1 - Cell Injury and Cell Death Flashcards
Why does cell injury occur
If cells are exposed to a mild injurious agent/stress (change in environ or increase in demand) they may be able to adapt but if the agent exceeds the cells adaptive capacity cell injury will occur. Cell injury may be reversible or not and lead to cell death
What are 6 causes of cell injury?
- Physical injury - trauma, heat, radiation, decrease O2,
- Chemical injury - pH, free radicals, O2 changes, poison
- Biological injury - factors released from micro-organisms, factors released from IS, infection, lack of growth factors
- Immunological Injury - hypersensitivity due to autoimmune reactions
- Genetic Derangements - inherited genetic malformation i.e. congenital malformations or change in genetics that influences how susceptible the cell is to injury
- Nutritional Imbalances - protein or calorie deficiencies, anorexia, excess lipid or cholesterol leading to atherosclerosis. It can also alter how cells respond to injury
Summary (flow diagram) of the effects of stress and cell injury on individual cells
Injury/ Stress Stimuli
> Decrease in ATP = Loss of energy dependent functions
> Membrane Damage > Mitochondria =
Decrease in ATP and cell death
> Lysosome =
Enzymatic digestion of cellular components
> Plasma =
Loss of cellular components
> Increase in intracellular Ca = Protein break down and DNA damage
> Increase in reactive oxygen species = Protein breakdown and DNA damage
Does cell injury impact one cell component?
No, when injured/stressed a stimulus often targets and affects several cellular components rather than one isolated part of the cell. This is known as synergistic events. All diseases involve some type of cell injury
How does a decrease in ATP production affect cells and how does it occur?
- Occurs in cell injury by a decrease in O2, damage to enzymes in the cytoplasm and damage to mitochondria
- Decrease in ATP available to enzymes the repair DNA and proteins
- Less ATP to ATP driven membrane ion pump; important to control the ionic/osmotic homeostasis in cells and organelles. If these pumps are less active then water and Na will accumulate in the cells/organelle causing swelling. Intracellular Ca will increase causing damage to cellular components by signalling destructive enzymes
- Less ATP for protein synthesis and causes ribosomes ro detach from the ER
- Decrease in ATP available to enzymes the repair DNA and proteins
How does damage to cell membranes occur and how does it affect cells?
Damaged by ROS/free radicals, low oxygen/hypoxia, membrane targeting bacterial toxins, failure of the Ca pump
- Plasma:
- Loss of cellular components (proteins, enzymes, RNA), loss of osmotic balance due to solutes moving and in/outflux of ions
- transmembrane pumps injured OR function inhibited by drop in ATP causing disruption to osmotic balance - Lysomes:
- Leakage of enzymes into cytoplasm and digestion of cellular components (autolysis) causing the cell to become red and homogenous - Decrease in membrane phospholipids as phospholipase are activated during cell injury as well as a decrease in ATP decreasing lipid synthesis
- Mitochondria:
- Damage results in the formation of non-selective high conductance channels in the inner membrane i.e. the Mitochondria Permeability Transition and this removes the transmembrane potential needed for ox phos to occur.
- allows leakage of cytochrome c into the cytosol which primes the cell for apoptosis (its loss from the mito also causes and decrease in ox phos and so ATP production)
How does an increase in cytosolic Ca occur and affect cells?
May be release from extracellular, ER, mitochondria. Increase in cell due to a decrease in activity of the membrane Ca pump. Destructive enzymes are then activated
- ATPases - further depleting ATP
- Phospholipase’s - damage to lipid components in membrane causing more Ca release)
- Proteases - membrane and cytoskeletal breakdown
- Endonucleases - damage DNA
What are free radicals/ROS?
Is a secondary form of injury in cells exposed to stressors
They are reactive molecules with an unpaired free electron in the outer orbit which release energy through reactions with adjacent molecules. An accumulation of these causes oxidative stress.
