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Flashcards in Cystic Fibrosis Deck (39):


Cartilaginous and fibromuscular tube
Tracheal wall has 4 different layers - mucosa, submucosa, cartilage/muscle, adventitia
Main cell type = ciliated, goblet



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



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



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



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



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
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



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
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



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

1. 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