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BMS346 - Epithelial Physiology > Lecture 2 - ALS and Influenza > Flashcards

Lecture 2 - ALS and Influenza Flashcards

1
Q

What is the ASL

A

Airway surface liquid layer

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2
Q

Where is the ASL

A

It sits on top of epithelial cells in the respiratory tract

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3
Q

What is the ASL composed of

A

Mucous layer

Periciliary layer

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4
Q

What is the PCL important in

A

Height is important in the clearance of mucous

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5
Q

How is the ASL the first line of defence against respiratory pathogens

A

The mucous moves up and is swallowed

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6
Q

Describe how there is a volume load in the lungs - what is the effect of this on the control of the ASL

A

Proximal airways have diameter of 2m^2
Distal airways converge in the bronchial region at only 50cm2
So there has to be a way to regulate this height to maintain an optimum level

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7
Q

What are the two control mechanisms of the ASL

A

ACTIVE and PASSIVE

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8
Q

Describe the active control of the ASL

A

Active transport of ions and solutes - therefore water

Comlimentary pathways of ENaC and CFTR (when one is active then the other is inactive)

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9
Q

Describe the passive control of the ASL

A

Mucous is able to act as as reservoir - if the height of the PCL is too high then water is able to move into the mucous layer

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10
Q

Describe Pfleugers 2003 experiment looking at the changes in the height of the PCL

A

Grow epithelial cells in culutre
Addition of liquid to the apical surface to 30um (much too hight)
Over time (in the first 24 hrs or so) the PCL is brought down to the optimum level (7-7.5um)

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11
Q

What is the optimum height of the PCL for cells in culture

A

7-7.5 um

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12
Q

What happens to the PCL when the height is too high

A

Na re absorption predominates - upregulation of ENaC (inhibition of Cl secretion through CFTR)
Net movement of Na+ into the cell (transcellular) leads to water movement out of the ASL by paracellular transport reduciing the height of the airway surface liquid layer

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13
Q

What happens to the PCL when the height is too low

A

Cl secretion predominates - upregulation of CFTR - inhibition of ENaC

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14
Q

When the height is at optimum what can be said

A

There is no net movement of solute and so no net movemebt of water

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15
Q

Why is ENaC required at birth?

A

Lungs full of water at irth

ENaC upregulation required to remove this (Na+ reabsorption and water follows)

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16
Q

What does looking at %inhibition of the Vte show

A

How much an ion channel contributes to Vte

E.g if add amiloride and see a 50% reduction in the Vte then can say that ENaC is responsible for 50% of the Vte

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17
Q

Describe the results seen when looking at the ASL (starting too high) and Vte in the presence of amiloride

A

T=0 then 65% (majority) of Vte from ENaC
Since ENaC must be high to drive Na re absorption to the bring down the height of the ASL
At T=48 height is back to optimum so ENac activity decreases so is balanced with CFTR function

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18
Q

Why would bumetranide be used?

A

Blocker of NKCC1 - if this is blocked the DF for Cl secretion is lost - indirectly blocking CFTR

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19
Q

Describe the results seen when looking at the ASL (starting too high) and Vte in the presence of bumetanide

A

At t=0 activity of CFTR is low - around 20% contribution to Vte
At t=48 this value is higher as balance to maintain optimum height

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20
Q

When the height is high

A

Upregulation of ENaC

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21
Q

When the height is low

A

Upregulation of Cl secretion through CFTR

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22
Q

Describe the upper airway cell model

A

APICAL
ENaC (na in)
CFTR (Cl out)

BASAL
Na/K ATPase
NKCC1 (Na 2Cl and K in)
K channel (K out)

23
Q

Most of the water movement is

A

PARACELLULAR

24
Q

What does paracellular mean

A

Between cells

25
Q

Give some inherited conditions that arise from the competition between CFTR and ENaC

A

CF
Atypical CF
PHA type 1

26
Q

Give some causes of acquired conditions that arise from the competition between CFTR and ENaC

A

Infections
Smoking
Vaping

27
Q

Death rates from influenza
UK
USA

A

12-61K individuals/year USA

600-13k individuals/year UK

28
Q

10% of hospital conditions are due to

A

Influenza linked bronchopneumonia and oedema

Acquiired respiratory distress syndrome

29
Q

Why is influenza being studied in the context of this module

A

Alters ENaC and CFTR function which then impacts on the ASL

30
Q

MURINE NASAL PDs - RESPONSE TO PR8
What is PR8
What was recorded
What were the different experimental groups

A

Influenxa strain

Recorded Vte across the nasal epithelium

Control, 5 days infected, 15 days infected

31
Q

When amiloride was added what does this shift in potential correlate to

A

The function of ENaC = a large shift in potential= suggestes ENaC makes a large contribution to Vte

32
Q

Why is forskolin added

How does it worK?

