Cystic Fibrosis

Question 1

Diagnosis of CF

Answer 1

• sweat tests = test [NaCl]
• genotyping = 2 CF mutations an abnormal sweat [electrolyte] is generally CF
• clinical testing = symptoms of malabsorption + response to pancreatic enzyme treatment; congenital absence vas deferens; obstructive azoospermia = CF

Question 2

CF airways

Answer 2

• thick mucus secretion blocks narrow airways
• viral infections and bacteria can also colonise lungs
• viruses can descend to cause bronchitis
• Psuedomonas present in later stages of CF

Question 3

Why is CF respiratory epithelium prone to infection?

Answer 3

theory 1 - defensins
theory 2 - mucus clearance hypothesis
theory 3 - bacterial receptor theory

Question 4

Why is CF respiratory epithelium prone to infection? Theory 1 - defensins

Answer 4

• bacteria multiplied in epithelia
• killing bacteria requires low [NaCl]
• high [NaCl] in CF
• correct by decreasing [NaCl] and gene therapy with CFTR adenovirus

Question 5

Why is CF respiratory epithelium prone to infection? Theory 2 - mucus clearance hypothesis

Answer 5

• airway epithelia regulate volume of airway surface liquid (ASL) to optimise mucus clearance
• in CF, isotonic ion and water transport too high so decreased ASL volume
• so increased mucus
• retention of mucus = plaques
• which are basis of infection

Question 6

Why is CF respiratory epithelium prone to infection? Theory 3 - bacterial receptor theory

Answer 6

• CFTR helps lungs eliminate bacteria by acting as a receptor
• so bacteria engulfed and digested
• no CFTR = no bacterial receptors
• cannot internalise
• lung becomes bacterial breeding ground

Question 7

Salty sweat and CF

Answer 7

• primary sweat moves along reabsorptive duct and most salt is reabsorbed
• sodium enters cells through eNaC then to blood via sodium/potassium exchange
• chloride forced out down electrochemical gradient into ductal cells through CFTR
• chloride conductance abolished in CF
• so salt appears in sweat

Question 8

Pseudomonas and CFTR

Answer 8

• Pseudomonas killed early by, for example, NO
• Pseudomonas stimulates rapdi CFTR movement to membrane to bind and internalise bacteria
• leads to desquamation of cell with internalised bacteria
• shedding in mucus for bacterial removal
• initiation of apoptosis
• innate immune response
• neutrophils phagocytose extracellular Pseudomonas then undergo apoptosis
• ingestion of apoptotic cells by dendritic cells - present antigens to T-cells
• promote inflammation resolution

Question 9

Advantage of CF

Answer 9

• if had no benefit, CF would be eliminated due to natural selection
• carriers may be protected in middle ages cholera outbreaks
• carriers have half the number of CFTR proteins, so lose less water
• protection from diarrhoea
• alternative theory - salmonella invades GI cells by attaching to normal CFTR
• or typhoid cannot bind triangleF508 mutated CFTR