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NancyMEDSCI203 > Lecture 6: Cell Injury&Reversible Effects On Cells > Flashcards

Lecture 6: Cell Injury&Reversible Effects On Cells Flashcards

1
Q

How can DNA be damaged?

A

Physical- radiation
Chemical- alkylation
Biological- dietary deficiency

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2
Q

What is ionising radiation

A

Electromagnetic waves such as x rays and gamma rays has sufficient energy to break chemical bonds

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3
Q

What did Rudolph Virchow propose?

A

The basis of pathology is injury to cells

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4
Q

What is the main target of ionising radiation in cells

A
  1. Water as it undergoes radio lysis to H radical and OH radical
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5
Q

What does ionising radiation do?

A

Causes DNA strand breaks followed by

  • repair
  • mis repair (incorrect rejoining leads to translocation s)
  • cell death
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6
Q

What do acute toxic effects include?

A
  • damage to vascular endothelial cells
  • dilation of arterioles with erythema
  • leakage of plasma with oedema
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7
Q

What are the effects of vascular endothelial cell death?

A
  • long term ulceration
  • scarring
  • atrophy of surrounding tissues
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8
Q

What happens to cells undergoing UV radiation?

A
  • DNA bases are damaged

- adjacent pyrimidines (C,T) become linked

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9
Q

What does UV radiation lead to?

A
  • repair
  • mis repair (C-to-T mutations underlie cancer development
  • death of keratinocytes (sunburn) with ageing of skin
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10
Q

Describe how crystals can damage lipids

A
  • cells take up crystals into the lysosomes
  • these crystals juncture lysosomal membranes causing release hydrolytic enzymes to activate inflammasome to generate damaging inflammation
  • crystals include Silica, asbestos. Monosodium urate, cholesterol, hydroxyapatite.
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11
Q

What are inflammasomes?

A

They are a sensor of danger signals

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12
Q

What does alkylate mean?

A

Reacts covalently with

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13
Q

What is erythema

A

Skin reddening

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14
Q

What does the fungal metabolite aflatoxin B1 alkylate with?

A

Proteins and guanosine bases

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15
Q

What happens when fungal metabolite aflatoxin B1 alkylates with protein?

A

Liver injury occurs (aflatoxicosis) acutely at high doses

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16
Q

What happens when fungal metabolite aflatoxin B1 alkylates with guanosine bases?

A

G-to-T mutations and liver cancer results, chronically, at low doses

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17
Q

Where does fungal metabolite aflatoxin B1 accumulate

A

In poorly stored food

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18
Q

Folic acid and cyanocobalamin are needed for what?

A

DNA synthesis and repair

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19
Q

What happens when the body is deficient of folic acid and/or cyanocobalamin ?

A

Megaloblastic anaemia occurs

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20
Q

Why is deficiency in vitamin B9 and B12 more prominent in autoimmune gastritis?

A

The lack of the intrinsic factor prevents B12 absorption

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21
Q

List the ways lipids can be damaged

A

Physical- crystals
Chemical- oxidants
Biological- lipases

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22
Q

Describe how crystals damage lipids

A

Crystals are taken up by cells into lysosomes
They puncture lysosomal membranes causing the release of hydrolytic enzymes which activate inflammasomes and generate damaging inflammation

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23
Q

List some examples of crystals that cause damage to lipids

A 
Silica
Asbestos
Monosodium Urate 
Cholesterol
Hydroxyapatite (calcium sulfate from bone )
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24
Q

What is an inflammasome?

