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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
Q

Where does super oxide come from?

A

Approx 1% of oxygen consumed by mitochondria is converted into super oxide.

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26
Q

What detoxifies super oxide?

A

Super oxide dismutase

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27
Q

What does superoxide dismutase detoxify super oxide to?

A

Hydrogen peroxide and oxygen

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28
Q

What sort of reactions does hydrogen peroxide participate in?

A

Oxidation reactions

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29
Q

What detoxifies hydrogen peroxide?

A

Catalase

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30
Q

What is hydrogen peroxide detoxified into?

A

Oxygen and water

31
Q

What is the most destructive radical?

A

Hydroxyl radical OH dot

32
Q

Why is hydroxy radical the most destructive radical?

A

It can damage all biological molecules

It is the common effector of many type of injury

33
Q

List the different kinds of radicals which cause membrane damage to occur

A

Carbon centred radical
Lipid peroxyl radical
Lipid hydroperoxides

34
Q

What do further lipid molecules become involved in?

A

Chain reactions

35
Q

Describe the lipid molecule chain reaction

A

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
Q

List the conditions where reactive oxidation species (ROS) may be generated

A 
Oxygen therapy
Inflammation
UV radiation
damaged mitochondria
Radiotherapy
37
Q

How do oxidants damage lipids

A

Free radicals and reactive oxygen species may react with and damage biological molecules

38
Q

How is ROS generated in oxygen therapy

A

Premature babies have inadequate antioxidant defences

When exposed to supraphysiological oxygen concentrations,

May lead to lungs damage

39
Q

How is ROS generated in inflammation?

A

ROS generation in inflammation is mediated by neutrophils and macrophages

40
Q

How is ROS generated in uv radiation?

A

UV radiation excites biological molecules.

These transfer energy or electrons to oxygen

This produces singlet oxygen 1O2 and O2- radical respectively

41
Q

How do lipases damage lipids

A

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
Q

Which specific endocrine cells are damaged in acute haemorrhagic pancreatitis?

A

Endocrine cells which synthesise digestive enzymes

43
Q

How can proteins be damaged?

A

Physically by heat
Chemically by glycation
Biologically by proteases

44
Q

How does heat damage proteins

A

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
Q

How are the presence of denatured proteins demonstrated by?

A

Production of heat shock proteins

46
Q

What can heatstroke arise from

A

High ambient temperatures or exertion

47
Q

What is glycation?

A

The non-enzymatic addition of sugars to proteins

Also known as maillard reaction

48
Q

How is glycation different to glycosylation ?

A

Glycosylation is the ENZYMATIC addition of sugars to proteins

49
Q

How does glycation damage proteins?

A

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
Q

How do AGE injure cells?

A
  • 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
Q

What are receptors of AGE called?

A

RAGE

E.g. On vascular and inflammatory cells such as monocytes

52
Q

What are some adaptive responses of cells?

A

Transcriptional responses

  • transcription factors activated
  • bind their respective response elements in gene promoters
  • gene transcription leads to an adaptive response
53
Q

What are some examples of transcription responses

A

DNA damage response

Antioxidant response

Heat shock response

Unfolded protein response

Hypoxia response

54
Q

Describe the DNA damage response

A

P53 transcription factor regulates :

  • repair
  • cell cycle arrest (or with sever damage)
  • cell suicide (apoptosis)
55
Q

What is the antioxidant response ?

A

This is when oxidative stress activates Nrf family transcription factors.

These induce genes coding SOD1 and catalase (among others)

56
Q

What is the heat shock response ?

A

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
Q

What is the unfolded protein response?

A

Production of unfolded proteins in ER is induced by many stressors

The unfolded protein response induces synthesis of chaperones

58
Q

What are some examples of ER stress that induce unfolded protein responses

A

Virus infection
hypoxia
reactive oxygen species
metabolic abnormalities e.g. Hyperlipidaemia, inflammation

59
Q

What is the hypoxia response?

A

This response is where hypoxia induceable factors (HIF) induce a genetic programme which help cells adapt to hypoxia

60
Q

What are some targets of the hypoxia response?

A

Glucose transporters
Glycolysis enzymes
Factors to increase development of erythrocytes and blood vessels

61
Q

What is DNA damage induced by

A

DNA damage
Hypoxia
Reactive oxidative species

62
Q

Which transcription factor is involved in the DNA damage response

A

p53- causes cells to repair DNA

63
Q

What are some examples of targets or effects of DNA damage response

A

DNA repair
Cell cycle arrest
Cell suicide

64
Q

What inducers antioxidant response?

A

Oxidative stress

65
Q

What transcription factor is involved in antioxidant response?

A

Nrf2

66
Q

What are some target/ effects examples of antioxidant response

A

SOD1, catalase

67
Q

What induces heat shock response?

A

Any agent that denatures proteins

68
Q

Which transcription factor are involved in heat shock response

A

Heat shock factors

69
Q

What are some examples of targets/effectors of heat shock response

A

Chaperones aka heat shock proteins

70
Q

What induces unfolded protein response?

A

Any agent that causes ER stress

71
Q

What is the target of unfolded protein response?

A

Chaperones

72
Q

What induces hypoxia response

A

Hypoxia

Reactive oxidative species

73
Q

What is the transcription factor involved in hypoxia response

A

Hypoxia inducible factors HIF

74
Q

What does hypoxia response target?

A

Glucose transporters, glycolysis enzymes, red blood cells, blood vessels

NancyMEDSCI203 (12 decks)

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