Lecture 2

Question 1

Examples of Physical Injury to a cell?

Answer 1

trauma

heat

cold

radiation

electricity

O2 deprivation

Question 2

Examples of Chemical Injury to a cell?

Answer 2

Carbontetrachloride injuring cells in the liver

pH

extremes free radicals

low or high oxygen concentration

poisons

drugs

Question 3

Examples of Biological Causes to a cell?

Answer 3

factors arising from microorganisms

damaging factors released during immune responses

nutritional imbalances

lack of growth factors

Question 4

Examples of Immunological injury Injury to a cell?

Answer 4

autoimmune reactions

autoimmune disease

Question 5

Examples of Genetic Derangements to a cell?

Answer 5

range from severe cognital malformations

subtle variations in genetic makeup -both influence the susceptibility of cells to injury

• genome sequencing has increased our knowledge of how genetic determinates alter how cells respond
• not very strong determinents
• often large numbers which interact with one another and other aspects of the disease

Question 6

Examples of Nutritional imbalances to a cell?

Answer 6

range from severe protein-calorie deficiencies in third world

starvation

anorexia nervosa

excess intake of lipids and cholesterol

• predisposing atherosclerosis
• directly injury
• modulate how other factors injure cells

Question 7

What is the anagram to remember the causes of cell stress and injury?

Answer 7

PiC’N BIG

Physical

Chemical

Nutritional

Biological

Immunological

Genetic derangements

Question 8

What are 4x things that cause damage to the cell membrane?

Answer 8

1. Directly due to Free Radicals
2. After Hypoxia (stress induced due to low O2)
3. membrane targeting bacterial toxins (a-toxin of Clostridium Perfringens)
4. Ca2= plasma membrane pump failure

Question 9

What is an example of a bacterial toxin that targets the plasma membrane?

Answer 9

a-toxin of Clostridium Perfringens

Question 10

What 4 things happen when the plasma membrane is damaged?

Answer 10

1. loss of cellular contents
2. loss of proteins, enzymes, co-enzymes and RNA (ribo-nucleic acids)
3. loss of osmotic balance
4. influx of fluids and ions

Question 11

What is the function of transmembrane pumps and how can they be injured?

Answer 11

Transmembrane pumps control the ionic and iso-osmotic balance or cells and organelles

1. injured directly
2. decreased function due to decreased ATP availability

Question 12

What is Autolysis?

Answer 12

Lysosomal membranes injured

= enzymes leak into cytoplasm

= digestion (autolysis) of cellular components

Question 13

What is severe cell injury often associated with and how does this arise?

Answer 13

Severe cell injury = assoc. decreased content of membrane phospholipids

Caused by combination of two factors:

1. cell injury activation of phospholipases +
2. decreased ATP causing decreased synthesis of phospholipids

Question 14

What happens when there is decreased Ca2+ membrane pump activity?

Answer 14

1. increased Ca2+ influx into cytosol
2. activation of destructive Ca2+ dependant enzymes
   a) ATPases (faster ATP depletion)
   b) Phosopholipases (damages lipid parts of membrane)
   c) Proteases (breaks down both membrane and cytoskeletal proteins)
3. Endonucleases (breaks down both DNA and chromatin into fragments (fragmentation))

Question 15

What do proteases break down?

Answer 15

both 1. Membrane and 2. Cytoskeletal proteins

Question 16

What do endonucleases break down?

Answer 16

both 1. DNA and 2. Chromatin into fragments (fragmentation)

Question 17

What is a secondary form of injury?

Answer 17

Free Radical damage

-occurs on cells which have been exposed to a variety of injurious agents or stressors

Question 18

What are Free Radicals?

Answer 18

Reactive molecules

Single unpaired electron in outer orbit releases energy via reacting with adjacent molecules

Question 19

What is oxidative stress?

Answer 19

an accumulation of free radicals

Question 20

What are reactive oxygen species?

Answer 20

free radicals generated during cell injury

Question 21

What is a generatlisation regarding the effects of stress and cell injury on individual cells?

Answer 21

Multiple components of cells are often injured at the same time

Often the effects of injuring one compoenents, flow through to alter another components

LINKAGE

Not one thing going on at once

Series of events will differ slightly due to what part has beendamage –> but will flow on to later effect other components

Question 22

What are the elements behind a decrease in ATP?

Answer 22

Production: Mitochondrial Oxidative phosphorylation or Glycolysis

Common for ATP to be depleted

1. Lack of O2- Infarction. BV blocked, tissue becomes hypoxic and low in O2 = cell injury via loss of ATP
2. Damage to enzymes. Cell mediators. Directly. Sunburn injury enzyme in keratinosites + cell DNA
3. Mitochondria. most important. Produce ATP via ox. phosphorylation

Results:

1. Repair needs energy. Enzymes need the ATP to repair damaged DNA and proteins.
2. ATP driven membrane ion pumps (maintin conc). Inability to pump cations and anions through membrane pumps. - Na pump doesnt work as well, NA and H2O accumulate inside. Cell Swelling. - Ca2+ pump, Ca2+ influx into cytocol . Activates Destructie Ca2+ dependant enzymes
3. Protein Synthesis - in order to repair cell.

Question 23

What are the elements behind damage to cell membranes?

Answer 23

1. Lysosomes - release of digestive lysosomal enzymes into cytosol, digets cell from inside=Autolysis = major amount of damage
2. Mitochondria (ATP oxidative phosphorylation dependant on complex membranes). Non selective high conductance channel formation. Removes transmembrane potential and cytochrome C required for oxidative phosphorylation. Signalling cell cytochrome C also leaks into cytosol and primes cell for Apoptosis
3. Plasma membrane - loss of cell contents + osmotic balance(H2o influc cell swelling) + Influx of fluids and ions + loss of proteins, enzymes, coenzymes and RNA

Question 24

What are the elements behind Increase in Intracellular Ca2+ levels?

