Session 1

Question 1

What are the different causes of hypoxia?

Answer 1

Hypoxaemic - arterial content of O2 is low (eg altitude)
Anaemic
Ischaemic - interruption of blood supply
Histiocytic- inability to utilise O2 (eg cyanide poisoning)

Question 2

What are common methods of cell injury?

Answer 2

Hypoxia
Physical agents (trauma, heat, cold, radiation)
Chemical agents (poisons, alcohol, drugs)
Microorganisms
Immune mechanisms (autoimmune/hypersensitivity)
Dietary insufficiencies/excesses
Genetic abnormalities

Question 3

What are the targets for cell injury?

Answer 3

Cell membranes, nucleus, proteins, mitochondria

Question 5

Describe the reversible cell changes due to hypoxia

Answer 5

Production of ATP decreases. Activity of Na/K ATPase decreases, Na in the cell increases leading to swelling (oncosis).
Increased amount of glycolysis for ATP, decreasing pH through the production of lactic acid. Enzyme activity is affected and chromatin clumping is seen.
Ribosomes detach from the ER (usually requiring energy) and protein synthesis is depleted. Leads to accumulation of denatured proteins.

Question 6

Describe the irreversible changes due to hypoxia

Answer 6

Cells die by oncosis and tissues will appear necrotic.
There is an increase in membrane permeability leading to a massive increase in cytosolic Ca2+. Several enzymes are thus activated (ATPase, endonucleases, proteases, phospholipases).
Lysosomal membranes are damaged which leak enzymes and further damage cell.

Question 7

What is ischaemia reperfusion injury?

Answer 7

If blood flow is returned to an ischaemic tissue that is not yet necrotic the damage could be worse than if it wasn’t restored (eg more ROS produced)

Question 8

What is the function of heat shock proteins?

Answer 8

They are concerned with protein repair in injured cells. They either correct misfolded proteins or destroy them using ubiquitin.

Question 9

What are the structural changes of an injured cell seen under an electron microscope?

Answer 9

Reversible:
-swelling of cell and organelles due to Na/K pump failure
-Cytoplasmic blebs (bumps on membrane surface where cytoskeleton has detached)
-clumped chromatin due to reduced pH
-ribosome separation from ER
Irreversible:
-nuclear changes
-membrane defects
-appearance of myelin figures (damaged membranes)
-amorphous densities in swollen mitochondria

Question 10

What is oncosis?

Answer 10

Cell death with swelling. Commonly seen in hypoxia.

Question 11

What is apoptosis?

Answer 11

Cell death with shrinkage, self regulated

Question 12

What is necrosis?

Answer 12

The morphological changes that occur after a cell has died. Follows oncosis.

Question 13

What are the two morphological appearances a cell can take when dying?

Answer 13

Oncosis - Cell swells while nucleus fades away by karryolysis (dissolution). Plasma membrane rupture. Passive.
Apoptosis - cell shrinks while nucleus become very dense and breaks up. Membrane integrity preserved. Active.

Question 14

What are the different types of necrosis?

Answer 14

Coagulative and liquefactive (main) and caseous and fat.

Question 15

What is Coagulative necrosis and where is it seen?

Answer 15

Protein denaturation is the dominant feature over release of active enzymes. Denatured proteins then coagulate (solid white consistency). Cellular outline somewhat preserved. Seen in solid organs where there has been an infarct (eg heart).

Question 16

What is liquefactive necrosis and where is it seen?

Answer 16

Release of active enzymes is the dominant feature over protein denaturation. Tissue is lysed and disappears (liquifies). Seen in infarct of the brain and infections.

Question 17

What is caseous necrosis and where is it seen?

Answer 17

Characterised by amorphous (structure less) debris - “half way” between liquefactive and Coagulative. Particularly associated with infections - especially TB.

Question 18

What is fat necrosis and where is it seen?

Answer 18

Occurs when there is a destruction of adipose tissue, such as in acute pancreatitis where there is a realise of lipases and in direct trauma to fatty tissue (eg breast).

Question 19

What is gangrene and what are the different types?

