Etiology, injury and cell death (I) Flashcards
What can a cell do during stress?
Respond to stimuli and trigger adaptation mechanisms
Is cell death always a pathological condition?
No there can also be physiological death
What is path-physiologic death of cells?
Outcome of cell damage or missed adaptation to injurious stimuli
What is physiologic cell death?
Intrinsic property of normal cells underlying tissue regulation
What is necrosis?
Accidental cell death
What is apoptosis?
Regulated cell death
What are the two types of cell death?
Necrosis
Apoptosis
What does irreversible injury of cells lead to?
Cell death
2 models for cell death
Conversion model
Competition model
What is the conversion model?
All or nothing
What is the competition model?
Signals promoting and inhibiting cell death start at the same time
What kind of cell death are the conversion and competition model relevant for?
Both apoptosis and necrosis
Different name for accidental cell death
Passive necrosis
What is passive necrosis?
Pathological event not controlled or modified by the cell
What causes passive necrosis?
Severe exogenous/endogenous injury
What can cause passive necrosis?
Chemical
Physical
Biological
External factors
Why does passive necrosis typically involve a group of cells?
Because it is random and caused by an external factor
What characterises passive necrosis?
Massive protein denaturation (like by lowering pH)
ATP depletion
Cell and organelle swelling
Increased membrane permeability
What does increased membrane permeability cause?
Leakage of the intracellular content (damp) which causes inflamation
Is apoptosis an inflammatory trigger?
No
Why is apoptosis not an inflammatory trigger?
Because there is compartmentalisation, there is no damage in the membran and no leakage of intracellular content
What cleans up after apoptosis?
Phagocytes clean up the fragments
What cleans up after necrosis?
Macrophages and Nucleophiles which cause inflammation
What is the main event of passive necrosis?
Irreversible cell damage
Measuring levels of which enzyme in the blood can show signs of necrosis?
LDH
Why can LDH levels show signs of necrosis?
Because it typically lives inside the cell which means that if high levels are detected in the blood there is tissue damage somewhere
What is coagulative necrosis caused by?
Massive protein denaturation
Where does coagulative necrosis often happen?
In tissue with singular vascularisation
What causes caseous necrosis?
Massive protein denaturation in lungs
What causes colliquative necrosis?
Protein lysis
What causes pyogenic infection?
Bacteria
What is the key event of necrosis?
Fall of ATP
What happens with the fall of ATP?
Loss of energy to maintain the hydro-osmotic equilibrium and cell membrane integrity
What does osmotic imbalance cause?
Cells to swell
What does the influx of Ca2+ cause?
Over activation of enzymes that cause lipid degradation which causes membrane degradation
Where does the influx of Ca2+ come from?
ER and mitochondria
What is apoptosis useful for?
Eliminate damaged and infected cells through the activation of a genetic program
Can the same stimuli that trigger necrosis also trigger apoptosis?
Yes, depends on intensity and length of stimuli
What is apoptosis important to prevent?
Overreactive T cells
What happens to T-cells that bind with high affinity to self epitope antigen-MHC complexes?
Apoptosis
Does apoptosis involve a group of cells
Not always, can be very specific to one single cell
2 pathways of apoptosis singalling
Extrinsic pathway
Intrinsic pathway
Which apoptosis signalling pathway is receptor dependant ?
Extrinsic
What activates the intrinsic pathway of apoptosis signalling?
Intracellular signals from the mitochondria and damage of DNA
Different name for the intrinsic pathway of apoptosis signalling?
Mitochondrial pathway
What is the active form of cell death and why?
Apoptosis, because it requires ATP
What do all forms of extrinsic pathway death have?
Death domain
Different name for the extrinsic pathway of apoptosis
Receptor mediated
Receptors used in the extrinsic pathway of apoptosis
Fas and FasL (ligand)
Does the extrinsic pathway of apoptosis always trigger apoptosis?
No it can also trigger adapting proteins which trigger survival
Which immunological phenomena are Fas-FasL mediated apoptosis involved with?
Homeostasis of T-cells
Cytotoxic activity of T-cells
Immune-privilege
Neoplastic cells
Why is it important for apoptosis to control immune responses?
To avoid inflammation
What is MOMP?
Mitochondrial outer membrane permeability
Which effector protein is found in apoptosome complex?
CASPASE 9
Which phases of the extrinsic and intrinsic pathways are the same?
The effector phases
What does p53 do?
Stop reproduction of cells if there is DNA damage
Example of diseases associated with inhibition of apoptosis
Cancer
Autoimmune
Glomerulonephritis
Viral infections
Example of diseases associated with excessive stimulation of apoptosis
AIDS
Neurogenerative disorders
Myelodysplastic syndromes
Damage from schema
Toxic liver disease
What is programmed Necrosis?
Mix between necrosis and apoptosis
Necrosis, but regulated
Different name for programmed necrosis
Necroptois
What is PARP?
Poly ADP-ribose polymerase
Is there inflammation in necroptosis?
Yes
What is the result of necroptosis the same as?
Necroses, there is a disruption of cell membrane and inflammation
What is the biological meaning of autophagy?
To degrade cellular components that don’t work like unfolded proteins
Produce energy
3 steps of autophagy
Nucleation
Formation of a vesicle
Maturation
Name of the vesicle formed in autophagy
Autophagosome
Is autophagy and apoptosis independant processes?