Answer 24

Membrane damage of membrane compartments that contain Ca2+

Membrane pumps not working as not enough Ca2+

Signalling molecule that can turn on destructive enzymes which breakdown proteins and DNA. Activates:

1. ATPases - further decrease ATP
2. Phosopholypates - decreased phospholypid (bilayers)
3. Proteases: Disrupts enzyems and cytoskeletal membrane components - furthers membrane damage
4. Exo/Endonucleases - digest DNA

Question 25

What are the elements of Reactive Oxygen species?

Answer 25

Oxidative phosphorylation reduced Build up of Reactive Ozygen species- e.g.Superoxide further protein and DNA damage Reactive oxidative species= Free radicals e.g. Irradiation, Metabolism of chemicals or drufs, oxygen toxicity, inflammation, reperfusion Set up autocatalytic chains- generate more free radicals - damage more molecules 1. Attack Double bonds and Unsatruated Fatty Acids(UFAs) = Lipid Peroxidation which damages membrane 2. Oxidise Enzyme AA side chains = damaged enzymes 3. React with Thymine = DNA damage

Question 26

What are the possible outcomes of Cell injury or stress?

Answer 26

Adaptation or cell injury Cell injury: Physically and Functionally damaged after injury exposure. NOT unable to adapt. Injury is wrong sort or just too great. Irreversible or Reversible(repair, reverse and replace mechanisms) Cell injury Irreversible Necrotic death(overwhleming injury or cells murdered/ passively wiped out) or Apoptotic Death (preprogrammed suicide, when cannot repair, clean: packaged blebs, phagocytosed. Allows Reuse)

Question 27

What is "Adaptation" in regards to cells?

Answer 27

Adaptation of cells so they can change their functions and sometimes their structure, in order to better function, stay alive and better resist an injury

Question 28

What are the elements of the cell's internal processes/adaption to damage?

Answer 28

Signalling Pathways 1. Heat shock factors. transcriptions factors which regulate expression of heat shock proteins, which help damaged protein- chaperone/hold together and move to correct place for repair. Or arrange for targetted degridation. 2. Stress enzymes. a) p38 MAP kinase & Jun N-terminal Kinase enzymes. Top of/intiiate phosphorylation cascades, cells damage response, so cells can try adapt and limit effects. b) DNA damage activates p53 which stops cell division (stops progression into daughter cells) and sometimes induced cell suidice/apotosis. c) BCL2 protein family, Integrates responses to cell stress, to adaption or suicide:BMF (detects actin cytoskeleton damage), Bim ( detect microtubule damage, Bad (detect cell stress due to inadequate stimulation by growth factors)

Question 29

What are the elements of Adaptation?

Answer 29

Mild injurious agents: Chronic Irritant Mild Stress: Altered environmental Conditions allows cells to continue function, Without being injured, despite stress or change in environment Manners which cells deal and adapt to stress: 1. Hypertrophy (gym, muscle fibres stress, and individual cells adapt by becoming larger)-blocked aortic valve=ventricular thickening due to stress. Hyperplasia (demand on tissue greater than what the tissue can deliver, stem cells divide so Number of cells increases) 2. Atrophy (cells get smaller - loss growth factor stimualtion, nerves that have lost innvervation) 3. Metaplasia (Stem cells reprogrammed. Change cell type, as no longer right cells to deal with injurious agent) - Oesophagus. Squamous epithelium. Changed to be better at resisting gastric acid-acid reflux disease. Stem cells reprogrammed to form Glandular epithelium.

Question 30

What does a cell need to die by Apoptosis and not Necrosis?

Answer 30

Energy- Lack of ATP

Question 31

What are the elements of Necoris?

Answer 31

Passive= Happens when not enough ATP for apoptosis to occur Murdered by overwhelming damage OFten affects large numbers of adjacent cells in a tissue Oncosis Myocardial infarction, Coronary artery blockage- cells dont have enough BF and die. 1. No nuclei - common feature. 2. Contraction bands 3. Homogneous 4. RBC enter as BV are damaged. Die. Heamorrage in tissue Cells swell. Nuclei breaks into parts=Cariorecsus. Nuclie dissolves completely = Cariolysis - featureles cell appeance Autolysis: Lysosomal membrane rupture (inner digestion)= Eosinophilic red protein soup (proteins digestion) Leakage of cytosolic contents induces inflammatory response (WBC Inflammation) Featureless Cytoplasm and Faded/fragmented chromatin Renal cortex- BV blockage. Pale as dont have basophilic Blue staining of DNA as have dissolved (endo/exonulceases + cariolysis) Myocardium

Question 32

What are the elements of Apoptosis?

Answer 32

Requires ATP - sufficent time and energy to commit suicide When cells arent overwhelmingly damage Package DNA, organelles and contents into Blebs. Then Phagocytosed by adjacent cells or Phagocytes. Characterisitic: Membrane Blebs. Shrinakge. Pyknosis Phagocytosed by Macrophages + Neighbouring cells Alternative Apoptosis: cell suicide seen in specialised cells 2x pathways: 1. Mitochondria. activation of UPSTREAM Caspase enzymes, which activate digestion and containing via membrane blebs 2. Death receptors on cell surface. Tumornecrosis receptors. Activate siganls which use Upstream Caspase enzymes to intiate apoptotic wrapping of membranes Liver. Virus. Individual cells dying, not whole tissue. Thymus: cells which develop potential autoimmunitiy are deleted. White cells = Marcrophages, which Reuse Cellular debris