L2 - ASL, Influence and Ion Channels Flashcards
Where is the ASL found?
Sits on top of epithelia cells in the respiratory tract
Epithelia cells either
- Upper airway cells
- Alveolar cells
What is the structure of the upper airway?
Perciliary layer sits on top of the bronchial epithelia cells
Cilia project from the bronchial epithelial cells
What do cilia do in the upper airway?
They beat constantly - moves ASL and mucus up respiratory tract
First line of defence against infection/respiratory pathogens
What happens if the height of the ASL is disrupted?
Effects your ability to clear pathogens
Pathogens them themselves have an impact on the ASL
Why do the lungs have to be dynamic in how they control the ASL?
Proximally - small airways –> 2m2
Problem - small airways converge in bronchial region –> 50cm2
- As fluid moves up respiratory tract the height of the ASL increases as surface area decreases
- This is why the body needs to have control mechanisms
Distally - upper respiratory tract
- In this region there are mechanisms to control the height of the ASL - allows us to fight infection
- Active and passive mechanisms
What are the passive mechanisms to control the ASL?
Mucous layer acts as a reservoir
Excess fluid moves into the mucous layer or moves out if too little fluid
What are the active mechanisms to control the ASL?
Active ion transport controlling salt level in periciliary layer
- Water follows the ion movement
- Movement of water is mostly between cells –> paracellular
- Where ENaC and CFTR play a role
- When one ion channel pathway is active, the other pathway is inactive
Which pathway is more important the active or passive?
Active
What happened when they grew upper airway epithelial cells in culture and added liquid to the apical surface of the cells to a height of 30 microns?
Cells in culture actively decrease the height of ASL to optimum over time
Most of it happens within the first 24 hours
What is the optimum ASL height in vitro?
7-7.5 microns
What happens when ASL is too high?
Na absorption dominates –> ENac activity upregulated
What happens when the ASL is at steady state?
Cl secretion dominates –> CFTR activity upregulated
Need a balance between Na absorption and Cl secretion
- No net water movement across epithelium
What channel is important in lung fluid clearance at birth?
ENaC
How did they test that ENaC and CFTR are involved in the height of the ASL?
Set high ASL height in cultured cells and monitored over time
What happened when they het high ASL height in cultured cells and monitored over time?
ASL height over time decreased
Transepithelial potential decreased
What happened when they het high ASL height in cultured cells and monitored over time after adding amiloride and bumetanide?
Looked at transepithelial potential shift
The bigger the shift in the potential –> the bigger the function of the blocked channel
Drop in transepithelial potential –> drop in channel function
Amiloride - blocks ENaC
- At 0h - nearly 70% inhibition - shows ENaC important
- At 48h - drop to 30% inhibition - ENaC more important when ASL high
Bumetanide - blocks NKCC1 - blocks Cl secretion
What channels are active when ASL is high?
ENaC function high/upregulated
What channels are active when ASL is steady?
ENaC function drops and NKCC1 upregulated
What channels are active when ASL is low?
NKCC1 function high/upregulated
What inherited mutations are there in ENaC or CFTR?
Cystic Fibrosis - treatments that might target ENaC
Atypical cystic fibrosis - either 1 or no CF gene mutations
PHA type 1 - pseudohypoparathyroidism
What acquired mutations are there in ENaC or CFTR?
Infections
Smoking
Vaping
How many people does influenza kill a year?
12 – 61 thousand a year USA
600 -13 thousand a year UK
10% hospital admissions during flu season are due to?
Influenza linked bronchopneumonia and oedema
Acquired respiratory distress syndrome
- Lung function impaired so much –> can’t get oxygen in –> hospitalised
What channels does influenza impact?
Alters ENaC and CFTR function
This means the ASL is also impacted