A

A sensor of damaging signals

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25
Where does super oxide come from?
Approx 1% of oxygen consumed by mitochondria is converted into super oxide.
26
What detoxifies super oxide?
Super oxide dismutase
27
What does superoxide dismutase detoxify super oxide to?
Hydrogen peroxide and oxygen
28
What sort of reactions does hydrogen peroxide participate in?
Oxidation reactions
29
What detoxifies hydrogen peroxide?
Catalase
30
What is hydrogen peroxide detoxified into?
Oxygen and water
31
What is the most destructive radical?
Hydroxyl radical OH dot
32
Why is hydroxy radical the most destructive radical?
It can damage all biological molecules It is the common effector of many type of injury
33
List the different kinds of radicals which cause membrane damage to occur
Carbon centred radical Lipid peroxyl radical Lipid hydroperoxides
34
What do further lipid molecules become involved in?
Chain reactions
35
Describe the lipid molecule chain reaction
Water --> H radical + OHradical OH radical --> Water + Lradical (carbon centred radical) Lipid radical + Oxygen --> LO2radical (lipid peroxyl radical) LO2radical + L-H --> LO2H + Lradical (lipid hydroperoxide) LO2H --> fragmentation (aldehydes and ketones)
36
List the conditions where reactive oxidation species (ROS) may be generated
``` Oxygen therapy Inflammation UV radiation damaged mitochondria Radiotherapy ```
37
How do oxidants damage lipids
Free radicals and reactive oxygen species may react with and damage biological molecules
38
How is ROS generated in oxygen therapy
Premature babies have inadequate antioxidant defences When exposed to supraphysiological oxygen concentrations, May lead to lungs damage
39
How is ROS generated in inflammation?
ROS generation in inflammation is mediated by neutrophils and macrophages
40
How is ROS generated in uv radiation?
UV radiation excites biological molecules. These transfer energy or electrons to oxygen This produces singlet oxygen 1O2 and O2- radical respectively
41
How do lipases damage lipids
Acute haemorrhagic pancreatitis can arise from damage to exocrine cells or from blockage to ducts that deliver the enzymes do the duodenum. Activated digestive enzymes (phospholipases and lipases) digest cell membranes and triglycerides respectively
42
Which specific endocrine cells are damaged in acute haemorrhagic pancreatitis?
Endocrine cells which synthesise digestive enzymes
43
How can proteins be damaged?
Physically by heat Chemically by glycation Biologically by proteases
44
How does heat damage proteins
Prolonged tempratures > 42 degrees C are not compatible with life These can be experienced during high fever, heat stroke, in certain susceptible people treated with anaesthetics High temperatures denature proteins
45
How are the presence of denatured proteins demonstrated by?
Production of heat shock proteins
46
What can heatstroke arise from
High ambient temperatures or exertion
47
What is glycation?
The non-enzymatic addition of sugars to proteins Also known as maillard reaction
48
How is glycation different to glycosylation ?
Glycosylation is the ENZYMATIC addition of sugars to proteins
49
How does glycation damage proteins?
Reducing sugars such as glucose react with amino groups (either in the N things of proteins or on lysine and arginine residues) and generate - reversible early stage Schiff base products - irreversible rearrangements to form Amadori products - further rearrangements to advanced glycation end products (AGE)
50
How do AGE injure cells?
- inhibiting protein function - cross linking, aggregating, precipitating proteins - generating reactive oxygen species - binding to receptors of AGE on vascular inflammatory cells which reduce blood flow and cause inflammation
51
What are receptors of AGE called?
RAGE | E.g. On vascular and inflammatory cells such as monocytes
52
What are some adaptive responses of cells?
Transcriptional responses - transcription factors activated - bind their respective response elements in gene promoters - gene transcription leads to an adaptive response
53
What are some examples of transcription responses
DNA damage response Antioxidant response Heat shock response Unfolded protein response Hypoxia response
54
Describe the DNA damage response
P53 transcription factor regulates : - repair - cell cycle arrest (or with sever damage) - cell suicide (apoptosis)
55
What is the antioxidant response ?
This is when oxidative stress activates Nrf family transcription factors. These induce genes coding SOD1 and catalase (among others)
56
What is the heat shock response ?
Heat shock factors are activated by any agent that damages proteins These factors induce the expression of molecular chaperones (heat shock proteins) which bind to denatured proteins and - prevent their aggregation (which is cytotoxic) - aid in their renaturation - promote proteolytic destruction if proteins that are too damaged
57
What is the unfolded protein response?
Production of unfolded proteins in ER is induced by many stressors The unfolded protein response induces synthesis of chaperones
58
What are some examples of ER stress that induce unfolded protein responses
Virus infection hypoxia reactive oxygen species metabolic abnormalities e.g. Hyperlipidaemia, inflammation
59
What is the hypoxia response?
This response is where hypoxia induceable factors (HIF) induce a genetic programme which help cells adapt to hypoxia
60
What are some targets of the hypoxia response?
Glucose transporters Glycolysis enzymes Factors to increase development of erythrocytes and blood vessels
61
What is DNA damage induced by
DNA damage Hypoxia Reactive oxidative species
62
Which transcription factor is involved in the DNA damage response
p53- causes cells to repair DNA
63
What are some examples of targets or effects of DNA damage response
DNA repair Cell cycle arrest Cell suicide
64
What inducers antioxidant response?
Oxidative stress
65
What transcription factor is involved in antioxidant response?
Nrf2
66
What are some target/ effects examples of antioxidant response
SOD1, catalase
67
What induces heat shock response?
Any agent that denatures proteins
68
Which transcription factor are involved in heat shock response
Heat shock factors
69
What are some examples of targets/effectors of heat shock response
Chaperones aka heat shock proteins
70
What induces unfolded protein response?
Any agent that causes ER stress
71
What is the target of unfolded protein response?
Chaperones
72
What induces hypoxia response
Hypoxia | Reactive oxidative species
73
What is the transcription factor involved in hypoxia response
Hypoxia inducible factors HIF
74
What does hypoxia response target?
Glucose transporters, glycolysis enzymes, red blood cells, blood vessels

NancyMEDSCI203 (12 decks)

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