Caspase activation leads to what changes in cell
Morphological changes of cell: Shrinkage Chromatin condensation DNA fragmentation Plasma membrane blebbing
Describe the features of apoptosis
Single or few cells selected.
Programmed cell death.
Irreversible once initiated.
Events are energy driven.
Cells shrink as the cytoskeleton is disassembled.
Orderly packaging of organelles + nuclear fragments in membrane bound vesicles.
New molecules expressed on vesicle membranes stim phagocytosis = no inflammatory response
Describe the nuclear changes in apoptosis
Nuclear chromatin condenses on nuclear membrane
DNA cleavage
Describe the cytoplasmic changes in 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
Describe 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 and explain the role of TNF
TNF = tumour necrosis factor
FADD = fas-associated protein w/death domain = FADD = adaptor protein,
Bridges members of TNF
PC-8 activated = autoproteolysis
TNF induces the formation of a death-inducing signalling complex = DISC
What is cytochrome C
Mitochondrial matrix protein
Released in response to oxidative stress by “permeability transition”
Any inducers of the permeability transition also eventually induce apoptosis
Describe and explain the role of C-c
C-c binding site for APAF domain
Caspase recruitment domain binds protease domain (PC-9)
Cytochrome c induces the formation of a death-inducing complex
C-c release regulation
If cells receiving correct survival signals then PKB responds = then bad is phosphorylated thus inactive
When active = Bad outcompetes bcl-2 for bax binding
Intracellular stress leads to…
IS - transcription (e.g. by p53)
There is membrane insertion of bax
Death due to APAF/caspase-9
Describe the link between p53/apoptosis and cancer
Mutations in the p53 gene are the most common mutations in cancer
Some mutations destroy the ability of p53 to induce apoptosis
