Understand the cellular mechanisms involved in chloride secretion
refer to L24
Understand and describe how a defect in chloride secretion can cause the diverse clinic symptoms associated with Cystic Fibrosis
refer to L24
Have insight into the excitement associated with physiological research
refer to L24
What is the process of chloride secretion?
- Tight junctions divide cells into apical and basolateral membrane domains.
- Sodium pump sets up ion gradients.
- The NaK2
Cl symporter uses the energy of the Na+ gradient to actively accumulate chloride above
its concentration gradient. - Cl-
leaves the cell by passive diff usion through an ion channel; - Na+ exits via the basolateral sodium pump and K+ exits via its channel.
- The transport of Cl-
across the epithelium induces paracellular Na+ and water fl uxes.
What is Cystic Fibrosis?
Cystic Fibrosis (CF) is a complex inherited disorder that affects children and young adults.
It is
inherited in an autosomal recessive fashion.
Heterozygotes have no symptoms but are carriers.
The child of two carriers have a 1 in 4 chance of getting cystic fibrosis.
The frequency of the disease
varies among ethnic groups.
In Northern Europeans, 1 in 2500 newborns are aff ected and 1 in 25
are carriers.
Cystic Fibrosis is less common in other ethnic groups.
People with CF have a very salty sweat. Formation of sweat is a two stage process:
- A primary isotonic secretion of fl uid by acinar cells.
- A secondary reabsorption of NaCl to produce a hypotonic solution.
The failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl produces the salty sweat
in CF patients
What is the cure for cystic fibrosis?
- Chest percussion to improve clearance of infected secretions.
- Antibiotics to treat infections.
- Pancreatic enzyme replacement.
- Attention to nutritional status.
What is the rate limiting step in Chloride secretion?
Although Cl- is accumulated above electrochemical equilibrium it can not leave the cell unless the Cl- channel is open
The opening of the Cl- channel is strictly regulated (gated)
Thus the opening of the Cl- channel is the rate-limiting step in Cl- secretion
The Cl-channel has been identified at the molecular level as the Cystic Fibrosis Transmembraneconductance Regulator (CFTR)
CFTR over stimulation has been implicated in secretory diarrhea and its dysfunction causes cystic fibrosis
What are the features of Secretory diarrhoea
- Caused by excessive stimulation of the secretory cells in the crypts of the small intestine and colon
- Excessive stimulation could be due to abnormally high concentrations of endogenous secretagogues produced by tumours or inflammation
- More commonly it is due to the secretion of enterotoxins from bacteria such as Vibrio cholerae
- Enterotoxins irreversibly activate adenylatecyclasecausing a maximal stimulation of CFTR lead to a secretion that overwhelms the absorptive capacity of the colon
What is the molecular mechanism of chlorea?
refer to lecture 24 slides
How do you treat secretory diarrhoea?
Oral rehydration therapy can be used to treat secretory diarrhoea caused by cholera
- Glucose stimulated water flux for absorption via Villus
- Over stimulationof secretion for secretion via Crypt
What are the organs affected by cystic fibrosis?
airways, liver, pancrease, small intestine , reproductive tract
A common theme is the involvement of epithelial tissues
Most cases of mortality are due to respiratory failure
What is the median survival age for cysric fibrosis?
38 years
What is CFTR?
Cystic fibrosis transmembrane conductance regulator
CFTR is an Cl channel regulated by protein kinase A dependent phosphorylation of the R domain and binding of ATP to the NBD
Blocking Cl- secretion contributes to lung pathology
rewatch lecture
-
Cystic fibrosis a defect in Cl- secretio slide
rewatch lecture
How does Blocking Cl- secretion contribute to lung pathology ?
lecture slide
What is the mechanism for sweat formation?
Lecture 24
