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PHYL 4504 > Cystic Fibrosis > Flashcards

Cystic Fibrosis Flashcards

1
Q

CF is caused by what?

A

Loss of function mutations in gene encoding CFTR protein

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2
Q

What is the main problem in CF?

A

deficient epithelial anion (Cl-) permeability

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3
Q

What are the organs affected?

A

Airways, Sweat Glands, Pancreas, Small intestine

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4
Q

What mode of inheritance does CF show?

A

Autosomal recessive

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5
Q

Symptoms

A

cough with mucous, wheezing and SOB, chest infections, bowel disturbances, weight loss or failure to thrive, salty tasting sweat, infertility

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6
Q

CFTR is a member of what large family of membrane transport proteins?

A

ATP-Binding Cassette (ABC) transporters

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7
Q

What does CFTR stand for?

A

Cystic Fibrosis Transmembrane Conductance Regulator

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8
Q

What are the domains of CFTR?

A

2 NBDs, 2 MSDs, R domain

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9
Q

Why is this a unique ABC protein?

A

Because the rest use ATP to power active transport, this one hydrolizes ATP

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10
Q

Channel activity is regulated by what?

A

Phosphorylation of a cytoplasmic regulatory domain (R domain)

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11
Q

What chromosome is CFTR gene located on?

A

Chromosome 7

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12
Q

What is the anion transported mediated by?

A

cAMP- mediated

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13
Q

What other anions does CFTR transport?

A

Cl-, HCO3-, gluthathione, I-, SCN- (thiocyanate)

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14
Q

What does the absence of functional CFTR result in?

A

increased viscocity of secretions, ciliary dysfunciton, mucous dehydration, mucous impaction, failure of MCC, repeated infections, neutrophilic inflammatory response, tissue damage, resp insufficiency

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15
Q

What is the most common mutation?

A

Phenylalanine 508 deletion

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16
Q

Loss of CFTR activity linked to over-activity of what?

A

ENaC

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17
Q

Class 1 CFTR mutation

A

No functional CFTR, nonsense frameshift

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18
Q

Class 2 CFTR mutation

A

CFTR traficking defect, misense amino acid deletion, Phe508del

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19
Q

Class 3 CFTR mutation

A

Defective channel regulation, amino acid change

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20
Q

Class 4 CFTR mutation

A

Decreased channel conductance, amino acid change

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21
Q

Class 5 CFTR mutation

A

Reduced synthesis of CFTR, splicing defect

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22
Q

Class 6 CFTR mutation

A

Decreased CFTR stability, increased turnover, amino acid change

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23
Q

most common deletion and what percentage of all mutations it accounts for

A

F508del, 70%

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24
Q

What percentage of mutations not associate with disease

A

15%

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25
Q

MCC in normal airways

A

PCL height maintained at 7 micometers via coordinated Na absorption via ENaC and Cl secretion via CFTR

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26
Q

MCC in CF

A

no CFTR, unrestrained Na hyperabsorption occurs with loss of Cl secretion = decreased PCL and failure of MCC

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27
Q

When excess PCL is present:

A

Na absorption via ENaC is dominant and Cl is abosrobed passivlet via paracellular pathway

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28
Q

When PCL volume is low:

A

ENaC is inhibited which makes the apical membrane potential more negative, so generating a driving force for Cl- secretion, Na follows paracellularly

29
Q

Abnormal Ion transport in CF results in what?

A

mucostasis - due to increased ion absorption across large airways, thickened mucous, plaques and plugs which adhere to airways

30
Q

CFTR transports HCO3- as well as Cl, so influences:

A

local pH

31
Q

local pH can influence

A

local proteins and ion channels (ENaC)

32
Q

Normal ASL pH =

A

7.0

33
Q

what is pH mediated by?

A

CFTR HCO3- secretion

34
Q

Experiments with cell line Calu-3 revealed CFTR will:

A

trnasport Cl or bicarb depending on activity of basolateral membrane

35
Q

Whole animal studies showed:

A

increased bicarb secretion in response to cAMP and calcium-inducing agnosit

36
Q

CF newborns show _____ ASL pH, why?

