Cystic Fibrosis Flashcards
What is cystic fibrosis?
- Autosomal recessive condition with up to 1000 different mutations in CFTR
- One of the most common life-limiting genetic conditions in western world
- Life expectancy 40 years
- ∆F508 mutation- phenylalanine (main)
What is CFTR?
cystic fibrosis transmembrane conductance regulator
What is normal CFTR?
- Chloride expressed in epithelial cells throughout body
- Channel opening regulated by ATP binding to nucleotide binding domains and phosphorylation of regulatory domain
Describe the processing of normal CFTR
- Synthesised in endoplasmic reticulum
- Chaperones facilitate correct folding
- Transported to Golgi
- Glycosylated
- Inserted into membrane in inactive form
- Activated by binding of ATP and phosphorylated of the regulated domain
How does CFTR function in bronchial epithelium?
- transports 90% of Cl- ions
- CRTR has a negative regulatory effect on epithelial sodium channel
- Closes it so sodium cannot enter cell
- Na+ comes in through airway lumen
- Rapidly transported out of the base of cell
- K+ enters when this happens
- Na+/K+/Cl- co-transporter
What is the role of mucus in bronchial epithelium?
- Thin layer of mucus with high elasticity and low viscosity traps pathogens and particulates
- Movement from base of lung to glottis
- Thin watery periciliary fluid supports mucus layer
What can go wrong with CFTR?
- Failure of CFTR can affect salt/water balance
- Results in production of large amounts of thick sticky mucus that are not cleared by muco-ciliary escalator
How is ∆F508 CRTR processed?
- Synthesised in endoplasmic reticulum
- Loss of Phe509 means it does not fold correctly
- Misfolded protein targeted for destruction in proteasome
- No surface expression of CFTR and no Cl- movement
What is the effect of ∆F508 in CF bronchial epithelium?
- No down regulation of sodium channel
- Na+ flooding into cells
- Increase in Na+/K+ ATPases to move Na+ out
- Trying to maintain sodium levels
- More ATP used to move Na+ out
- Only a small mount of chloride moving out (alternative chloride channels)
What are the consequences of ∆F508 on mucus production in the lung?
- Mucus becomes thick and dessicated
- Colonised with bacteria
- Cilia compressed and fail to clear mucus
- Water and salt absorbed into lung
- Neutrophils recruited to combat bacterial infection
Why are neutrophils so damaging to the lung?
- Large numbers of bacteria present in CF lung
- Neutrophils fail to destroy them in the normal way
- Frustrated phagocytosis
- Results in release activates oxygen and neutrophil proteases into extracellular space where they damage lung tissue as well as bacteria
What are the other types of CFTR defect (6 groups)?
- 1- no synthesis of CFTR at all
- 2- processing defect- not able to embed on surface
- 3-regulatory defect- issue with opening and interacting
- 4- altered conductance- issue with ion movement through channel
- 5- reduced synthesis- not enough channels
- 6- increased turnover, more quickly broken down
What are the clinical problems in CF?
- Diagnostic triad
- Persistent chest infection (2-3 year old)- accumulation of mucus in airways
- Failure to thrive- children fail to gain weight, increased metabolic demand
- Salty sweat- 79mM as NaCl not reabsorbed in sweat glands
How is desiccated mucus treated in CF?
- Physiotherapy to clear mucus
- Mucolytic agents (N-Acetyl cysteine, DNase)
- Increase in survival from <5 years to >40 years
How is infection treated in CF?
- Prevents respiratory infections
- Aggressive early treatment with antibiotics
