Medsci 203 - Cell Death And Irreversible Effects

Front 1

Oncosis/Necrosis (unregulated)

Back 1

→ 'accidental death' following trauma causing:
1. cell/organelle swelling
2. leakage of intracellular components; inflammation via macrophages
3. tissue repair via fibroblasts

Front 2

Necroptosis (Regulated)

Back 2

→ death ligands (tumour necrosis factor TNFα and FasL) signal via receptors (TNFR1 and Fas) which signal through protein kinases (RIP1) that lead to:
1. mitchondrial dysfunction
2. ROS production
3. lipase activation
→ displays morphological features of necrosis

Front 3

Necrostatins

Back 3

→ inhibits RIP1 kinase activity - they occur following ischaemic and traumatic injury to suppress cell death, inflammation and loss of brain function

Front 4

Pyroptosis

Back 4

→ occurs in presence of intracellular infections that activate inflammasomes and protease caspase-1 (inactivates regulation - overall necrosis)
→ this leads to cell lysis and inflammation
→ purpose of pyroptosis is to:
1. prevent bacterial proliferation
2. alert other immune cells for pathogenic presence

Front 5

Apoptosis (Highly Regulated)

Back 5

→ removes old, dying or damaged cells that are in excess, proceeds via:
1. cell rounding, shrinkage (pyknosis) and fragmentation to produce apoptotic bodies
2. maintains cell/organelle integrity
→ the remnant cell is dealt with in 2 different manners:
1. phagocytes engulf the apoptotic bodies without inflammation
2. if there is excess apoptotic bodies in ratio to present phagocytes, then no phagocytosis occurs and results in membrane disintegration with release of cellular content + inflammation

Front 6

Autophagy (Regulated)

Back 6

→ appearance of double membrane enclosed vacuoles - containing cytoplasm/organelles (autophagosomes)
→ autophagosomes fuse with lysosomes = autolysosomes
→ acidic lysosomal hydrolases degrade cell contents (including inner membrane)
→ purpose of autophagy is to remove misfolded proteins and damaged organelles, but also sustains cell viability by degrading disposable components for nutrients
→ excess autophagic vacuolisation = cell death

Front 7

Mechanism of Necrosis/Oncosis

Back 7

→ caused by ischemia, hypoxia or anoxia, therefore cease of oxidative phosphorylation = no anaerobic glycolysis = no ATP
→ cascade of events occur:
1. ↓ ATP = ↓ Na+/K+ ATPase activity = ↑ intracellular Na+
2. ↑ glycolysis = ↑ lactic acid = ↓ cytoplasmic pH
3. activates Na+/H+ exchanger = Na+ enters cell
4. ↑ Na+ = Na+/Ca2+ exchanger to be activated = ↑ Ca2+ in cell
5. ↓ ATP = ↓ Ca2+ efflux pump = Ca2+ conc. are not properly controlled
6. Activation of Ca2+ dependent phospholipases = ↑ fatty acids + lyso-phospholipids (detergents) = they damage membrane
7. Activation of Ca2+ dependent proteases (calpain, cathepsins) = cleave cytoskeletal component = damage membrane
8. cell lyses = cell contents spill = inflammation

Front 8

Differentiate between ischemia, hypoxia and anoxia

Back 8

→ ischemia is loss of blood flow
→ hypoxia is reduced tissue oxygen concentrations
→ anoxia is the effective lack of oxygen

Front 9

Factors that induce apoptosis

Back 9

1. engagement of death ligands (TNF, FasL) with death receptors (TNFR1, Fas) - resulting in recruitment of Fas-associated death domain (FADD) adaptor protein + proteolytic enzymes (initiator caspase)
2. DNA damage → induces multi protein complex in nucleus to activate the initiator caspase
3. absence of growth/survival factors
4. loss of epithelial cell adhesion to ECM → anoikis (homelessness)
5. stress activates p53

Front 10

What happens when apoptosis is induced?

Back 10

→ these signals allow for the opening of pores in outer mitochondrial membrane to allow release of death proteins (+ cytochrome c), cytochrome c in cytoplasm = cell killer
→ these activate apoptotic protease-activating factor-1 (Apaf-1) and an effector caspase cascade

Front 11

Caspases

Back 11

→ usually stored in cells as inactive precursors (zymogens)
→ they are activated via oligomerisation and proteolytic cleavage
→ they contain cysteine active sites and degrade substrate protein by cleaving aspartate

Front 12

What is the final stage of apoptosis?

Back 12

→ they release a 'find me' (ATP) signal and display 'eat me' (phosphatidylserine, PS) signals
→ apoptotic cells express PS on outer face unlike normal cells that have it in the inner face
→ apoptotic bodies are phagocytosed by macrophages = suppresses inflammation:
1. release less pro-inflammatory TNF (tumour necrosis factor)
2. release more anti-inflammatory TGFβ (transforming growth factor β)

Front 13

Inadequate Apoptosis

Back 13

→ autoimmune diseases - lymphocytes will have no effect on antigens; they are not eliminated
→ neoplastic diseases (cancers) - cells accumulate as they have reduced ability to undergo apoptosis

Front 14

Excessive Apoptosis

Back 14

→ occur in acute ischaemic injury to the heart (infarctions) + brain (strokes)
→ chronic heart failure = cardiomyocyte (ongoing apoptosis)
→ chronic neurodegeneration = Alzheimers, Parkinson's
→ loss of β-cells in pancreatic islets (diabetes)

Front 15

Coagulatative Necrosis via Ischaemia

Back 15

→ arises following myocardial infarctions where dead tissue remain firm, with initially good architecture
→ they are removed by inflammatory reactions = scarring
→ large infarcts may be inaccessible to inflammatory cells = persist for years

Front 16

Colliquative (liquefactive) Necrosis via Ischaemia

Back 16

→ follows cerebral artery occlusion; released lysosomal hydrolases digest brain tissue to a protein rich gel
→ glial cells react to form a cyst (solid fluid filled cavity)

Front 17

Gas Gangrene via Ischaemia

Back 17

→ occur when deep wounds sever blood supply = growth of soil anaerobe (Clostridium perfringens)
→ α toxin (phosphlipase) destroys cells = putrefaction
→ affected tissue will feel crepitant (crackly) + CO2 bubbles, turn black as haemoglobin is degraded + iron sulfide deposited

Front 18

Dry Gangrene via Ischaemia

Back 18

→ occurs in slow limbed arteries = atherosclerosis
→ ischemia leads to necrosis, dessication and de-colourisation

Front 19

Liquefactive Supperative (pus forming) Necrosis via Infection

Back 19

→ occurs with bacterial infections; neutrophil hydrolyases liquefy tissue = abscess forms (boil)

Front 20

Caseous Necrosis via Infection

Back 20

→ associated with tuberculosis; Tuberculous granulomas have central necrotic tissue = dead cells persist as cheese like debris

Front 21

Fat Necrosis via Injury

Back 21

→ injury to adipose tissue + acute haemorrhagic pancreatitis
→ released lipid digesting enzymes (proteases and phospholipases) digest cell membrane and intracellular triglyceride
→ fatty acids released with Ca2+ form white soaps