Cystic Fibrosis Flashcards
Trachea
Cartilaginous and fibromuscular tube
Tracheal wall has 4 different layers - mucosa, submucosa, cartilage/muscle, adventitia
Main cell type = ciliated, goblet
Cilia
Tiny “hair-like” structures on the surface of the cell that sweep mucus/dust/bacteria up to the back of the throat for swallowing
Goblet cells
Secret mucus to protect to protect the mucous membrane that lines the respiratory tract
Bronchi
Division of the trachea
Relatively large lumen
Surrounded by cartilage
Contain mucous and serous cells
Serous cells
Secrete serous fluid - a pale yellow/transparent bodily fluid, benign in nature
Bronchioles
Branches of the bronchi
No longer contain cartilage or glands in their submucosa
Generally < 1 mm diameter
Contain ciliated, goblet and club cells
Club cells
Bronchiolar exocrine cell
Main function is to protect the bronchiolar epithelium through secretion of substances and detoxification of harmful substances that are inhaled into the lungs
Can also act as stem cells - multiply and differentiate into ciliated cells to regenerate bronchiolar epithelium
Alveoli
Site of gas exchange with the blood
Each alveolus is wrapped in capillaries
Typical pair of human lungs contains 700 mil alveoli
Alveolar cells =
= pneumocytes
Type I alveolar cells
Squamous, cover 90-95 % of alveolar surface
Involved in gas exchange
Cannot replicate, susceptible to toxic insults
Type II alveolar cells
60 % of alveolar cells but cover small fraction of alveolar surface area
Involved in surfactant production and ion secretion
Precursor of type I cells - can differentiate into type I cells in the event of damage
What is the main driving force for fluid movement across the alveolus?
Sodium movement
Sodium enters alveolar epithelial cells through…
…the apical membrane via epithelial sodium channels (ENaC)
Sodium is pumped out of alveolar epithelial cells through…
…the basolateral membrane via Na/K-ATPase
How does water move out of alveolar epithelial cells?
Passively down its osmotic gradient either paracellularly or through aquaporins (type I)
Adaptations to lung fluid at birth
Foetal lungs are fluid-filled to provide a growth environment. ‘Leaky’ epithelium and low expression of ENaC
At birth, the lungs need to be cleared of fluid. Hormone surge from the mother leads to increased catecholamines (activate Na/K-ATPase) and increased corticosteroids (increase ENaC expression)
This leads to rapid movement of Na from alveolar lumen into tissues, bringing water with it down the osmotic gradient
ARDS
Acute Respiratory Distress Syndrome Caused by 'direct' and 'indirect' damage/clinical insults Direct = lung infection, aspiration Indirect = sepsis, shock, trauma Leads to ALI (Acute Lung Injury)
Acute Lung Injury
Injury of the alveolar-capillary membrane
Inflammation
Increased permeability leading to pulmonary oedema
Impaired gas exchange
How does lung infection lead to pulmonary oedema?
Infection leads to the release of interferons that downregulate Na/K-ATPase
ENaC activity is consequently reduced and there is a decreased ionic drive for water resorption - the diminished Na transport decreases alveolar fluid clearance
Therapies for pulmonary oedema
Beta agonists e.g. i.v. salbutamol
Salbutamol increases Na resorption
But actually increased mortality - thought to be due to systemic effects of salbutamol
Hypoxic Pulmonary Oedema
Acute altitude sickness leads to regional pulmonary vaso/venoconstriction
This leads to increased perfusion pressure and an increased hydrostatic drive of fluid into the lungs
Cystic Fibrosis
The most common lethal genetic disorder
Caused by a defect in Cl ion transport
1 in 25 carriers in Western populations, with 1 in 2500 live births affected
Lungs infection and dysfunction are the most common causes of morbidity
Structural changes associated with cystic fibrosis
Thickening of the bronchial wall
Bronchiectasis (permanent enlargement/dilation of the bronchial tree)
Pneumothorax (abnormal collection of are in the pleural space between the lungs and chest wall)
Neutrophilic inflammation
= the massive infiltration of neutrophils into the airways as a consequence of epithelial secretion of pro inflammatory mediators
Consequences of neutrophilic inflammation
Frustrated phagocytosis
Failure to clear bacteria/dying neutrophils
Epithelial damage
Decline in lung function
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator
Cl- channel
Cystic fibrosis is caused by no/mutated expression of CFTR
Structure of CFTR
2 transmembrane domains, each connected to a nucleotide-binding domain in the cytoplasm
The NBDs are connected via a regulatory domain
Gating of CFTR
“ATP-gated ion channel”
CFTR opens when the R domain is phosphorylated by PKA and ATP is bound at the NBDs
Cl- flows down its electrochemical gradient (generally export from the cell in airways), which means sodium will follow, which means water will follow
Normal CFTR
There is a balance between ion flow and water entry/export
This leads to a thin layer (approx. 7 micrometres) of fluid on the apical surface of the epithelial cells
Defective CFTR
There is no Cl- flow out of the cell so there is no gradient for water to move out of the cell
Leading to a thin ‘Air-Surface Liquid’ (ASL) layer (approx. 1 micrometre)
This leads to sticky/viscous mucus that is difficult for the cilia to clear, providing a growth environment for bacteria
Established therapies for cystic fibrosis
Neonatal screening for early recognition - proper nutrition and enzyme supplements
Antibiotics e.g. inhaled tobramycin against pathogens
Beta agonists to activate residual CFTR activity
Hypertonic saline
Mucolysis
Gene therapy trials ongoing
CFTR gene
Nearly 300 mutations in the CFTR gene have been descibed
These mutations have many molecular consequences for the synthesis of CFTR and its transport through the cell to the cell surface
Defects in CFTR
Class I = defective/reduced protein production (10 %), e.g. nonsense mutations/premature termination codon, e.g. G542X
Class II = defective processing (88 %), i.e. no transport from the ER to the Golgi. Resulting from in-frame deletion e.g. DF508
Class III = defective regulation (2-3 %), i.e. no transport from the Golgi to the cell surface. Resulting from substitution e.g. G551D (and DF508)
Class IV = defective conduction (< 2 %), where CFTR reaches the cell membrane and some of the protein is functional, but Cl- transport is reduced due to channel narrowing
Class V = decreased surface expression (least common). Normal CFTR but less of it is expressed
Class VI = decreased surface stability (mutations in PDZ binding domain)
CFTR activators and potentiators
Lumacaftor = ‘chaperone’ during protein folding, increases number of CFTR trafficked to cell surface
Ivacaftor = ‘potentiator’ of CFTR already at the cell surface, increases the probability of a defective channel being open for Cl- to pass through
These 2 drugs have ‘synergistic’ effects
Ivacaftor
For treating patients with G551D mutation (class III)
Lumacaftor/ivacaftor combination
For treating patients with DF508 mutation (class II)
Other therapeutic strategies for cystic fibrosis
- Activation of alternative Cl- channels
2. Blocking sodium resorption
Activation of alternative Cl- channels as a therapy for cystic fibrosis
e.g. activators of calcium-activated chloride channels (CACC)
e.g. Denufusol = P2Y2 agonist
Second phase III trial showed compound to be ineffective at maintaining lung function - possibly because Cl- channels in goblet cells were also activated, which would increase mucus production
Blocking sodium resorption as a therapy for cystic fibrosis
e.g. through blocking ENaC (but does present risk of hyperkalaemia)
e.g. Amiloride = kidney diuretic, tested in CF but had a very short half life in the airways
New compounds may be more effective - some Na+ channel blockers are in the pipeline e.g. QBW276, SPX-101, AZD5634
