CF patients Flashcards
CF is inherited in which manner?
Autosomal recessive manner
CF is caused by mutations in the?
Gene encoding the CFTR
What is the CFTR?
Cystic Fibrosis Transmembrane Regulator
What problems in the CFTR can cause CF?
Dysfunctional CFTR CFTR targeted for degradation Not enough CFTRs expressed CFTR unable to be activated CFTR may not be synthesised at all
What is the most common CFTR mutation?
Delta F508
What is the delta F508 mutation?
Lacks phenylalanine at position 508
Produces an abnormal CFTR which cannot fold properly
This protein does not escape the endoplasmic reticulum for further processing. Leads to degradation in the ER.
Cystic fibrosis has multiple organ involvement including?
- Lungs
- Gut & liver
- Reproductive tract
- Sweat glands
What is the CFTR?
Cystic Fibrosis Transmembrane Regulator
What is the main function of the CFTR?
- Secretes chloride ions, causes sodium and water to follow passively
- Regulates Na+ absorption by inhibiting ENaC.
What is the delta F508 mutation?
No phenylalanine at position 508
CFTR cannot fold properly
Does not escape the endoplasmic reticulum for further processing and is degraded in the ER
Defects in the CFTR lead to?
- Not enough chloride ions are secreted
- ENaC cannot be controlled and is upregulated
What is the function of the CFTR?
- To secrete chloride ions, passively followed by Na+ and water
- To regulate Na+ absorption by inhibiting ENaC
What happens in the absence of a functional CFTR?
Not enough chloride ions are being secreted. Lots of reabsorption of Na+ and water as the ENaC is upregulated. This leads to a thick dehydrated mucus layer
What is the ASL?
Airway Surface Liquid
What is the ASL made up of?
The mucus layer and the periciliary layer (PCL)
Where is the periciliary layer located?
Below the mucus layer
In normal individuals?
The ASL is hydrated as chloride ions are secreted by the functional CFTR which is passively followed by Na+ and water. The mucus is normal and can be swept away by the cilia- mucociliary escalator is functional. The ENaC is being inhibited and Na+ absorption is controlled by the CFTR.
In CF individuals?
CFTR is not functional
There is not enough chloride secretion
There is a lot of Na+ and water reabsorption by the ENaC which is now upregulated due to the dysfunctional CFTR
Leads to the accumulation of thick dehydrated mucus which then collapses the PCL- periciliary layer. The mucus now sits directly on top of the epithelial cells and cannot be shifted.
CF patients are much more susceptible to?
P.aeruginosa infection
What type of infection establishes in CF patients?
Chronic infection
By adulthood how many CF patients are infected with P.aeruginosa?
80% of adults
Most common antibiotics used in treatment include?
Tobramycin and colistin
Last resort antibiotic?
Polymyxin
Polymyxin is a type of?
Colistin
How does P.aeruginosa have antibiotic resistance?
- Against beta lactam antibiotics via the beta lacatamases
- Intrinsic resistance provided by the biofilm
- Low permeability of the bacteria
- Changes in LPS structures
- Upregulation of efflux pumps
Example of a negative regulator of an efflux pump?
MexZ
OprD is an?
Outermembrane protein, a small peptide/basic amino acid channel
Loss of OprD allows resistance to?
Carbapenems
Cabapenem beta lactams enter via?
OprD
Loss of OprD also allows?
Acid resistance
Resistance to serum killing
Only four antibiotics effective against P.aeruginosa?
Beta-lactams
Aminoglycosides- tobramycin
Colistins- Polymyxin
Fluoroquinolones