No
What happen when the apoptotic pathway fails?
The cell might trigger alternative death process like for example autophagy
2 things that can trigger autophagy
Nutrient deprivation
Depletion of growth factors
What is inhibited during nutrient deprivation?
mTOR
Can autophagy produce energy?
Yes
Does autophagy need ATP to start?
Yes
What way of death happens if ATP is present?
Apoptosis or autophagy
Types of programmed cell death
What is pyroptosis?
capase-1-dependant cell death subroutine
What does pyroptosis amplify?
Inflammation
What is entosis?
Cell death when 3 specific conditions are met
What happens during the pyknosis phase of necrosis?
hyper chromatic nuclei are shrunk compared to normal cell
What is the karyorrhexis phase of necrosis?
The random degradation of DNA
What is the karyolysis phase of necrosis?
Complete loss of intracellular nuclei and DNA has been released due to activity of the endonuclease
What is coagulative necrosis caused by?
Massive protein denaturation
Example of coagulative necrosis
Cardiac myocyte during ischemic insult
What is the cause of coagulative necrosis in ischemic insult?
Protein denaturing dur to lowering of intracellular pH
What happens to the tissue texture in ischemic insult?
Texture is conserved which makes it difficult to distinguish living cells and necrotic cells
What is the main difference in necrotic cells and living cells in coagulative necrosis caused by ischemic insult?
The absence of DNA due to absence degradation caused by necrosis
What is liquefactive necrosis due to?
Causes are not completely clear
Protein lysis
Lack of extracellular matrix makes it possible that disruption of tissue is faster than repair
What is fat necrosis due to?
Triglyceride hydrolysis mediated by the release of lipolytic enzymes of the pancreas
Example of would could cause triglyceride hydrolysis to trigger fat necrosis?
Trauma or pancreatitis
What is the key event in necrosis?
Decrease of concentration of ATP in the intracellular space
What is necrosis typical during?
Ischemic injuries where oxygen supply is interrupted and cells cannot perform respiration as it decreases the synthesis of ATP
What happens as consequence of the concentration of ATP decreasing during necrosis?
Hydro-osmotic equilibrium is completely lost
Permeability to selective ions is lost
Does necrosis involve a specific cut of DNA?
No
What does selective ion permeability require?
Energy consumption (ATP)
Membrane integrity
Ion channel efficiency
Structural integrity (cytoskeleton)
What is ischemia?
Restriction in blood supply causing shortage of oxygen and nutrients
What happens to the control of calcium and sodium during ischemic cell death?
Loss of control in them between cell and extracellular space
What does the disfunction of the sodium pump during ischemic cell death cause?
Inability to diffuse
Loss of osmotic balance which causes cell to swell
What does the influx of calcium into the cell during ischemic cell death cause?
Over activation of enzymes that cause lipid degradation which causes membrane degradation and loss of permeability
Where does the influx of calcium come from in ischemic cell death?
ER and mitochondria
Can osmotic catastrophe be counteracted in patient with hyperglycaemia?
No
Does programmed/regulated cell death require energy?
Yes
7 types of programmed cell death
Apoptosis
Mitotic catastrophe
Paraptosis
Autophagy
Programmed necrosis
Condroptosis
Accelerated senscence
What kind of phenomenon is Apoptosis?
Physiologic
What is apoptosis important in?
Regulation of embryogenisi, cell turnover in high proliferating tissues (ex. epidermis), in intestine its crucial to maintain number of cells (homeostatic condition) and restore some dysfunctions
Why is apoptosis important during inflammation?
Because it controls the activity of macrophages and neutrophils
What is the signal that activates apoptosis called?
Priming
Is there inflammation during apoptosis, why/why not?
No because there is no damage to the cell membrane
Why does the cell shrink during apoptosis?
Water and electrolyte leakage
What eliminates apoptotic bodies?
Phagocytes
What cleaves DNA in apoptosis?
Ca/mg dependant endonuclease and degradation of chromatin-associated proteins by protease
How does phagocytes recognise apoptotic bodies?
Exposure of thrombopadin, vitronecting and phosphatidylserine (flip-flop)
What is the main executor of the apoptotic action?
Capases
What kind of enzyme is camases?
Zymogen enzyme
4 phases of apoptosis
Initiating the signal
Control the integration
Common executive phase (between the 2 phases)
Removal of the dead cells (apoptotic bodies)
What is the phagocytosis of apoptotic bodies called?
Efferocytosis
Differen name for the extrinsic pathway of apoptosis
Receptor dependant
What activates the extrinsic pathway of apoptosis?
Interaction of extracellular membrane receptors w/their specific ligands which activates intracellular signalling pathway that actives the program controlling apoptosis
Death signals of the extrinsic pathway of apoptosis
FAS
TNFR
TRAIL receptors (TRI-4)
How can FasL exist?
In soluble form or integrated into the plasma membrane of killing cells
What are the main target for cells carrying FasL?
Fas expressing cells
What happens when the cells carrying FasL interacts with Fas expressing cells?
Fas expressing cells are killed
What is FADD?
Fas death domain
What does pro caspase-8 turn into when activated?
Active capase-8
What 4 immunologic are Fas-FasL mediated apoptosis involved in?
Homeostasis of T-cells
Cytotoxic activity of T-cells
Immune-privilege
Neoplastic cells
