Transport Across Epithelia

Question 1

What is chloride secretion

Answer 1

• A two step process where a cotransporter located in the basolateral membrane accumulates chloride above its electrochemical gradient.
• This enables chloride to leave the cell via a chloride channel located in the apical membrane.
• Sodium moves via the paracellular pathway to preserve electoneutrality.

Question 2

What are the key features of chloride secretion across an epithelial cell

Answer 2

1. tight junctions divide into apical and basolateral membrane
2. Na pump sets up ion gradients
3. The NaK2Cl symporter uses the energy of the Na gradient to actively accumulate chloride above its electrochemical gradient
4. Cl leaves the cell by passive diffusion through an ion chennl.
5. Na exits via the basolateral Na pump and K+ via channel
6. The transport of Cl across the epithelium induces paracellular Na and water fluxes.

Question 3

What is the rate limiting step in chloride secretion

Answer 3

The opening of the Cl- channel

Question 4

Describing the rate limiting step

Answer 4

• Although Cl- is accumulated above electrochemical equilibrium is 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.

Question 5

What is one cause (least common) of secretory diarrhoea?

Answer 5

• Excessive stimulation of the secretory cells in the crypts of the small intestine and colon.
• This could be due to abnormally high concentrations of endogenous secretagogues produced by tumours or inflammation.

Question 6

Two causes of secretory diarrhoea

Answer 6

Excessive stimulation of the secretory cells in the crypts of the small intestine and colon and more commonly, the secretion of enterotixins from bacteria such as Vibrio cholerae.

Question 7

What is the second cause of secretory diarrhoea (most common)?

Answer 7

• Due to secretion of enterotoxins from bacteria such as Vibrio cholerae.
• Enterotoxins irreversibly activate andeylate cyclase causing a maximal stimulation of CFTR lead to secretion that overwhelms the absorptive capacity of the colon.

Question 8

What is the molecular mechanism of cholera

Answer 8

Cholera toxin irreversibly activates adenlylate cyclase causing activation of CFTR. This catalyses the production of ATP to cAMP which activates protein kinase A which phosphorylates CFTR.

Question 9

How do we treat secretory diarrhoea caused by cholera?

Answer 9

Through oral rehydration therapy.

Question 10

What is cystic fibrosis

Answer 10

A complex inherited disorder that affects children and young adults.

Question 11

Organs affected by cystic fibrosis

Answer 11

Patients infected have a wide range of symptoms. A common theme is the involvement of epithelial tissues. Most cases of mortality are due to respiratory failure.

Question 12

How does cystic fibrosis affect the liver

Answer 12

Plugging of small bile ducts impedes digestion and disrupts liver function in perhaps five percent of patients.

Question 12

How does cystic fibrosis affect the airways

Answer 12

Clogging anf infection of bronchial passages impeded breathing. The infections progressively destroy the lungs. Lung disease accounts for most deaths from cystic fibrosis.

Question 13

How does cystic fibrosis affect the pancreas

Answer 13

Occlusion of ducts prevents the pancreas from delivering critical digestive enzymes to the bowel in 85% of patients. Diabetes can result as well.

Question 14

How does cystic fibrosis affect the reproductive tract

Answer 14

Absence of fine ducts, such as the vas deferens, renders 95% of males infertile. Occasionally, women are made infertile by a dense plug of mucus that blocks sperm from entering the uterus.

Question 15

How does cystic fibrosis affect the skin?

Answer 15

Malfunctioning of sweat glands causes perspiration to contain excessive salt (NACl). Measurement of chlride in seat is a mainstay of diagnosis.

Question 16

What does clinical managemtn of cystic fibrosis include?

Answer 16

• chest percussion to imporove clearance of infected secretions
• antibiotics to treat infections
• pancreatic enzyme replacement
• attention to nutritional status

Question 17

What is CFTR (cystic fibrosis transmembrane conductance regulator?

Answer 17

• CFTR is a Cl- channel that mediates the passive diffusion of Cl- doewn its electrochemical gradient.
• It is regulated by protein kinase A, and dependent on the phosphorylation of the regular domain and binding of ATP to the NBD (nucleotide binding domain)

Question 18

In a patient with cystic fibrosis, what does a defect in Cl- secretion look like.

Answer 18

• The defective Cl- channel prevents isotonic fluid secretion and enhances Na+ absorption to give a dry lung surface. The mucus becomes thick and difficult to remove.
• Bacteria proliferate and attract immune cells, which can damage healthy tissue. DNA released from bacteria and lung cells added to the stickiness.
• Airways become plugged and begin to deteriorate.

Question 19

What do epithelial cells of a normal lung look like

Answer 19

• There is a balance between secretion and absorption keeps the lung surface moist but prevents excessive fluid build up.
• The thin, wet mucus traps inhaled particles, allows clilia to push mucus up to the throat for removal and keeps the airways clear for breathing.

Question 20

Blocking Cl- secretion contributes to lung patholog

Answer 20

• CFTR gene defect
• defective ion transport
• airway surface liquid depletion
• defective mucocillary clearance
• mucus obstruction - infection - inflammation

Question 21

Formation of sweat.

Answer 21

Formatin of sweat is a two stage process
* primary isotonic secretion of fluid by acinar cells
* a secondary reabsorption of NaCl but not water. produces a hypotonic solution.

Question 22

How is the salty sweat produced in CF patients

Answer 22

Failure of epithelial cells in the ducts of sweat glands to reabsorb NaCl produces the salty sweat in CF patients.

Question 23

Sweat formation in CF patients

Answer 23

In the duct cells, the membrane potential is depolarised and Cl- wants to enter the cell down its electrochemical gradient.

In CF patients, CFTR is defective and Cl- accumulates in the duct lumen producing salty sweat.