A

Added to stimulate the CFTR channels

Activation of cAMP production and activation of PK-A phosphorylation of CFTRs R domain

33
Q

A large shift in Vte when a blocker was added suggests what?

A

That this has a large function

34
Q

What is the amiloride sensitive potential

A

How big the shift when amiloride added - if closer to zero there is less function

35
Q

Describe the effect of PR8 of ENaC

A

At day 5 see inhibition of ENaC
But this shift is short lived
TRANSIENT INHIBITION

36
Q

Describe the effect of PR8 on CFTR function

A

Same as before - see stimulation leads to less activation cf the wildtype

37
Q

Sum up the studies in mice infected with influenza

A

By day 5 inhibition of CFTR and ENaC are seen

38
Q

Describe the data obtained from HBE Monolayers with Ussing Data?

A

Two traces one control and one 48 hours post infection

CONTROL
Drop in SSC when amiloiride is added (shows contribition from ENaC). FSK added and SSC peaks shortly after that then plateaus. Large reduction in SCC when a CFTR blocker is applied

48H INFECTED
Initial SSC much lower - reduced drop when amiloiride added, reduced activation of CFTR by FSK and reduced inhibition when inhibitor added

39
Q

What are the two properties likely to change during the infection

A

N - number of channels

Po - the open probability

40
Q

Describe the technique used to investigate effects on Po

A

Virus tagged w/ GFP so all virus infected cells are green
Patch clamp indiviudal cells that are green
SINGLE CHANNEL RECORDINGS

41
Q

What is seen when perofrming single channel recordings on H1N1 infected cells

A

Non-infected - frequent channel openings
Mean data Po around 0.3 for the control

Infected - reduced Po and a reduction in the number of opening events

REDUCTION IN PO

42
Q

Infection is reducing the _____ of ENaC channeles

A

Po

43
Q

What technique was used to look to see if the virus was effecting N number of CFTR and ENaC

A

Look at expression levels

44
Q

What is the normal subuint strucutre of ENaC

What other subunit is there and where is this found

A

aby

delta - lungs

45
Q

Can alpha ENaC form functional channels?

A

Yes but the currents recorded fro this are very small

46
Q

Describe the reuslts of looking at the expression levels of a-ENac/b-ENaC and yENaC, CFTR, a-ATPase and b-ATPase

A

a-ENac/b-ENaC and yENaC, CFTR, a-ATPase - ALL DOWN

b-ATPase unchanged

47
Q

What is the effect of H1N1 reducing the number of Na/K ATPase

A

Na/K ATPase sets up the driving force - by inhibiting the cell has a reduced ability to allow Cl and Na movement

48
Q

What is the effect of the virus on HBE and mouse on the ASL

A

ASL reduced

49
Q

The fact that the height of the layer has dropped in these studies suggests …

A

There is a biggr impact on CFTR than on ENaC

And that there is more inhibition on CFTR than there is on ENaC

50
Q

What is the effect of the virus of the ciliary beat frequency

A

Post infection there is a drop in ASL and the CBF goes down

51
Q

What problem does reduction of CBF cause

A

Problems clearing liquid and mucous from the lungs

52
Q

What is unusual about CBF and ASL post infection

A

ASL remains low but the CBF frequency has reocvered? Unsure about the mechanisms of this

53
Q

Infection with H1N1 impacts on CFTR in two ways…

A

Decrease Po of CFTR and decreased abundance of CFTR in the membrane

54
Q

What is a possible pharmacological correct for infection with H1N1

A

Idea to get more channels to the membrane to reverse the drop of the ASL

Lumacaftor - correct - causes trafficking of CFTR to the membrane (increases N)

Treat infected cells and see that height of the ASL has made somewhat of a recovery

Could moleucles that are used to treat CF be used in this case

BMS346 - Epithelial Physiology (10 decks)

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