CF Flashcards
What is CF?
Cystic fibrosis is an autosomal, recessive disorder caused by mutations in the cystic fibrosis transmembrane conductor (CFTR) gene
What is the CFTR protein?
- an ion channel expressed in epithelial cell membranes that regulates the osmotic balance of lining fluid
Is CFTR mutation always the same?
CF patients do not all have the same CFTR mutation: various classes exist with varying levels of function
Function of CFTR gene?
- CFTR functions to help maintain hydration of secretions within glands & ducts (e.g. airways)
What does hydration of lining fluid depend on?
- osmotic balance (movement of water to maintain equilibrium in the overall concentration of solutes)
How does ion movement occur?
- via membrane channels
- H2O moves to maintain isotonicity
- The presence of an ion gradient induces movement of H2O
Function of Cilia and Mucus?
- Cilia & mucus help to protect the respiratory system for microorganisms & particles
- trap and remove microorganism’s and particles
What does cilia function rely on?
- maintaining a minimum periciliary layer thickness
What does absence of functional CFTR lead to?
- dehydration of airway surface liquid & impaired mucociliary clearance
What 2 things need to br maintained in order for correct functioning?
- Airway surface liquid diameter + mucus layer viscosity
- Alterations in ion balance due to CFTR dysfunction = movement of water = reduced periciliary thickness = disrupted mucociliary function
Describe CF mutation in terms of CL-/Na+
- 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
What does loss of mucociliary function lead to?
- respiratory infections and airway pathology
Mucus Dehydration pathway?
- Mucus dehydration
- decreased airway surface fluid
- Cilia dysfunction
- Less mucus clearance
- more resp infections
- chronic airway inflammation
- Bx
- T2 resp failure
What is airway inflammation in CF?
- Neutrophilic
- Exaggerated
- Self-Perpetuating
- Ineffective at clearing infection
Bacterial Infection Pathway?
- bacterial infection
- airway inflammation (neutrophilic)
- increase protease
- cell and tissue injury
- cilia damage and increased mucus secretion
What is airway remodelling?
long term-irreversible, changes to airway structure & function)
What is Bx/Bronchiecstasis?
pathological widening of the airways
What is Bronchomalacia?
degradation and weakening of airway structure
How does chronic inflammation within the airways lead to respiratory failure?
- 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
Overall treatment strategy?
- to help patient breath and limit long term damage to the airways
4 treatment aims?
- 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.
How to
CFTR gene mutation ↓ CFTR protein dysfunction ↓ ASL depletion ↓ Mucus plugging ↓ Infection ↓ Inflammation ↓ Airway obstruction ↓ Respiratory failure
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
SUMMARY CARD:
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.
