cystic fibrosis Flashcards
Describe the typical presentation of a CF patient
Neonate
Possible meconium ileus (bowel obstruction)
Childhood
Pancreatitis (endocrine and digestive dysfunction, diabetes)
Failure to thrive (poor absorption of nutrients)
Persistent cough & chest infection
Adulthood
Worsening airway/lung function (eventual effects on CVS)
Digital clubbing
CF patients do not all have the same CFTR mutation: various classes exist with varying levels of function.
Explain.
severity of the class shows severity
1 and 2 are worst
5 and 6 are least
depending on the typeof CFTR mutation
In the normal CFTR gene you get normal Cl- conductance and the protein functions well
In 1, the protein isn’t synthesised, in 2 there is a folding defect, in 3 there is a block in regulation leading to channel opening defect, in 4 there is an ion transport defect etc
What is the role of CFTR in tissues
The cystic fibrosis transmembrane conductance regulator (CFTR) protein helps to maintain the balance of salt and water on many surfaces in the body, such as the surface of the lung. When the protein is not working correctly, chloride – a component of salt – becomes trapped in cells.
Hydration of lining fluid depends on osmotic balance (movement of water to maintain equilibrium in the overall concentration of solutes).
Ion movement occurs via membrane channels. H2O moves to maintain isotonicity. The presence of an ion gradient induces movement of H2O.
role of cilia and mucus and what happens when cftr is lost
Cilia and mucus function to trap and remove microorganisms and particles
Function of cilia relies on maintaining a minimum periciliary (between mucus cell layer andscretory cells) layer thickness
as cilia moves backwards, it doesn’t come in contact with the thick layer of mucus
only in pericillary layer which is less viscous
when it moves forward, it comes in contact with the mucus gel layer which helps to push it forward
if there is too much water in the pericillary layer, then the forward stroke will cause the mucus to not make contact with the pericillary layer
this HYDRATION of the pericilary layer is what is controlled by the CFTR channel because that controls the movement of ions thus controlling the movement of water
when CFTR is lost, causes a shift in ion balance
water moves away from lining fluid or pericillary layer into the cytosol
causes dehydration of the lining fluid of the mucus
cilia cant beat effectively- disrupted mucus and function
Effect of CFTR 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 = reduced periciliary thickness = disrupted mucociliary function.
At the airway surface, deletion of CFTR causes hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content, which impairs mucociliary clearance.
In submucosal glands, loss of CFTR-mediated salt and water secretion compromises the clearance of mucins and a variety of defense substances onto the airway surface.
Impaired mucociliary clearance, together with CFTR-related changes in the airway surface microenvironment, leads to a progressive cycle of infection, inflammation, and declining lung function.
role of CFTR in mucociliary clearance
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
in absence of CF protein you get changes in chloride ion movement and loss of inhibition of Na channels
causes net movement of sodium from lining fluid to cytosol
change in osmotic balance
water follows these ions
dehydrates pericillary layer
problems in the way cilia beat
disrupted mucus clearance
CFTR mutation ↓ Mucus dehydration + ↓ airway surface fluid (& acidification due to ↓HCO3- secretion) ↓ Cilia dysfunction ↓ reduced Mucus clearance
Increased Respiratory infections Chronic airway inflammation Mucus hypersecretion + productive cough Airway dysfunction & obstruction Bronchiectasis & bronchomalacia Type II respiratory failure + pulmonary heart disease (cor pulmonale)
if the person is more vulnerable to respiratory infection you get infection inflammation injury to surrounding tissues fibrosis of tissue tissue injury and scarring (injury and remodelling)
Why is bacterial infection and chronic inflammation damaging to the airways?
TLRs detect specific fragments on surface of bacteria
triggers inflammatory response like release of cytokines and chemokines like IL 8
attracts immune cells to the airways like neutrophils
causes degranulation
in CF, neutrophils are recruited
granulocytes contain pro-inflammatory mediators
destroys the bacteria
causes protease release, destroys bacteria
various ROS released due to degranulation of neutrophils damage surrounding tissue
leads to tissue injury
Airway inflammation in CF is: Neutrophilic Exaggerated Self-perpetuating Ineffective at clearing infection
Long term injury causes airway remodelling:
Bronchiectasis
Bronchomalacia
Airway obstruction
when normal person has a bacterial infection even tho they can get ROS
there a proteins and mediators within tissues act to inhibit these
anti proteases stop proteases working
glutathione reduces potential damge from ROS
as you get fibrosis and repeated infection these processes get overwhelmed from ros and proteases
this cycle gets worse further damaging airway tissue
causing airway remodelling
bronchiectasis: pathological widening of airways- mucocilary clearance is even harder, more obstructed by accumulated mucus, proportion of airway able to conduct air is small
bronchomalacia: weak and floppy ariways- airway can’t cope with compressive forces or pressure changes during expiration similar to COPD. can’t handle as it’s been degraded so it collapses due to reduced airway patency
How type 2 resp failure can lead to cardiovascular failure
airway obstruction reduces ability to ventilate alveoli because the airways are blocked
leads to alveolar hypoxia- in severe ACUTE cases can cause asphyxia
on a CHRONIC basis, will cause hypoxic vasoconstriction of pulmonary blood vessels. If level of oxygen decreases in surrounding tissue, causes the blood vessels to constrict in order to divert blood to alveoli that are not hypoxic.
But if lungs as a whole become hypoxic, you increase vascular resistance throughout pulmonary circulation
causes pulmonary hypertension
heart has to work harder to pump thorugh
leads to right ventricular hypertrophy
helps heart in short term but leads to heart becoming less efficient
heart won’t be able to cope with force required to pump blood through pulmonary system -right heart failure
cor pulmonale
Q: Given the nature of the CF respiratory pathophysiology we have discussed, what therapies or therapeutic strategies (e.g. what changes we want to achieve?) could be used to treat patients?
Overall treatment strategy (to help patient breath and limit long term damage to the airways):
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.
CFTR modulators try to increase function CFTR proteins in membrane (a class of CF patients that have protein expressed in the membrane but the function is not good)
saline can hydrate airway secretions
physio can manually remove mucus through massage of the thorax and back
in the long term antibiotic resistance- psuedomonas develop biofilms making it harder to treat and clear
bronchodilators can help temporarily but they don’t deal w the problem at hand as they stop contraction of airway smooth muscle and SM contraction isn’t the real problem
bacterial infections can re-occur after transplant
with similar inflammatory processes
CFTR gene mutation GENE THERAPY ↓ CFTR protein dysfunction CTFR MODULATORS ↓ ASL depletion HYPERTONIC SALINE ↓ Mucus plugging PHYSIOTHERAPY, N ACETYLCYSTEINE ↓ Infection ANITBIOTICS ↓ Inflammation CORTICOSTERIOIDS ↓ Airway obstruction BRONCHODILATORS ↓ Respiratory failure LUNG TRANSPLANT
Summary of points
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).