Answer 19

Clinical term for grossly visible necrosis.
Dry gangrene - necrotic tissue modified by air, Coagulative, eg umbilical cord after birth.
Wet gangrene - infected necrotic tissue, can lead to septicaemia, liquefactive
Gas gangrene - wet gangrene that has become infected by clostridium perfringens, producing visible bubbles of gas

Question 20

What are the two different types of infarct and where are they found?

Answer 20

White - occurs in solid organs after occlusion to an end artery (e.g. Heart, spleen and kidneys). Most are wedge shaped and appear as Coagulative necrosis.
Red - occurs when there is extensive haemorrhage into dead tissue (e.g. Gut, lung). Due to a dual blood supply, numerous anastomoses or venous insufficiency.

Question 21

What can cause an infarct?

Answer 21

Thrombus/embolism (most) or external compression or twisting of vessels.

Question 22

What does the consequences of an infarct depend on?

Answer 22

Alternative blood supply
How quickly the ischaemia occurred
How vulnerable the tissue is to hypoxia
The oxygen content of the blood

Question 23

What are the principal molecules released by an injured cell?

Answer 23

Potassium - stops heart in high concentrations
Enzymes - indicates the organ involved and extent of injury
Myoglobin - from dead myocardium/striated muscle

Question 24

What are the methods of hydroxyl production?

Answer 24

Radiation, Fenton and Haber-Weiss reactions

Question 25

What happens to DNA during apoptosis?

Answer 25

Characteristic, non random cleavage

Question 26

Where can apoptosis occur physiologically?

Answer 26

Cells no longer needed are removed to provide a steady state
During hormone controlled involution
In cytotoxic T cell killing of damaged cell
Embryogenesis

Question 27

Describe the changes that occur to a cell during apoptosis

Answer 27

Cells are shrunken and eosinophillic. Chromatin condensation and fragmentation is seen. Cells show cytoplasmic budding (not blebbing) which progresses to fragmentation into apoptic bodies which are removed by macrophages. No leakage of cell contents occurs so does not induce inflammation.

Question 28

Outline the 3 stages of apoptosis

Answer 28

Initiation - apoptosis triggered either by intrinsic (mitochondrial) or extrinsic (receptor mediated) mechanisms.
Execution
Degradation/phagocytosis

Question 29

List some important apoptopic molecules

Answer 29

p53 - the guardian of the genome - mediates apoptosis in response to DNA damage
Caspases - effector molecules of apoptosis
APAF1, cytochrome C, caspase 9 - form the apoptosome which activates various caspases
Death Ligands and receptors - eg TRAIL and TRAIL-R

Question 30

What are the main abnormal cellular accumulations seen when metabolic processes fail with injury?

Answer 30

Water and electrolytes - eg in cell injury
Lipids
Proteins
Pigments
Carbohydrates

Question 31

What is the name of when TAGs accumulate in the liver and what are the causes?

Answer 31

Liver steatosis, due to alcohol abuse, DM, obesity and toxins.

Question 32

What are two conditions that result in excess protein accumulation?

Answer 32

Mallory’s hyaline - seen in alcoholic liver disease
Alpha 1 anti trypsin deficiency - liver produces abnormally folded protein which cannot be packaged in the ER. Systemic defiance of this enzyme means elastin in the lung is not inhibited, leading to emphysema.

Question 33

What are examples of cellular accumulations of exogenous pigments?

Answer 33

Coal dust - leads to blackened lung tissue (anthracosis) and coal workers pneumoconiosis (fibrous) as the macrophages phagocytose pigments.
Tattooing

Question 34

What are examples of cellular accumulations of endogenous pigments?

Answer 34

Lipofuscin - brown pigment seen in aging cells
Haemosiderin - yellow/brown Fe storage molecule formed during excess Fe e.g. Bruising
Bilirubin - when bile flow is obstructed, levels in blood increase

Question 35

What is dystrophic and metastatic calcification and where do they occur?

Answer 35

Both examples of pathological calcification - abnormal deposition of Ca in tissues.
Dystrophic - occurs in areas of dying tissue, atherosclerotic plaques and TB lymph nodes. No abnormality in Ca metabolism.
Metastatic - systemic hypercalcaemia

Question 36

What causes replicative senescence?

Answer 36

Telomeres shorten with each replication until they can no longer divide. Germ cells, stem cells and cancer cells produce the enzyme telomerase which allows the cells to divide indefinitely.