They are generated by radiation, metabolism of chemicals, O2 toxicity, inflammation, repurfusion (lack blood and suddenly comes back) and normal metabolism
Hyperplasia
When glandular epithelium needs to do more work so increases the cell number
What do cells undergoing autolysis look like?
Red and homogenous due to denatured proteins and chewed up DNA as are destroyed by own cells enzymes
Acute Inflammation
The body’s NON-SPECIFIC response to cell injury
How do free radicals cause injury to cells?
- Attack double bonds in unsaturated fatty acids so disturbs membranes (membrane potential/cellular components
- Oxidises amino acids side chains so decreases enzyme function
- Reacts with thymine to cause DNA damage
This initial damage leads to autocatalytic reactions where molecules they react with are converted in to ROS themselves and chain of damage is propagated
How to protect against free radicals?
Cells have defensive mechanisms in place to prevent injury from ROS’s. Antioxidants (Vit E, A, C…) and enzymes such as catalase.
How does damage to proteins occurs and how does it affect cells?
Can be injured directly by free radicals or increase in Ca dependent proteases, but also by a decrease in protein synthesis by depletion of ATP. May also be damaged by GLYCATION as occurs in diabetes. Damage to cytoskeletal proteins may detach the membrane from the cell/cytoskeleton
How does damage to DNA occur and affect cells?
Ionising radiation (X/gamma rays) - break chemical and DNA bonds UV radiation - structural changes in DNA bases which may lead to cell death (sunburn) Chemicals, ROS, genetic causes, nutritional deficiencies of B12/folic acid. Cells have evolved repair enzymes as DNA is constantly damaged
Signalling pathways initiate the cells response to injury by sensing the degree of damage. This is often accompanied by the activation of … AND …
Heat Shock Factors and Stress Kinases
What are heat shock factors?
Heat shock factors are transcription factors that induce expression of heat shock proteins which are molecular chaperones; they bind to damaged proteins, help refold and hold the protein together until they can be repaired.
Stress Kinases?
For example p38 MAP kinase and Jun N-Terminal Kinase.
These initiate phosphorylation signalling cascades that co-ordinate and amplify (more enzymes involved at each stage) a cell’s response to damage. Specific damage activates specific cascades.
- p53; DNA damage and STOPS cell division to allow repair or will induce suicide
- BMF; damage to actin cytoskeleton
- BIM; damaged microtubules
- Bad; inadequate stimulation by growth factors
When may a cell show an adaptive response?
Mild injurious agent or mild stress - increased workload, altered environment, chronic irritant. Adapt to allow the cell to continue to function without being injured despite the stress or change in enviorment
What are the 3 adaptive responses?
Hypertrophy/hyperplasia, Atrophy and Metaplasia
Hypertrophy/hyperplasia
Hypertrophy refers to an increase in the SIZE of cells, hyperplasia is an increase in the number of cells especially in glandular epithelium in order to make more substance. Is in a response to increased functional demand and stimulation. Intracellular signalling pathways are stimulated and activate lots of cellular genes. Hyperplasia involves the division of cells as well as STEM cells that move into the adapting tissue from BONE MARROW
Atrophy
Due to decrease in functional demand, nutrients, growth factors, stimulation through nerves and results in cell SHRINKAGE (atrophy). Involves proteolytic systems like lysosomes (autophagy - cellular components digested) and a cellular destruction machine called ubiquitin-proteasome pathway
Metaplasia
Reversibly changing from one cell type to another when a type of cell is better able to withstand the adverse environment.
E.G. oesophagus exposed to ^ gastric acid then the stratified epithelium will be replaced by reprogrammed stem cells into glandular epithelium to better withstand the environment
Results from reprogramming the stem cells via signals of growth factors and ECM components. The reprogrammed stem cells then differentiate along a new pathway via complex molecular cascades
When does cell death occur
Injury/stress is too severe or persist too long and the cell has an inability to reverse damage.
