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
Q

Describe the cascade of events that may lead to cell death

A
  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
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26
Q

what are lipophospholipids also known as?

A

detergents

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27
Q

name some Ca2+ dependent proteases

A

calpain,

cathespin

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28
Q

What can apoptotic death be induced by?

A
  • 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
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29
Q

What does anoikis mean

A

homelessness

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30
Q

What stresses activate p53?

A

DNA damage, hypoxia, oxidative stress

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31
Q

What do signals which induce apoptotic death activate?

A

Intracellular proteases INCLUDING apoptotic caspases which initiate celldeath pathways

apoptotic caspases are different from inflammatory caspases

32
Q

How do apoptotic caspases initiate celldeath pathways?

A
  • 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
Q

What is FADD

A

Fas-associated death domain

34
Q

what is Apaf-1

A

apoptotic protease-activating factor-1

35
Q

How are caspases stored in cells?

A

They are stored as inactive precurosrs called zymogens

36
Q

How are caspases activated?

A

By oligomerisation and proteolytic cleavage

37
Q

How do caspases degrade substrate proteins

A

Caspases have active site cysteins

they degrade substrate proteins by cleaving them after aspartate

38
Q

What are excutioner or effector caspases?

A

Caspases that ultimately excute apoptosis

39
Q

What signals do apoptotic cells release?

A

ATP and PS signals

40
Q

What is PS?

A

Phosphtidylserine

a signals released by apoptotic cells which induce eat me responses

41
Q

Where is PS normally expressed

A

on the inner face of the plasma membrane

42
Q

Where is PS not expressed on apoptotic cells?

A

On the outer surface of the plasma membrane

43
Q

What type of cells phagocytose apoptic bodies?

A

Neighbouring epithelial cells, macrophages

44
Q

What macrophage functions are suppressed when they phagocytose apoptic bodies?

A

Macrophage inflammatory functions

45
Q

What do macrophages release (when phagocytosing apoptic bodies)

A
  1. less pro-inflammatory TNF

2. More anti-inflammatory TGFβ

46
Q

What is TNF

A

Tumour necrosis factor

47
Q

What is TGFβ

A

Transforming growth factor β

48
Q

List situations Where loss of normal apoptosis occurs

A
  • Autoimmune diseases

- Cancers

49
Q

How does loss of normal apoptosis occur in auto immune diseases?

A

Lymphocytes which react against self antigens are not destroyed when they should be

50
Q

How does loss of apoptosis occur in cancers?

A

Cells accumulate becahse they have a reduced ability to undergo apoptosis

51
Q

List situations where excessive apoptosis may occur

A

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
Q

What is Necrosis

A

The structural change that follows extensive cell death

53
Q

Which pathways contribute to necrotic lesions?

A

Oncotic and necrotic pathways

programmed celldeath (Necroptosis) pathways

54
Q

Name the types of necrosis arising from ischaemia

A

Coagulative

Colliquative (liquefactive)

Gas gangrene

Dry gangrene

55
Q

Where is coagulative necrosis commonly seen?

A

with myocardial infarcts

56
Q

Describe coagulative necrosis

A

Firm dead tissue

initially retaining general architecture

57
Q

In coagulative necrosis, What is necrotic tissue removed by?

A

an inflammatory reaction

58
Q

In coagulative necrosis, what is the necrotic tissue replaced by?

A

a scar

59
Q

What may happen to large infarcs in coagulative necrosis?

A

They may be inaccessible to inflammatory cells

they may persist for years/

60
Q

When does colliquative (liquefactive) necrosis occur?

A

After cerebral artery occlusion

61
Q

Explain the process of colliquative necrosis

A

Lysosomal hydrolases are released

these digest the brain tissue to a protein rich gel

the Glial cells then react to form a cyst

62
Q

What does brain tissue lack?

A

A supporting intercellular stroma

63
Q

When does gas gangrene occur?

A

When deep wounds sever the blood supply and allows the growth of the soil anaerobe Clostridium perfringens

64
Q

How does gas gangrene work

A

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
Q

Describe crepitant

A

crackly

66
Q

What do affected tissues in gas gangrene turn black

A

haemoglobin is degraded

ion sulfide deposited

67
Q

Where does dry gangrene occur

A

In limbs where arteris are slowly and progressively narrowed

68
Q

List some situations which may lead to dry gangrene

A

Atherosclerosis

diabetes

nicotine from tobacco smoking

69
Q

how does mummification occur in dry gangrene

A

ischaemia leads to tissue necrosis with desiccation

70
Q

Why does black discolourisation occur in dry gangrene?

A

discolourisation Occurs from the breakdown of blood

71
Q

which type of necrosis are associated with infections?

A

liquefactive suppurative necrosis

caseous necrosis

72
Q

How does liquefactive suppurative necrossis occur?

A

with bacterial infections

neutrophil hyddrolases liquefy tissue, forming an ABSCESS (such as a boil)

73
Q

How does caseous necrosis occur

A

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
Q

What is caseous necrosis associated with?

A

tuberculosis

75
Q

Necrosis following injury releases what type of enzymes?

A

lipid - degrading

76
Q

What does fat necrosis occur with?

A

injury to adipose tissue and acute haemorrhagiv pancreatitis

77
Q

Describe the process of fat necrosis

A

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)