Lecture Seven: Cell Injury And Irreversible Effects: Death Flashcards
What does oncosis result from
Massive trauma
What is the term given to regulated cell death?
Programmed cell death
What is oncosis/necrosis?
Cell death due to massive trauma
List the morphological changes that occurs with oncosis
Cell and organelle swelling
Membrane permeabilisation and lysis
Leakage of intracellular components -> inflammation
Repair of tissue by scarring
What is necroptosis
Programmed cell death
Which is initiated in a regulated way
Shows morphological features of necrosis
Describe necroptosis
- Death ligands (e.g. TNF and FasL) signal through their receptors (TNFR1, Fas) and the RIP1/3 protein kinases
- leads to mitochondrial dysfunction, generation of ROS, lipase activation
What is TNF
Tumour necrosis factir
What are Necrostatins
Compounds which inhibit RIP1 kinase activity
Suppress cell death, inflammation and loss of function after ischaemia or traumatic brains injury
What is Pyrpotosis
Pro inflammatory suicide mechanism leading to cell lysis
Occurs to
- prevent replication if intracellular bacteria
- alert others of immune system to the presence of pathogens
Describe the pyroptosis process
Products from pathogenic bacteria in macrophages activat inflammasomes.
These activate inflammatory capase1 protease leading to cell lysis
What type of suicide mechanism is pyroptosis?
Pro-inflammatory
Why does pyroptosis occur?
- prevents replication of intracellular bacteria
- alerts other cells of immune system to the presence of pathogens
What is apoptosis
Cell suicide
What does apoptosis do?
Removes cells that are excess to requirements,
old and due to be turned over or
damaged
How does apoptosis proceed?
Via Cell rounding, shrinkage, fragmentation
Maintenance of membrane and organelle integrity
Either engulfment of apoptotic bodies by resident phagocytes with no tissue damage or inflammation OR
If the phagocytes are overwhelmed, apoptosis proceeds by membrane disintegration and release of cellular contents and inflammation
What is autophagic cell death
Cells that kill themselves by ingesting themselves
How does autophagic cell death work?
Vacuoles with double membranes enclose the cytoplasm or organelles in the cytoplasm
These fuse with lysosomes to generate autolysosomes in which the acidic hydroplanes degrade the contents (incl. inner membrane)
What is the function of autophagic cell death?
Remove mis folded and potentially toxic proteins and damaged organelles
Degrading disposable components to generate energy and metabolises for essential protein synthesis (in deprived cells)
Sustains cell viability
What does massive autophagic vacuolisation lead to?
Cell death
Injury to, or occlusion of an artery may cause what?
Ischaemia, hypoxia or anoxia
What is ischaemia
Loss of blood flow
What is hypoxia
Reduced tissue oxygen concentrations
What is anoxia
Effective lack of oxygen
What happens after ischaemia/hypoxia/anoxia?
Oxidative phosphorylation ceases and cell relies in anaerobic glycolysis for its ATP requirements
Describe the cascade of events that may lead to cell death
- Reduced ATP –> reduced Na+/K+ ion exchanger —> increased intracellular Na+ concentration
- glycolysis activated, generates lactic acid & decreases cytoplasmic pH
- activates Na+/H+ exchanger –> Na+ enters cell
- Elevated [Na+] activates Na+/Ca2+ exchanger –> Ca2+ accumulates
- Redcued [ATP] –> Reduced Ca2+ efflux pump activity –> [Ca2+] not adequately controlled
- Ca2+ dependent phospholipases are activated –> Fatty acids & lisophospholipids released –> Damage membranes
- Ca2+ dependent proteases cleave cytoskeletal components –> further damaging membranes
- Cell lyses
- Spilled cellular contents –> induce inflammation
what are lipophospholipids also known as?
detergents
name some Ca2+ dependent proteases
calpain,
cathespin
What can apoptotic death be induced by?
- Engagement of death ligands with their receptors (TNF with TNFR1 & Fas with Fas)
- Damage to DNA
- Absence of growth survival factors
- Loss of cell adhesion to ECM which activates anoikis (an apoptotic process)
- Stresses that activate P53
What does anoikis mean
homelessness
What stresses activate p53?
DNA damage, hypoxia, oxidative stress
What do signals which induce apoptotic death activate?
Intracellular proteases INCLUDING apoptotic caspases which initiate celldeath pathways
apoptotic caspases are different from inflammatory caspases
How do apoptotic caspases initiate celldeath pathways?
- Activated death receptors (e.g. Fas) recruit Fas-associated death domain adaptor protein that assembles and activates initiator caspases
- DNA dmage induces multiprotein complex in nucleus in which an initiator caspase is activated
-These signal & other apoptotic signals –> pore openings in outer mt membrane.
