Cystic fibrosis

Question 1

CF features

Answer 1

Autosomal recessive
High salt concentration in sweat
Failure of pancreas
Unable to absorb nutrients (malnutrition)
Recurrent and persistent lung infections
infertility

Question 2

CFTR

Answer 2

Cystic fibrosis transmembrane conductance regulator

Expressed in epithelial cells of pancreas, sweat glands, salivary glands, lung, intestine

Question 3

CFTR structure

Answer 3

Regulatory domain is phosphorylation site for PKA
Nucleotide binding sites for channel gating
TRL motif for anchoring to cytoskeleton
Two membrane spanning domains form the pore

Question 4

CFTR mutations

Answer 4

Class I defective protein synthesis (frame-shifts resulting in truncation)
Class II defective trafficking of protein resulting in loss of expression at membrane
Class III defective regulation of the channel
Class IV altered ion permeation
Class V mutations in promotor region (reduced transcription)
Class VI increased protein turnover

Question 5

CFTR severity

Answer 5

Total loss of function mutations are associated with the severe form

Mutations resulting in reduced Cl- current are associated with the milder form

Question 6

CFTR mutations and sweat glands

Answer 6

Normally, Na/K ATPase creates gradient for Na+ uptake
Cl- follows passively via CFTR to maintain electroneutral NaCl uptake
Duct epithelium impermeable to water

In CF, Cl- uptake from duct is inhibited. Na+ uptake causes depolarisation which reduces driving force for Na+ uptake. Reduced NaCl absorption

Question 7

Mechanical clearance

Answer 7

Primary defence mechanism for airways
Funnelling of airway surface liquid up converging airway surface
ASL composed of mucus layer and pericilia layer (PCL)

Hydration of ASL maintains mucus transport out of the lung

Question 8

ASL maintenance

Answer 8

At basal conditions, net Na+ influx via ENaC makes lumen side of lung more negative. Cl- moves across the junction (paracellular movement), inducing osmosis of water (absorbance)

If ASL too thin, CFTR is upregulated, inhibiting ENaC. Gradient favours Cl- efflux into lumen, followed by water (hydration).

CFTR is both Cl- channel and ENaC inhibitor

Question 9

Cystic fibrosis and ASL

Answer 9

CFTR mutation causes reduced ASL
Without functioning CFTR, ENaC not regulated so reduced Cl- efflux.
Collapse of periciliary layer and mucus layer sticks to epithelial layer (airway obstruction and inflammation)
Mucus layer forms biofilm for bacterial growth and reduces diffusion of antibacterial agents

Question 10

Modified ASL depletion hypothesis

Answer 10

Sufficient Cl- transport in most conditions due to other Cl- channels (CaCC) but infection increases vulnerability causing collapse of ASL and CF symptoms

Viral stress leads to upregulation of ENaC and influx of Na+. In normal lungs, CFTR would be present to boost Cl- efflux and downregulate Na+ influx

Question 11

Inhale hypertonic saline

Answer 11

Airway surfaces are permeable to water so salt is added to rehydrate surfaces.

Question 12

Transporter drugs

Answer 12

Redirection of transport to secretory direction
SPI-811 chloride channel opener (CLC-2)
PS552 blocks ENaC

Question 13

Ivacaftor

Answer 13

Increases open probability of CFTR channel.

Effective for 5% of patients that express the channel.

Question 14

Kaftrio

Answer 14

Treatment for cystic fibrosis
Consists of Ivacaftor, elexacaftor and tezacaftor
Elexacaftor and tezacaftor increase the number of CFTR proteins on the cell surface