L10.2 Cystic Fibrosis

Question 1

3 major components of mucociliary transport of the Normal lung epithelium - Sol phase

Answer 1

• Nonviscous serous fluid adjacent to bronchial epithelial cells
• Active fluid with innate defence molecules → primary defence
• Depth of fluid controlled precisely
  
  • Too deep → cilia cannot move mucous
  • Too shallow → cilia squashed and can’t move mucous

Question 2

3 major components of mucociliary transport of the Normal lung epithelium: Gel phase + Cilia

Answer 2

• Gel phase
  
  • Mucous layer formed by secretions of mucous glands
• Cilia
  
  • On surface of epithelial cells within sol phase, able to extend into gel phase → move mucous

Question 3

Features of CFTR

Answer 3

• CFTR (cystic fibrosis transporter R) is a chloride channel
  
  • Controls salt concentration and depth of fluid
  • Located in plasma membrane of lung epithelium (not uniquely located in the lungs)
  • Homo recessive disorder → no working copies of CFTR
    
    • GTFR is ethnically constrained (↑ in caucasians)

Question 4

Mechanism of CF

Answer 4

• Mutation in the CFTR gene
  
  • ↓Cl secretion → ↓H2O diffusion into sol layer → altered sol depth → altered cilia function → thick mucous
• Thick mucous → damage/dilate airways → have bad gas exchange

Question 5

Symptoms at birth

Answer 5

• Obstruction of bowel at birth
• Poor growth and weight gain despite good appetite
• Greasy, bulky stools
• Salty tasting skin
• Cough and other resp symptoms

Question 6

Symptoms with children

Answer 6

• Persistent coughing, may be with sputum, wheezing/shortness of breath
• Frequent resp infections
• Poor growth and difficulty with weight gain
• Malnutrition and vitamin deficiency

Question 7

Symptoms at adolescence

Answer 7

• Recurrent/persistent lung infections
• Chronic sinusitis
• Clubbing fingers/toes
• Male infertility with absence of sperm
• Malnutrition

Question 8

Symptoms at adult

Answer 8

• Progressive decline in lung function, exacerbation in lung infections
• CF-related diabetes
• Osteoporosis
• Malnutrition

Question 9

Selective advantage of CFTR mutation

Answer 9

• Evolved mutations in multiple regions of the protein
• Protein has been under beneficial selective pressure - with F508 gene mutation (common mutation)
  
  • Protective against cholera
  • Cholera is a pathogen in gut epithelium → activates CFTR → Cl efflux and H2O efflux → death by dehydration
    
    • Variant of CFTR may have provided protection

Question 10

6 classes which mutations are classified into (reflecting their effect on biology)

Answer 10

1. Defective protein syn
2. Abnormal processing
3. Defective activation
4. ↓conductiance
5. ↓syn
6. Defective regulation of other ion channels

Question 11

How do pathogens colonise the lungs?

Answer 11

• From weakened host defence → colonisation by pathogens
• Colonised with P. aeruginosa → rapid development to lung failure
• Transitions from free state (easy to kill with standard AB) → to live in biofilms in CF lungs
  
  • Becomes v hard to kill
  • Own immune system destroy lungs in the process of trying to eliminate aeruginosa

Question 12

Vicious cycle of chronic airway inflammation

Answer 12

1. Neutrophils killed by P. aeruginosa
2. Proteases release from neutrophil death
3. Recruit more neutrophils
4. Cycle repeats → destroy lung tissues overtime

Question 13

Treatment of CF

Answer 13

• AB
• DNase
• NSAIDs
• Ivacraftor + Lumacraftor

Question 14

Azithromycin

Answer 14

• Prevents elongation of polypeptide chain needed for bac protein synthesis
• Improves lung function
• Gains weight
• Anti-inflam & Antibiotic effect

Question 15

SE of Azithromycin

Answer 15

• ↑ risk of infection with nontuberculous mycobacteria
• Arrhythmia
• Deafness

Question 16

Tobramycin

Answer 16

• (inhaled)
• Toxic orally, ∴inhaled
  
  • ↑↑conc in lung mucosa

Question 17

Aztreonam

Answer 17

• Inhaled
• Similar to penicillin
• Inhibit mucopeptide syn in bac cell wall → block peptidoglycan crosslinking
  
  • Bactericidal

Question 18

Experimental anti-PA AB

Answer 18

• Binds to protein of PA that injects toxin into host cell to prevent its action

Question 19

DNase

Answer 19

• Viscosity of mucus due to mammalian DNA mixed with protein
• Breakdown DNA → makes mucus thinner and ∴ easier to take out
• But $$ and not much more effective than hypertonic saline

Question 20

Ibuprofen (NSAID)

Answer 20

• Better growth and less hospitalisation
• Adjunct therapy → limit damage of inflam

Question 21

Ivacaftor

Answer 21

• Opens G551D mutant of CFTR (also works on other mutations) → allowing it to be active again
  
  • Alters/improves conformation of the subunits → allow movement of ions
• Function could be improved if more R comes to the surface
• Not effective for CF patients homozygous for F508 mutation
  
  • Prevents CFTR moving into proper position
• 2x increase in channel activity

Question 22

Lumacraftor

Answer 22

• Approved for patients homozygous for F508del
• Acts on CFTR during folding → to prevent misfolding
  
  • ↑surface levels of CFTR
• Used in combination with ivacaftor