cystic fibrosis Flashcards
exocrine pancreas - 2 stages in secretion
by 1994 it was decided by the field that cftr was a chloride Channel
the acinar cells
- which secrete the digestive enzymes
-but this is of no use if you’ve not got an efficient mechanism for transporting the enzymes and that requires the secretion of bicarbonate and water.
- So you have a bicarbonate Rich fluid and that’s what the ductile cells do
- and cftr is responsible in large part for that.
CFTR and the pancreas
-CFTR expressed in pancreatic duct, so CF primarily affects ductal fluid secretion
- acinar secretion not directly affected but enzymes dont reach the intestine -> auto digestion (pancreatic insufficency
- with increased life expectancy -> autodigestion gradually destroys islet cells _> diabetes observed
ductal cell - basolateral transporters
carbonic anhydrase activity was found to be insufficient to support the secretion
steward and Ishiguro demonstrated NBCe1 (function) is vital for secretion
studies in rat and mice suggesting CFTR might be responsible for chloride secretion
studies in rats and mouse suggested that cftr might be responsible for chloride secretion.
it was suggested that there might be a chloride bicarbonate exchanger coupled to cftr that was responsible for the bicarbonate secretion.
- However, the protein responsible for this is in Electro neutral chloride bicarbonate exchanger called ae2 anion exchanger 2
- but again, this model can’t explain the huge amounts of bicarbonate that’s secreted. It just isn’tefficient enough
korean studies on chloride and bicarbonate secretion
the idea is that cftr, despite being thought of as a chloride Channel and not the bicarbonate Channel, might be responsible for the actual chloride secretion.
- So there’s another Electrogenic chloride carbonate exchanger whose molecular identity is known as SLC 26A6
- This was discovered that might help to explain this because it provides the driving force for bicarbonate secretion. However, what is also required is a bicarbonate Channel
- and what they discovered is that cftr can switch from transporting chloride to transporting bicarbonate depending on the specific ion gradients and pH changes.
the evidence now suggests that the cftr is not just a chloride Channel, but it’s
also a bicarbonate permeable channel - transports bicarbonate under specific conditions to allow the bicarbonate to accumulate within the Lumen of the pancreatic duct.
CFTR in the lungs
cystic fibrosis = decreased fluid at lung surface
-> thick viscous mucous
- impairs ‘much-cilliary escalator
- lungs become site of repeated infection
- chronic lung disease usual cause of death
lung - secretion and absorption
air surface liquid = balancing act between secretion and absorption
absorption depended on epithelial sodium channel
surface of the epithelial lining of the lungs
-goblet cells that secrete mucus
- You’ve got the epithelial cells with a cilia attached that waft this mucus along the surface until it gets to the throat and this helps to remove the bacteria
- and you’ve got this air surface liquid layer and there’s in it’s a real Balancing Act in terms of both secretion and absorption.
○ So you’ve got chloride that’s being secreted. But you’ve also got sodium that’s been reabsorbed.
○ And this absorption of sodium is governed by an epithelial sodium Channel or ENaC
and the balance of these two ion fluxes is absolutely essential for this the movement of this mucus layer on the top.
what happens with secretion and absorption with the disease cysstic fibrosis
- in the disease cystic fibrosis, there’s a lack of functional cftr which you would obviously deduce would prevent secretion of sodium chloride.
- therefore there’s less fluid secreted producing this thick mucus layer
- however, Cftr expression also inhibits ENaC activity. So if this is lost then there’s an increase in ENaC activity which makes the whole thing even worse.
○ So you end up having more sodium chloride being absorbed even though there’s less of it being secreted.
○ so you end up with this really thick mucus layer
bicarbonate secretion
thick mucous in CF observed in epithelia which secrete bicarbonate e.g. pancreatic duct, intestine, uterus, etc.
- further hypothesised that they airways must secrete bicarbonate
- bicarbonate facilitates the unfolding of mucous glycoproteins as they are secreted - so that they have that lubricating sort of property to allow the
movement of that thick mucus layer to the surface
types of defects in CF
the types of defects that might occur in the disease based on the many different mutations.
- So you could have a defect in the synthesis of the protein, or the trafficking, or the folding and then trafficking of the protein to the apical surface of the cells
○ So that defect means that they’ll be less protein at the membrane to transport chloride or bicarbonate
correctors and potentiators for treatment of CF
- there are drugs that could act as correctors to help get the protein in the membrane
- and then there are drugs that can be potentiators, So once they’re in the membrane that can actually increase the activity of the channel in the membrane,
what is CF caused by
cf is not caused by a single mutation. It’s caused by a single Gene,
- In fact, there’s around about 2,000 separate mutations that have been identified.
- That doesn’t mean that all of these are going to lead to a defect
there’s about 300 mutations that cause the disease
severe classes of mutations
class 1 - no protein sysnthesised
class 2 - defective maturation
class 3 - disordered regulation = decreased Po
potentiators - class 3
Target primarily the class three mutations where there’s a reduction in the open probability, but no changing current
