Lecture 6: Cell Injury: Reversible effects

Question 1

why is understanding cell injury crucial?

Answer 1

becuase cell injury is the core of any pathology - every pathology begins with cell injury

Question 2

what are the three agents of cell injury and what cell components are targeted

Answer 2

chemical, physical and biological
DNA, proteins and lipids

Question 3

what is the difference between misrepair and toxicity

Answer 3

misrepair - cell is able to survive but with mutations/damage done
toxicity - damage is too excessive that cell death mechanisms are triggered

Question 4

DNA: Physical

Answer 4

1. Ionising radiation eg. xrays
   - hydrolysis of water creating free hydroxyl radical causing double dna strand to break
   - misrepair: can lead to chromosome translocation - blooc cancers
   - toxicity: acute damage to endothelial cells that line our blood vessels. cells dying and surrounding tissues shrink, ulceration, bleeding, scarring
2. ultraviolet radiation eg. sunlight
   - pyrimidine crosslinking - dna adducts
   - misrepair: chronic damage can lead to accumulation of mutations and development of skin cancer
   - toxicity: acute damage to keratinocytes on the skin can lead to peeling sunburn

adduct - crosslinking on same strand

Question 5

DNA: Chemical

Answer 5

alkylation eg. aflatoxin B1
- DNA adducts, G to T transversions
- misrepair: chronic low doses can lead to liver cancer (heptocellular carcinoma)
- toxicity: leads to damage in the liver (becuase trying to remove toxin) and acute aflatoxicosis (injury) - at high doses

Question 6

DNA: Biological

Answer 6

dietary deficiency eg. Folic Acid
- needed for DNA synthesis and repair, building blocks
- diet or inability to absorb properly
- essential to make thymine and methionine
- misrepair: autoimmune gastritis, lack of protein called intrinsic factor prevents B12 absorption/deficiency and increases DNA damage leading to megaloblastic anaemia - incorrect development of red blood cells

Question 7

sum up the agents of cell injury in DNA

Answer 7

uv or IR
aflatoxin
dietary vitamin deficiency

Question 8

as a response to damage to DNA, list the ways a cell can respond

Answer 8

• survive but with accumulation of mutation=misrepair
• cell death/suicide

Question 9

Lipids: physical

Answer 9

crystals eg. MSU (monosodium urate), asbestos, cholesterol, hydroxyapetite

• formation of crystals, inflammation
• seen in gout, asbestosis, bone fractures
• lysosome phagocytose crystals but rupture relasing their enzymes intracellulary activating inflammation via inflammasome
• inflammation or cell death

Question 10

Lipids: Chemical

Answer 10

oxidants eg. oxygen therapy
- many forms of radical
- most common ROS, sequential reduction of oxygen
- react with lipids

formed naturally in the body
- protective mechanism by neutrophils to kill bacteria
- essential intermediates in enyzmatic reactions
- produced by mitochondria
- cells exposed to hypoxia or hyperoxia generate ROS
- act as signalling molecules to promote DNA replication and cell proliferation

key ROS enzymes
- superoxide dismutase (SOD) converst superoxide anion radical into O2 and hydrogen peroxide
- catalase converts hydrogen peroxide into water and oxygen
- hydroxyl radicals react with lipid hydrogens - lipid peroxidation

Question 11

explain what lipid peroxidation is and under what catgegory of cell injury it falls

Answer 11

• chemical
• modification of hydrogen group on lipid - cuases issues with membrane structure, rigidity, decreases activity of protein enzymes embedded in membrane (eg. sodium pumps), different activity of membrane receptors, cant identify signals from environment, make cells leaky

Question 12

List four ways that ROS injure cells

Answer 12

1. oxygen therapy given to premature babies can lead to lung damage
2. Inflammation mediated by macrophages and neutrophils during infection
3. UV radiation excites molecules which transfer energy or electrons to oxygen causing skin damage
4. radiotherapy (ionising radiation) induces hydroxyl radicals

Question 13

Lipids: Biological

Answer 13

Lipases eg. organ damage
inflammation of pancreas - damage to exocrine, enzyme packaged cells. leak and damage cells surrounding them digesting lipids within membranes

Question 14

Proteins: Physical

Answer 14

heat eg. sunstroke
- denaturation
- cant function properly
- activate heat shock proteins (chaperones)

Question 15

explain how chaperones work

Answer 15

• bind to denatured proteins
• stop their aggregation
• aid in renaturation
• promote proteolytic destruction of proteins that are too damaged

Question 16

Proteins: Chemical

Answer 16

Glycation eg. sugar
- AGE (advanced glycation end products)
- inhibit protein function
- cross-link, protein insoluble
- ROS generation
- bind to RAGE, signals to reducd blood flow and cause inflammation

Question 17

In what disease states does AGE play a role

Answer 17

diabetes, aging, chronic inflammation
cardiovascular disease
neurodegeneration - insoluble proteins blocking neuornal function
cataracts

Question 18

Proteins: Biological

Answer 18

Proteases eg. inflammation
- stored in cells
- released during inflammation
- cleave specific structural proteins, change shape and function and location of cells
- eg, cancer invasion - cleaved laminin allows cancer cells to migrate

Question 19

What 3 mechanisms do cells have to reverse injury?

Answer 19

1. acute intracellular oedema
2. abnormal storage
3. adaptive responses to stress

Question 20

explain what happens in acute intracellular oedema

Answer 20

• cell swelling due to:
• plasma membrane more permeable to sodium (eg through membrane lipid peroxidation), osmotic balance disrupted, water in cell

Question 21

explain what happens in abnormal storage

Answer 21

when cells cannot process molecules as normal, fats and glyocgen can accumulate
eg. liver hepatocytes usually take up FA from blood and convert them to TG
pathology - diabetes increases FA, alcohol decreaes TG oxidation (breakdown), Kwashiorkor decreaes VLDL export

Question 22

list some adaptive responses to stress

Answer 22

1. DNA damage response (DDR)
2. Hypoxia and antioxidant response
3. proteotoxic response (heat shock reponse)
4. unfolded protein response

Question 23

explain DDR

Answer 23

• DNA damage detected by p53
• p53 induced proteins involved with DNA repair and stops cell cycle so it can repair DNA before cell division
• if DNA damage is too extensive - apoptotic cell death

Question 24

Explain the proteotoxic response

Answer 24

• triggered by accumulation of unfolded, denatured and aggregated protein
• HSF1 (heat shock factor 1) activates transcription of chaperone proteins HSPs (Heat shock proteins)
• these promote refolding of denatured proteins, target damaged proteins for desctruction and prevent protein aggregation which si cytotoxic

Question 25

Explain the hypoxia response

Answer 25

• driven throuhg transcription factor HIF1alpha induced by low oxygen sensing (Hypoxia Inducible Factor alpha)
• activates expression of proteins enabling cell to survive in hypoxic environment eg. erythropoietin, vascular endothelia growth factor
• process supports the capacity of o2 transfer in erythrocytes and new vessels increase blood supply to hypoxic tissues

Question 26

explain the antioxidant response

Answer 26

triggered through detection of oxidative stress and ROS to upregulate antioxidatn enzymes to rebalance redox homeostasis

Question 27

explain the unfolded protein response

Answer 27

UPR is triggered by unfolded proteins in the ER
- induces production of more chaperons and targeting of damaged proteins
- supresses global protein production
- induced ER associated protein degradation
- promotes autophagy