This allows proteins (Cytochrome C in intermembrane space) to be released.
This activates apoptotic protease-activating factor-1 and a CASPASE CASCADE
What is FADD
Fas-associated death domain
what is Apaf-1
apoptotic protease-activating factor-1
How are caspases stored in cells?
They are stored as inactive precurosrs called zymogens
How are caspases activated?
By oligomerisation and proteolytic cleavage
How do caspases degrade substrate proteins
Caspases have active site cysteins
they degrade substrate proteins by cleaving them after aspartate
What are excutioner or effector caspases?
Caspases that ultimately excute apoptosis
What signals do apoptotic cells release?
ATP and PS signals
What is PS?
Phosphtidylserine
a signals released by apoptotic cells which induce eat me responses
Where is PS normally expressed
on the inner face of the plasma membrane
Where is PS not expressed on apoptotic cells?
On the outer surface of the plasma membrane
What type of cells phagocytose apoptic bodies?
Neighbouring epithelial cells, macrophages
What macrophage functions are suppressed when they phagocytose apoptic bodies?
Macrophage inflammatory functions
What do macrophages release (when phagocytosing apoptic bodies)
- less pro-inflammatory TNF
2. More anti-inflammatory TGFβ
What is TNF
Tumour necrosis factor
What is TGFβ
Transforming growth factor β
List situations Where loss of normal apoptosis occurs
- Autoimmune diseases
- Cancers
How does loss of normal apoptosis occur in auto immune diseases?
Lymphocytes which react against self antigens are not destroyed when they should be
How does loss of apoptosis occur in cancers?
Cells accumulate becahse they have a reduced ability to undergo apoptosis
List situations where excessive apoptosis may occur
Acute ischaemic injury (Myocaridal infarcts and strokes)
Chronic heart failure:cardiomyocyte loss
Chronic neurodegeneration
Pancreatic isle β-cells in diabetes
Lymphocytes in HIV-AIDS
What is Necrosis
The structural change that follows extensive cell death
Which pathways contribute to necrotic lesions?
Oncotic and necrotic pathways
programmed celldeath (Necroptosis) pathways
Name the types of necrosis arising from ischaemia
Coagulative
Colliquative (liquefactive)
Gas gangrene
Dry gangrene
Where is coagulative necrosis commonly seen?
with myocardial infarcts
Describe coagulative necrosis
Firm dead tissue
initially retaining general architecture
In coagulative necrosis, What is necrotic tissue removed by?
an inflammatory reaction
In coagulative necrosis, what is the necrotic tissue replaced by?
a scar
What may happen to large infarcs in coagulative necrosis?
They may be inaccessible to inflammatory cells
they may persist for years/
When does colliquative (liquefactive) necrosis occur?
After cerebral artery occlusion
Explain the process of colliquative necrosis
Lysosomal hydrolases are released
these digest the brain tissue to a protein rich gel
the Glial cells then react to form a cyst
What does brain tissue lack?
A supporting intercellular stroma
When does gas gangrene occur?
When deep wounds sever the blood supply and allows the growth of the soil anaerobe Clostridium perfringens
How does gas gangrene work
Soil anaerobe grows on wounds due to severed blood supply
Releases α toxin (which is a phospholipase) which destroys cells
This leads to putrefaction (rotting)
Affected tissues feel crepitant
They have CO2 bubbles
They turn black
Describe crepitant
crackly
What do affected tissues in gas gangrene turn black
haemoglobin is degraded
ion sulfide deposited
Where does dry gangrene occur
In limbs where arteris are slowly and progressively narrowed
List some situations which may lead to dry gangrene
Atherosclerosis
diabetes
nicotine from tobacco smoking
how does mummification occur in dry gangrene
ischaemia leads to tissue necrosis with desiccation
Why does black discolourisation occur in dry gangrene?
discolourisation Occurs from the breakdown of blood
which type of necrosis are associated with infections?
liquefactive suppurative necrosis
caseous necrosis
How does liquefactive suppurative necrossis occur?
with bacterial infections
neutrophil hyddrolases liquefy tissue, forming an ABSCESS (such as a boil)
How does caseous necrosis occur
Tuberculous granulomas contain central necorsos composed of the remains of chronic inflammtory and tissue cells and bactera.
The dead cells persist as amorphous, lipid and protein rich debris (cheese like)
What is caseous necrosis associated with?
tuberculosis
Necrosis following injury releases what type of enzymes?
lipid - degrading
What does fat necrosis occur with?
injury to adipose tissue and acute haemorrhagiv pancreatitis
Describe the process of fat necrosis
Proteases and phosphlipases are released and digest cell membranes
lipases digest intracellular triglycerides.
The fatty acids which are rleased then precipiate with Ca2+ to form white opaque patches (soaps)
