L1 4 Mar 2019

Question 1

Cell injury, hallmark molecular and cellular triggers

Answer 1

1. reduced ATP synthesis/mitochondrial damage
2. loss of calcium homeostasis –> calcium influx
3. disrupted membrane permeability
4. free radical production

Question 2

free radical

Answer 2

• chemical species that have a single unpaired electron in an outer orbit; unpaired electrons are highly reactive and affect adjacent molecules, such as inorganic or organic chemicals - proteins lipids, carbohydrates, nucleic acids…
• some of these reactions are autocatalytic - whereby molecules that react with free radicals are themselves converted into free radicals

Question 3

Heat shock response genes

Answer 3

Heat shock response proteins, aka, chaperones; large group of genes, upregulated with cell stressors. serve to protect proteins from stress related damage and clean up damaged proteins from cell

Question 4

pre-stressing tissues/organs

Answer 4

use of pharmocological inhibitors -> to protect surrounding tissue, could activate heat shock proteins and/or activate survival pathways – adaptation, hasn’t gone to irreversible injury

Question 5

reactive oxygen species

Answer 5

• type of oxygen derived free radical
• produced normally during mitochondrial respiration and energy generation
• produced in excess by activated leukocytes

Question 6

oxidative stress

Answer 6

condition when cells have too much ROS

Question 7

hypoxaemia

Answer 7

oxygen problems, altitude sickness; haemoglobin problems - anaemia (could be genetic: sickle cell anaemia)

Question 8

oxidative phosphorylation inhibition

Answer 8

chemical poisoning -> blocks electron transport chain

Question 9

Is recovery possible?

Answer 9

after ischaemia/lack of O2 - outcomes vary between different cell/tissue types, main determinant is TIME

Question 10

reperfusion

Answer 10

restoration of blood flow, but!!! sudden reperfusion = increase ROS, free radicals = = reperfusion injury

Question 11

coagulative necrosis

Answer 11

• most common
• cell dead but tissue structure exists
• most cases - necrotic cells removed by inflamm. cells
• dead cell region may regenerate or be replaced by fibrosis (scars)

Question 12

liquefactive necrosis

Answer 12

• commonly due to large invasion by neutrophils - forms abscess
• e.g. ischaemic necrosis in the brain
• result in complete dissolution of necrotic tissue
• high ROS and protease release/conc.

Question 13

caseous necrosis

Answer 13

• accumulation of amorphous debris in area of necrosis
• no more tissue structure but still solid (not liquid)
• Usually associated with granulomatous inflammation of tuberculosis and some fungal infections

Question 14

infarction (red/haemorrhagic)

Answer 14

• venous occlusion
• loose/floppy tissue
• previously congested (fluid)

Question 15

white infarction

Answer 15

arterial occlusion

Question 16

apoptosis

Answer 16

• energy dependent
• physiological
• triggered by: lack of growth stimuli (growth factors), death signals (TNF and Fas), DNA damage (DNA damage sensing factors, e.g. p53)

Question 17

apoptosis - cell morphology and gross molecular changes

Answer 17

• cytoplasm shrinks (no membrane rupture)
• blebbing of plasma and nuclear membranes
• cell contents are membrane bound - no inflammation
• DNA cleaved at specific sites (200bp frags)

Question 18

extrinsic apoptosis

Answer 18

1. target cell is infected, tumour or damaged cytotoxic t cell with FasL attaches to Fas
2. adaptor proteins initiator caspases
3. executioner caspases lead to endonuclease activation and breakdown of cytoskeleton
4. cytoplasmic bleb becomes…
5. apoptotic body - gets eaten by phagocyte

Question 19

intrinsic apoptosis

Answer 19

1. cell injury
2. BCL2 family sensors and then effectors to mitochondria
3. CYTOCHROME C
4. initiator caspases activate executioner caspases
5. endonuclease activation and breakdown of cytoskeleton
6. cytoplasmic bleb becomes apoptotic body
7. gets eaten by phagocyte

Question 20

regulation of apoptosis

Answer 20

anti-apoptotic proteins (e.g. BCL2) and also activation of sensors - apoptotic (e.g. Bim)

Question 21

unfolded protein response and ER stress

Answer 21

decreases protein synthesis, increase chaperone production –> mature folded protein

Question 22

autophagy

Answer 22

cell eats itself, leads to either: autophagic survival or autophagic cell death (more likely)

Question 23

pyknosis

Answer 23

condensation of chromasomes

Question 24

karyorrhexis

Answer 24

fragmentation of nucleus

Question 25

karyolysis

Answer 25

complete dissolution of nucleus

Question 26

morphological features of reversible injury

Answer 26

intact cell structure and nucleus, stimulus is removed = return to normal

Question 27

morphological features of irreversible injury

Answer 27

no nucleus, loss of tissue architecture (ECM), cell will die, loss of function + lots of inflammation

Question 28

hypoxia induced effects

Answer 28

Question 29

production of ROS and pathologic effects

Answer 29

• produced due to cell injury, radiation, toxins and reperfusion
• can cause
  
  • lipid peroxidation: membrane damage
  • protein mods: breakdown/misfolding
  • DNA damage (very sensitive to ROS): mutations

Question 30

membrane and cytoskeletal damage mechanisms

Answer 30

Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also cause membrane damage.

Question 31

necrosis

Answer 31

death of groups of contiguous cells in tissue or organ