cystic fibrosis Flashcards
what is the overall function of the respiratory system?
Gas exchange: oxygen to tissues and remove CO2 produced from the body
Oxygen allows respiration (ATP energy production) whilst CO2 is toxic
what are functional changes that can cause the respiratory system to fail?
Airway remodelling–> e.g. constriction of airways/ airway obstruction= decreases airflow= decreases ventilation of respiratory structures to supply tissues with oxygen
Trauma/collapsed lung
V/Q mismatch:
- Ventilation/perfusion: oxygen or no blood flow (vice versa)
- In order to get oxygen from atmosphere to tissues–> not just respiratory system involved but also circulation!
what is Cystic fibrosis?
CF is an autosomal, recessive, genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene
describe the CFTR protein
The CFTR protein is an ion channel expressed in epithelial cell membranes that regulates the osmotic balance of lining fluid (including airways)
what is the typical clinical presentation of a CF patient?
Neonate:
Possible meconium ileus (bowel obstruction)
Childhood:
- Pancreatitis (leads to endocrine and digestive dysfunction, diabetes)
- Failure to thrive (leads to poor absorption of nutrients)
- Persistent cough and chest infection
Adulthood:
- Worsening airway/lung function (eventual effects on CVS)
- Digital clubbing
- Infertility particularly in men
CF patients do not all have the same CFTR mutation; various classes exist with varying levels of function.
describe these classes
- Class 1 is the worst: no synthesis of the CFTR protein at all
- Most functional is class 6 (however, the particular mutation means the protein has a shorter half-life in the membrane)
- Patients with class 1-3 tend to have the pancreatic symptoms
- Individuals with classes 5 and 6 tend to have sufficient CFTR function in order to avoid some symptoms/ better clinical presentation.
Describe the role of CFTR in tissues
*epithelial cell
• Hydration of lining fluid depends on osmotic balance (movement of water from the semi-permeable membrane to maintain equilibrium in the overall concentration of solutes in either side of membrane BALANCED).
• Ion movement occurs via membrane channels. H2O moves to maintain isotonicity. The presence of an ion gradient induces movement of H2O.
• A hypotonic solution is any solution that has a lower osmotic pressure than another solution. In the biological fields, this generally refers to a solution that has less solute and more water than another solution.
= out of the lining fluid into the tissue
• THEN WILL GET An isotonic solution refers to two solutions having the same osmotic pressure across a semipermeable membrane. This state allows for the free movement of water across the membrane without changing the concentration of solutes on either side.
How does the role of CFTR in tissues affect the function of the respiratory system?
Dehydrating the lining fluid= diameter of lining fluid decreased= cilia needs a particular depth to work.
mucus becomes thicker= harder to clear= clogging etc
Why is the respiratory system particularly vulnerable to CFTR dysfunction?
- Humans consume around 500 L of oxygen/day obtained from the atmosphere (therefore inhalation of around 8000L of air/day)
- The air we breathe is not pure gas. It contains a variety of potentially dangerous particles (e.g. pollutants, bacteria, viruses) that can cause infection/injury
- Due to problems in muco-ciliary clearance, leads to infection.
what is one adaptation present in the respiratory system to help defend against infection and injury?
Cilia and mucus function to trap and remove microorganisms and particles:
• Mucus: sticky substance that lines the airways–> inhaled pathogenic particles get trapped–> can’t reach the well innervated + delicate lower structures of the respiratory system–>
• Cilia: pushes the mucus up through the airways–> swallow/ cough out those dangerous particles
• 90% of mucus is produced by the submucosal glands, 10% of mucus is produced by goblet cells:
Submucosal glands are innervated by the parasympathetic nervous system.
PNS activation (e.g. due to chest infection) stimulates the mucus gland to secrete more.
what does the function of cilia rely on?
maintaining a minimum pericilliary layer thickness…
- Periciliary layer (less viscous) and then a thicker mucus gel layer
- Cilia beat rhythmically in a particular direction–> push the mucus layer in one direction
- Forward stoke of cilia= it is fully extended–> comes into contact with mucus gel layer + push it forward
- Reverse stroke= cilia compress–> not in contact with the mucus gel layer
- In order for the cilia to beat and the mucus gel layer to be moved in a coordinated manner= the depth of the periciliary layer needs to be within 4-7 micrometres.
If it becomes smaller= cilia won’t be able to beat as effectively= mucus ciliary clearance is affected/won’t protect lungs as effectively
what is the effect of CFTR dysfunction on the respiratory system?
- Airway surface liquid diameter & mucus layer viscosity needs to be maintained to function correctly (via adequate hydration).
- Alterations in ion balance due to CFTR dysfunction = movement of water/dehydration = reduced periciliary thickness = disrupted mucociliary function.
what is the role of CFTR in mucociliary clearance?
- CFTR is predominantly involved in chloride transport (into epithelial cell)
- When the channel is active= it inhibits particular signalling pathways in the cell e.g. ENaC (sodium channel that moves sodium into the epithelial cells from apical membrane)
- CFTR mutation = ↓Cl- transport & ↑Na+ absorption (no ENaC inhibition) into cell & beyond
- =↑ absorption of H2O from airway surface liquid due to osmotic pressure (ASL becomes hypotonic) = dehydration of ASL & mucus.
what effect will impaired mucociliary function have on the respiratory system?
Loss of mucocillary function leads to lung infections and airway pathology
what is the consequence of the CFTR mutation (pathology wise)?
CFTR mutation ↓ Mucus dehydration + ↓ airway surface fluid (& acidification due to ↓HCO3- secretion) ↓ Cilia dysfunction ↓ ↓Mucus clearance ↓ - increase respiratory infection - chronic airway inflammation - mucus hypersecretion and productive cough - airway dysfunction and obstruction - bronchiectasis and bronchomalacia - Type II respiratory failure + pulmonary heart disease (cor pulmonale)
bronchiectasis: pathological widening of the airways–> bad thing:
even though the overall diameter of the airway structure is increased, the lumen is still decreased (the bit where the air goes through is decreased as it is taken up by fibrosis and thickening of the wall as well as a lot of mucus)
