L7 Cystic Fibrosis I

what is the most common life-limiting autosomal recessive disease in white Caucasians

Cystic fibrosis

what is cystic fibrosis caused by

loss-of-function mutations in the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) gene

CFTR is an anion channel that regulates…

the volume and pH of epithelial secretions

what is CF characterised by

severe lung and pancreatic disease

• GI tract, reproductive tracts and sweat glands affected

how much morbidity and mortality does CF lung disease account for

90%

how many people in the UK have CF

>11,000

how many people worldwide have CF

~150,000

what is the probability of being a CF carrier

1 person in ~25

how many people in the UK are carriers

~2.3m in the UK

how many live births does CF equate to

1:2500

In 1964, median life expectancy (MLE) was …

5 years

MLE has risen to …. (for those born in 2020) and is increasing due to better treatments

5 years

CF females have … MLE than males

lower

only since 2013, there were more adults than…

children with CF

how many mutations (variants) of CF have been identified

over 2000

how many CF variants have been shown to cause disease

~1085

what is the most common CF mutation

F508del

how does F508 del occur

loss of phenylalanine at position 508 in NBD1

~50% of pwCF are… for F508 del

homozygous

~35% of pwCF are compound…

heterozygotes (e.g. F508del/G542X)

what is found in at least one allele in 85% of people with CF (pwCF)

F508 del

give an example of pwCF compound heterozygotes

• F508 del

• G542X

what do only 5 other CF mutations have a frequency of

1%

• G551D

• G542X

what is the ratio of black americans with CF

~1:15,000

what is the ratio of asians with CF

~1:32:000

Give an example of CFTR I

G542X (a)

what is CFTR I

no protein

what is CFTR II

no traffic

give an example of CFTR II

F508del

what is CFTR III

no function

give an example of CFTR III

G551D

what is CFTR IV

less function

give an example of CFTR IV

R117H

what is CFTR V

less protein

give an example of CFTR V

A455E

what is CFTR VI

less stable

give an example of CFTR VI

rF508del

what classes are minimal (or no) function (MF) mutations

class I, II and III

what classes are residual function (RF) mutations

Class IV, V and VI

what classes of CFTR produce the most severe phenotype for CF?

class I, II and III

what is the genotype phenotype relationship of the lungs

poor

what is the genotype phenotype relationship of the pancreas

good

what is the genotype phenotype relationship of the sweat gland

good

what percentage of people born with CF are pancreatic insufficient

85%

what does CFTR in the conducting airways maintain

proper hydration and pH of the airway surface liquid (ASL), which includes the PCL layer and the mucus (or gel) layer

what does proper hydration and pH of the airway surface liquid ensure

efficient mucociliary clearance (MCC) which removes pathogens that get trapped in the mucus layer

what also secrete antimicrobial peptides (AMPs) into the ASL

submucosal glands

in healthy airways, an efficient mucociliary clearance (MCC) removes…

pathogens trapped in the mucus layer

what does failure in MCC lead to

lung disease in CF

In CF, the ASL is…

dehydrated and more acidic

what does dehydrated and acidic ASL lead to

• viscous mucus (mucus stasis)

• mucus accumulation and obstruction

• failure in MCC

what does mucus stasis and obstruction lead to

• chronic bacterial colonisation

• airway inflammation

• respiratory failure

what does ASL pH drive

CF pathogenesis

in CF what is ASL pH

more acidic

what does lack of CFTR function reduce

HCO3- secretion into the ASL

Together with active H+ secretion (via an apical proton ATPase) from the airway cells what does this produce

a more acidic ASL pH

what are the consequences of a more acidic ASL

• increases fluid absorption due to enhanced ENaC activity

• increased mucus stasis and viscosity

• decreased bacterial killing

how is increasing fluid absorption due to enhanced ENaC activity a consequence of a more acidic ASL

due to increased Channel Activating Proteases (CAP) activity (cathepsin B and neutrophil elastase) and decreased SPLUNC1 function

how is increased mucus stasis and viscosity a consequence of a more acidic ASL

due to decreased mucin release and expansion (unfolding) on release from goblet cells, and conformational changes in mucins making them more rigid

how is decreased bacterial killing a consequence of a more acidic ASL

due to reduced AMP activity

describe how a defect in CFTR causes lung disease

• decreased Cl- and HCO3- transport

• decreased ASL volume and pH

• increased ENaC function

• increased mucus obstruction

• decreased MCC

• decreased antimicrobial activity

• increased bacterial and viral infections

• increased inflammation

• destruction of lung

what is mucus clogging

physiotherapy and mucolytics

what happens during the restoration of ASL

nebulised hypertonic saline of mannitol

how does nebulised hypertonic saline or mannitol improve hydration

draws water from the body into the airways

whats a disadvantage of mucus clogging and restoring ASL

the effect is transient

whats the treatment for recurrent lung infections

antibiotics

• oral, IV and inhaled depending on bacteria and extent of infection

majority of pwCF eventually get chronically infected with…

Pseudomonas aeruginosa

what does Pseudomonas aeruginosa cause

~1% loss of lung function per year

how do you treat overactive immune response

NSAIDs

how do you treat the destruction of lung

lung transplant