Lecture Seven: Cell Injury And Irreversible Effects: Death Flashcards

1
Q

What does oncosis result from

A

Massive trauma

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2
Q

What is the term given to regulated cell death?

A

Programmed cell death

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3
Q

What is oncosis/necrosis?

A

Cell death due to massive trauma

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4
Q

List the morphological changes that occurs with oncosis

A

Cell and organelle swelling
Membrane permeabilisation and lysis
Leakage of intracellular components -> inflammation
Repair of tissue by scarring

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5
Q

What is necroptosis

A

Programmed cell death
Which is initiated in a regulated way
Shows morphological features of necrosis

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6
Q

Describe necroptosis

A
  • 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
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7
Q

What is TNF

A

Tumour necrosis factir

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8
Q

What are Necrostatins

A

Compounds which inhibit RIP1 kinase activity

Suppress cell death, inflammation and loss of function after ischaemia or traumatic brains injury

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9
Q

What is Pyrpotosis

A

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
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10
Q

Describe the pyroptosis process

A

Products from pathogenic bacteria in macrophages activat inflammasomes.

These activate inflammatory capase1 protease leading to cell lysis

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11
Q

What type of suicide mechanism is pyroptosis?

A

Pro-inflammatory

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12
Q

Why does pyroptosis occur?

A
  • prevents replication of intracellular bacteria

- alerts other cells of immune system to the presence of pathogens

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13
Q

What is apoptosis

A

Cell suicide

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14
Q

What does apoptosis do?

A

Removes cells that are excess to requirements,
old and due to be turned over or
damaged

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15
Q

How does apoptosis proceed?

A

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

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16
Q

What is autophagic cell death

A

Cells that kill themselves by ingesting themselves

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17
Q

How does autophagic cell death work?

A

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)

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18
Q

What is the function of autophagic cell death?

A

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

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19
Q

What does massive autophagic vacuolisation lead to?

A

Cell death

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20
Q

Injury to, or occlusion of an artery may cause what?

A

Ischaemia, hypoxia or anoxia

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21
Q

What is ischaemia

A

Loss of blood flow

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22
Q

What is hypoxia

A

Reduced tissue oxygen concentrations

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23
Q

What is anoxia

A

Effective lack of oxygen

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24
Q

What happens after ischaemia/hypoxia/anoxia?

A

Oxidative phosphorylation ceases and cell relies in anaerobic glycolysis for its ATP requirements

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25
Describe the cascade of events that may lead to cell death
1. Reduced ATP --> reduced Na+/K+ ion exchanger ---> increased intracellular Na+ concentration 2. glycolysis activated, generates lactic acid & decreases cytoplasmic pH 3. activates Na+/H+ exchanger --> Na+ enters cell 4. Elevated [Na+] activates Na+/Ca2+ exchanger --> Ca2+ accumulates 5. Redcued [ATP] --> Reduced Ca2+ efflux pump activity --> [Ca2+] not adequately controlled 6. Ca2+ dependent phospholipases are activated --> Fatty acids & lisophospholipids released --> Damage membranes 7. Ca2+ dependent proteases cleave cytoskeletal components --> further damaging membranes 8. Cell lyses 9. Spilled cellular contents --> induce inflammation
26
what are lipophospholipids also known as?
detergents
27
name some Ca2+ dependent proteases
calpain, cathespin
28
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
29
What does anoikis mean
homelessness
30
What stresses activate p53?
DNA damage, hypoxia, oxidative stress
31
What do signals which induce apoptotic death activate?
Intracellular proteases INCLUDING apoptotic caspases which initiate celldeath pathways apoptotic caspases are different from inflammatory caspases
32
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
33
What is FADD
Fas-associated death domain
34
what is Apaf-1
apoptotic protease-activating factor-1
35
How are caspases stored in cells?
They are stored as inactive precurosrs called zymogens
36
How are caspases activated?
By oligomerisation and proteolytic cleavage
37
How do caspases degrade substrate proteins
Caspases have active site cysteins they degrade substrate proteins by cleaving them after aspartate
38
What are excutioner or effector caspases?
Caspases that ultimately excute apoptosis
39
What signals do apoptotic cells release?
ATP and PS signals
40
What is PS?
Phosphtidylserine a signals released by apoptotic cells which induce eat me responses
41
Where is PS normally expressed
on the inner face of the plasma membrane
42
Where is PS not expressed on apoptotic cells?
On the outer surface of the plasma membrane
43
What type of cells phagocytose apoptic bodies?
Neighbouring epithelial cells, macrophages
44
What macrophage functions are suppressed when they phagocytose apoptic bodies?
Macrophage inflammatory functions
45
What do macrophages release (when phagocytosing apoptic bodies)
1. less pro-inflammatory TNF | 2. More anti-inflammatory TGFβ
46
What is TNF
Tumour necrosis factor
47
What is TGFβ
Transforming growth factor β
48
List situations Where loss of normal apoptosis occurs
- Autoimmune diseases | - Cancers
49
How does loss of normal apoptosis occur in auto immune diseases?
Lymphocytes which react against self antigens are not destroyed when they should be
50
How does loss of apoptosis occur in cancers?
Cells accumulate becahse they have a reduced ability to undergo apoptosis
51
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
52
What is Necrosis
The structural change that follows extensive cell death
53
Which pathways contribute to necrotic lesions?
Oncotic and necrotic pathways programmed celldeath (Necroptosis) pathways
54
Name the types of necrosis arising from ischaemia
Coagulative Colliquative (liquefactive) Gas gangrene Dry gangrene
55
Where is coagulative necrosis commonly seen?
with myocardial infarcts
56
Describe coagulative necrosis
Firm dead tissue initially retaining general architecture
57
In coagulative necrosis, What is necrotic tissue removed by?
an inflammatory reaction
58
In coagulative necrosis, what is the necrotic tissue replaced by?
a scar
59
What may happen to large infarcs in coagulative necrosis?
They may be inaccessible to inflammatory cells they may persist for years/
60
When does colliquative (liquefactive) necrosis occur?
After cerebral artery occlusion
61
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
62
What does brain tissue lack?
A supporting intercellular stroma
63
When does gas gangrene occur?
When deep wounds sever the blood supply and allows the growth of the soil anaerobe Clostridium perfringens
64
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
65
Describe crepitant
crackly
66
What do affected tissues in gas gangrene turn black
haemoglobin is degraded ion sulfide deposited
67
Where does dry gangrene occur
In limbs where arteris are slowly and progressively narrowed
68
List some situations which may lead to dry gangrene
Atherosclerosis diabetes nicotine from tobacco smoking
69
how does mummification occur in dry gangrene
ischaemia leads to tissue necrosis with desiccation
70
Why does black discolourisation occur in dry gangrene?
discolourisation Occurs from the breakdown of blood
71
which type of necrosis are associated with infections?
liquefactive suppurative necrosis caseous necrosis
72
How does liquefactive suppurative necrossis occur?
with bacterial infections neutrophil hyddrolases liquefy tissue, forming an ABSCESS (such as a boil)
73
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)
74
What is caseous necrosis associated with?
tuberculosis
75
Necrosis following injury releases what type of enzymes?
lipid - degrading
76
What does fat necrosis occur with?
injury to adipose tissue and acute haemorrhagiv pancreatitis
77
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)