A

reduced (more acidic) - because dysregulation of CFTR causes abnormal acid base balance

37
Q

Changes in pH affect airway clearance:

A

transient acidification of normal ASL increases trate of absorption while alkalinization leads to a slowing of absorption and restores ASL heigh

38
Q

What serine protease with trypsin like activity is involved in ENaC activation and is inactive below pH 7

A

Prostasin

39
Q

SPLUNC1 is another regluator of ENaC activity , and does ??? in acidic CF airways

A

unable to inhbit ENaC, so promoted Na hyperabsorption

40
Q

prior to secretion how are mucin molecules packaged

A

as small granules with electric charges masked by calcium

41
Q

when mucin released in neutral environment what happens?

A

bicarb complexes with calcium, negative charges revealed, repel each other and sliperiness and lubrication is possible

42
Q

IN CF airways, reduced biarb transport impais:

A

expansion of mucin

43
Q

are proteins required to cleave mucins

A

yes

44
Q

In CF is there long sticky strands of mucins that remain attached? Why?

A

yes, due to pH sensitivity of cleavage proteins

45
Q

Bacterial killing is highly dependent on

A

pH

46
Q

Does CFTR transport glutathione?

A

Yes

47
Q

excessive inflammatory response in absence of infection is common

A

Yes

48
Q

cytokine response?

A

IL-8 leads to neutropgil recruitment to airways, damage lung tissue

49
Q

CFTR deficient cells exhibit

A

innate pro-inflammatory state

50
Q

high concentration of what inflammaotry mediators?

A

IL-6,8,1B and decreased IL-10 (antiinflammatory)

51
Q

excessive activation of transcirption factors such as

A

NF kappa B and AP-1

52
Q

CF neutrophils have…

A

reduced phagocytic capability

53
Q

upon death, CF neutrophils release

A

increased DNA and oxidases

54
Q

therapeutic strategies in CF 1

A

broad based inflammatory modulators: corticosteroids, Ibuprofen

55
Q

therapeutic strategies in CF 2

A

antibacterials with antiinflammatory properties: azuthromycin

56
Q

therapeutic strategies in CF 3

A

modulators of intracellular signaling: interferon gamma

57
Q

therapeutic strategies in CF 4

A

inhibitors of neutropgil influex: anti IL8

58
Q

therapeutic strategies in CF 5

A

inhibitors of neutrophil products: dornase-alfa

59
Q

therapeutic strategies in CF 6

A

anto oxidants - N acteyl cysteine

60
Q

therapeutic strategies in CF 7

A

anti proteases - alpha 1 protease inhbitor

61
Q

therapeutic strategies in CF 8

A

hyperosmolar agents, hypetonic saline, mannitol

62
Q

therapeutic strategies in CF 9

A

CFTR potentiators - improve Cl transport through CFTR, Halydeco

63
Q

therapeutic strategies in CF 10

A

CFTR correctors, resuce trafficking deffect - Lumacaftor

64
Q

therapeutic strategies in CF 11

A

Gene therapy - ineffective

65
Q

what do CFTR potentiators do?

A

increase acitivty of defective CFTR at cell surace by acting on gating defects or conductance defects

66
Q

What do CFTR correctors do?

A

overcome defective protein processinf that normally results in production of misfolded protein

67
Q

Potentiator: Kalydeco

A

good for class 3 mutations, increases open probability of channel, reduced sweat Cl, increase FEV1 weight gain, improve QOL

68
Q

Corrector: Lumacaftor

A

Class 2 mutations, molecular chaperone for protein folding, only modest effects on sweat Cl, no improvement in clinical outcomes

69
Q

Production correctors..

A

read through agents, promote readthrough of premature temrination codons in mRNA, which result in truncated protein - supress normal proofreading function of ribosome result in full length protein despite PTC, generating more CFTR - for class 1 mutations - still experimental

PHYL 4504 (8 decks)

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