CF

Question 1

What is CF?

Answer 1

Cystic fibrosis is an autosomal, recessive disorder caused by mutations in the cystic fibrosis transmembrane conductor (CFTR) gene

Question 2

What is the CFTR protein?

Answer 2

• an ion channel expressed in epithelial cell membranes that regulates the osmotic balance of lining fluid

Question 3

Is CFTR mutation always the same?

Answer 3

CF patients do not all have the same CFTR mutation: various classes exist with varying levels of function

Question 4

Function of CFTR gene?

Answer 4

• CFTR functions to help maintain hydration of secretions within glands & ducts (e.g. airways)

Question 5

What does hydration of lining fluid depend on?

Answer 5

• osmotic balance (movement of water to maintain equilibrium in the overall concentration of solutes)

Question 6

How does ion movement occur?

Answer 6

• via membrane channels
• H2O moves to maintain isotonicity
• The presence of an ion gradient induces movement of H2O

Question 7

Function of Cilia and Mucus?

Answer 7

• Cilia & mucus help to protect the respiratory system for microorganisms & particles
• trap and remove microorganism’s and particles

Question 8

What does cilia function rely on?

Answer 8

• maintaining a minimum periciliary layer thickness

Question 9

What does absence of functional CFTR lead to?

Answer 9

• dehydration of airway surface liquid & impaired mucociliary clearance

Question 10

What 2 things need to br maintained in order for correct functioning?

Answer 10

• Airway surface liquid diameter + mucus layer viscosity
• Alterations in ion balance due to CFTR dysfunction = movement of water = reduced periciliary thickness = disrupted mucociliary function

Question 11

Describe CF mutation in terms of CL-/Na+

Answer 11

• decreased Chloride ion transport
• increased Sodium ion absorption

(via reduced epithelial sodium channel (ENaC) inhibition into cell

-Increased absorption of water from airway surface liquid due to osmotic pressure (ASL becomes hypotonic) = dehydration of ASL and mucus

Question 12

What does loss of mucociliary function lead to?

Answer 12

• respiratory infections and airway pathology

Question 13

Mucus Dehydration pathway?

Answer 13

• Mucus dehydration
• decreased airway surface fluid
• Cilia dysfunction
• Less mucus clearance
• more resp infections
• chronic airway inflammation
• Bx
• T2 resp failure

Question 14

What is airway inflammation in CF?

Answer 14

• Neutrophilic
• Exaggerated
• Self-Perpetuating
• Ineffective at clearing infection

Question 15

Bacterial Infection Pathway?

Answer 15

• bacterial infection
• airway inflammation (neutrophilic)
• increase protease
• cell and tissue injury
• cilia damage and increased mucus secretion

Question 16

What is airway remodelling?

Answer 16

long term-irreversible, changes to airway structure & function)

Question 17

What is Bx/Bronchiecstasis?

Answer 17

pathological widening of the airways

Question 18

What is Bronchomalacia?

Answer 18

degradation and weakening of airway structure

Question 19

How does chronic inflammation within the airways lead to respiratory failure?

Answer 19

• Frequent & persistent airway bacterial infection
• Chronic airway inflammation
• Airway remodelling
  (bronchiectasis & bronchomalacia)
• Airway obstruction
  (blockage due to accumulation of viscous mucus)
• ↓alveolar ventilation
• Type 2 respiratory failure

Question 20

Overall treatment strategy?

Answer 20

• to help patient breath and limit long term damage to the airways

Question 21

4 treatment aims?

Answer 21

• Promote mucus removal
• Treat infections and inflammatory exacerbations as they arise
• Treat acute airway obstruction
• If suitable, use more recently developed CFTR modulators to limit pathology arising.

Question 22

How to

CFTR gene mutation
↓
CFTR protein dysfunction
↓
ASL depletion
↓
Mucus plugging
↓
Infection
↓
Inflammation
↓
Airway obstruction
↓
Respiratory failure

Answer 22

CFTR gene mutation –> Gene Therapy

CFTR protein dysfunction –> CFTR modulators

ASL depletion –> Hypertonic saline

Mucus plugging –> Physiotherapy, N-acetylcysteine, dornase-alfa

Infection –> Antibiotics

Airway obstruction –> Bronchodilators

Resp Failure –> Lung transplant

Question 23

SUMMARY CARD:

Answer 23

Cystic fibrosis is an genetic disorder caused by a mutation in the CFTR gene, which leads to protein dysfunction.

CFTR dysfunction results in disrupted epithelial ion transport, resulting in dehydration of airway lining fluid/mucus and impaired mucociliary clearance.

Failure to clear mucus effectively leads to infection and (primarily neutrophilic) inflammation of the airway. The excessive protease and ROS release causes cell and tissue injury, further impairing mucus clearance.

A vicious cycle is created resulting in progressively worsening airway obstruction (via accumulation of mucus), bronchiectasis, bronchomalacia. This eventually leads to type II respiratory failure (inadequate ventilation) and right heart failure.