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What are the types of cellular hypoxia?
What are possible causes of each?

Hypoxaemic - low arterial oxygen due to lung disease or reduced atmospheric concentration.

Anaemic - decreased ability of the blood to carry oxygen due to the anaemia or co poisoning

Ischaemic - interruption of blood supply to a region due to thrombus or shock

Histiocytic - inability of the cell to utilise oxygen due to poisoning such as cyanide, carbon dioxide or dinitrophenol

1

What are causes of cellular injury?

Hypoxia
Toxins
Immune response
Free radicals
Microorganisms
Dietary insufficiency or excess
Physical agent (heat, electricity, trauma etc.)

2

What reversible changes happen to a cell as it becomes hypoxic?Why?

Lack of oxidative phosphorylation
Fall in ATP
Loss of Na/K ATPase activity
Increased intracellular sodium and calcium and extra cellular potassium
Water follows osmotic gradient into cell causing blebbing of cytoplasm and swelling
Glycolysis increases to raise ATP resulting in lactic acid production lowering pH
This causes clumping of chromatin
Ribosomes detach decreasing protein synthesis

3

What are the irreversible changes of hypoxic cell injury including the DNA changes?

Cell death by swelling - oncosis
High calcium levels causing inappropriate activation of proteins (e.g. Proteases)
Pyknosis (chromatin shrinking)
Karyohexis (nucleus fragmentation)
Karyolysis (nucleus dissolution)

4

How can free radicles be created?

Radiation
Fenton reaction
Haber Weiss reaction

5

What are common mechanisms for cell damage other than hypoxia?

Membrane (including organelle) disruption
Nucleus
Proteins (enzymes and structural)
Mitochondria

6

What are the main mechanisms of free radical injury?

Lipid peroxidation - hydroxyl radical reacts with unsaturated hydrocarbon removing one hydrogen to create water. This radical lipid is then react with O2 creating an O2* side group. It can then react with a neighbouring chain creating a OOH side group and making the new chain a radical - this propagates on creating more radical chains.

DNA strand breaking and base alteration

Protein disulphide bridge formation by cysteine oxidation altering structure.

7

What is the mechanism of reperfusion injury?

Increase O2 for free radical production
Influx of inflammatory components such as neutrophils and complement

8

How do cells protect themselves from injury?

Heat shock proteins - mend or mark for degradation misfolded proteins e.g. Ubiquitin

ROS protection - SOD, catalase, glutathione, iron sequestration, antioxidants

9

Define necrosis

The morphological changes that occur after a cells has been dead for some time in a living organism.

10

What are the four main types of necrosis?

Coagulative - cell architecture preserved, proteins denatured
Liquifactive - cell degraded by own active enzymes
Caseous - tb - structureless debris form surrounded by granuloma
Fat - lipids released

11

What is gangrene? How can it be classified?

The clinical description of a mass of necrotic tissue

Dry - coagulative necrosis following arterial occlusion
Wet - liquifactive necrosis typically following infection
Gas - infection usually with Clostridium perfringens

12

What is infarction?

Necrosis resulting from ischaemia (thrombus, emboli, vessel twisting or external compression of vessel).

13

What are white and red infarcts?

White - occurs in solid organs on occlusion of an end artery - no haemorrhage can occur due to solid stroma.

Red - occurs in loose organs, on venous occlusion or where anastamoses or dual supply is present but insufficient to sustain the tissue. There can be haemorrhage into surrounding tissues.

14

How does potassium release cause damage to the heart?

danger around heart as it causes depolarisation towards threshold of myocytes raising the number of inactive vgNa channels slowing upstroke (and has the paradoxical effect of slowing conduction through HCN channels slowing heart rate)

15

What cell injury mechanisms can lead to hyperkalaemia around the heart?

Local - MI
Systemic - crush syndrome burns, tumour lysis sydrome

16

What toxins can be released from cells that die by oncosis?

Potassium
Enzymes (e.g CKMB, ALT)
Myoglobin

17

What is the main cause and effect of myoglobin release in cell injury?

Rhabdomyolysis - damage renal glomeruli causing acute kidney injury.

18

How does the process of apoptosis differ from oncosis?

Controlled
Few cells
Requires energy
Membrane integrity maintained
Ordered process

19

Give some examples of physiological apoptosis

Remodelling of an embryo
Distraction of a virus infected cell
Decreasing breast tissue after lactation

20

Give an example of pathological apoptosis

Parkinsons disease
Amylotrophic lateral sclerosis
Alzheimers

21

How is apoptosis initiated?

Intrinsic - DNA degradation or withdrawal of growth factors, increased mitochondrial permeability, release of cytochrome C, activation of capases

Extrinsic - binding of TRAIL to receptor, activates capases

22

How do cells degenerate in apoptosis?

Break into small membrane bound fragments called apoptotic bodies.

23

How are apoptotic bodies removed?

Phagocytosis by neighbouring cells or phagocytotic cells like macrophages.

24

What is the effector molecule of apoptosis?

Capases

25

What molecules accumulate in cells abnormally?

Lipids - fatty liver, xantholasma, athrosclerosis
Proteins - mallory hyaline in liver disease, misfolded proteins
Pigments - coal dust, tattooing ink, bilirubin, haemosiderin lipofusin

26

What are the two forms of calcification?

Malignant - raised serum calcium
Dystrophic - normal serum calcium

27

Why do cells age?

Telomeres shorten with every replication.

28

What is it termed when telomeres 'run out' for a cell?

Replicative senescence

29

What cells telomeres are immortal? Why?

Germ cells, some cancer cells
Telomerase enzyme