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epithelial > L4 > Flashcards

L4 Flashcards

1
Q

what is the incidence of cystic fibrosis?

A
  • 1 in 2000/2500 live births
  • 1 in 20 are carriers
  • most common lethal genetic disease in caucasians
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2
Q

give some features of CF

A
  • exocrine pancreas insufficiency - digestive issues
  • increase in sweat [Cl]
  • male infertility in 95% (vas deferens fails to form)
  • increased risk of developing airway disease/infection - unsufficient lung functionality/ tissue to support life
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3
Q

Why is there a higher risk of airway infection in CF patients?

A
  • reduced function of CFTR - less Cl- secretion, and less water movement into the lumen
  • Lower height of liquid layer
  • cilia bent over - cannot beat effectively due to low height of PCL - cannot clear mucous/bacteria from lungs/airway effectively
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4
Q

what was the shark rectal gland a good model for?

A
  • first important model for Cl- secretion - secretes large amounts of Cl- and is a robust tissue (unlike mammalian tissue)
  • leaky epithelia - secretes large amounts of NaCl
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5
Q

what channels are on the basolateral membrane of the shark rectal gland cells?

A

Na/KATPase - Na out of cell, K into cell
NKCC1 - Na, 2Cl and K into the cell
K+ channel - out of cell

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6
Q

what does barium block in shark rectal gland tissue and what are the consequences of this?

A
  • barium blocks K+ channel - the membrane depolarises more towards 0 - less driving force for Na movement as a decrease in NKCC1, this causes a decrease in Cl- secretio
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7
Q

what does ouabain block and what are the consequences of this?

A

Ouabain blocks Na/K+ ATPase - IC Na+ increases, therefore driving force for NKCC1 is less and this reduces the function of NKCC1 and other proteins which rely on a Na+ gradient

  • less Cl- comes into the cell
  • less Cl- available for secretion - less Cl- secretion
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8
Q

what does furosemide block?

A

furosemide (or bumetanide) blocks NKCC1

- block Cl- influx via the basolateral membrane, less Cl- available for secretion - reduction in Cl- secretion

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9
Q

what does Cl- secretion depend on?

A

depends on amount of K+ and Na+ in perfusate - determines driving for for Na+ and K+ movement

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10
Q

What happens is K+ or Na+ is removed from the perfusate?

A

If Na+ or K+ is removed form the perfusate Cl- secretion is inhibited

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11
Q

what basolateral channels/models are applicable to most cl- secreting epithelia?

A
  • NA/K ATPase
  • NKCC1
  • K+ secreting channel
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12
Q

what is meant by electrochemical equilibrium in terms of Cl-?

A
  • If there is am accumulation of Cl- in the cells, but then Cl- channels open - the cell drops to electrochemical equilibrium - no excess Cl- in the cell - just going straight out
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13
Q

what should [Cl-] be if it is passively distributed in the cell? What was shown in shark rectal gland?

A
  • if passively distributed, [Cl-] should be between 17-28mM
  • But was 70mM - shows [Cl-] is above electrochemical equilibrium - ACCUMULATING to a higher conc in cell then what is expected
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14
Q

what is accumulation of Cl- in cell above electrochemical equilibrium due to?

A
  • due to active transport by Na/K ATPase - use energy to set up Na gradient for NKCC1 to bring Na/K/Cl into the cell - causes Cl- accumulation
    ( is not passive)
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15
Q

what can bring cl- to equilibrium?

A

Use of furosemide - inhibits NKCC1 - brings Cl- to equilibrium - stops accumulation of Cl- into the cell

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16
Q

what does cAMP stimulate?

A

stimulates CFTR and Cl- secretion across the apical membrane

17
Q

How can distal obstructive syndrome be caused?

A

By no or inactive CFTR - less Cl-secretion - less water movement into lumen

18
Q

what can be caused by overactive CFTR?

A

Overactive CFTR - more Cl- secretion, more water secretion into the lumen

19
Q

what cells in the colon secrete Cl- via CFTR?

A

lower to mid crypt cells

20
Q

how can Cl- secretion be stimulated?

A

Cl- secretion can be stimulated by Ach or prostaglandins (e.g. PGE2)- increase Ca2+ or cAMP

21
Q

what happens to colon cells when Ach applied?

A

Ach increases the IC Ca2+ levels
- This activates Ca2+ activated K+ channels - drive K+ secretion
- this hyperpolarises the cell, and creates a driving force to NKCC1 to bring Na/K/Cl into the cell - drives more Cl- secretion
(NKCC1 causes Cl- accumulation into the cell)

22
Q

give some features of the CFTR channel

A
  • 12 TMD

- 2 NBDs (nucleotide binding domains) (bind nucleotide which regulates the opening and closing of the channel)

23
Q

What is the delta F508 mutation?

A
  • mutation - phenylalanine deletion in NBD1 (common mutaiton in CF, 70-90% of patients)
24
Q

What is the G551D mutation?

A

in 13% of CF cases

  • also in NBD1
  • mutation - aa substitution (glycine to aspartic acid)
25
Q

what are the 6 different classes of aa mutations?

A 
I - null production (unstable mRNA)
II - Trafficking mutants
III- regulation issues
IV- conduction issues
V - partial reduction in mRNA- less channels
VI - high turnover of CFTR in membrane
26
Q

what is the clinical threshold for sweat chloride concentration in CF patients?

A
  • clinical threshold is 60mM - Cl- above this value - CF?
27
Q

why are carriers of CFTR mutations assymptomatic?

A

In carriers predict 50% of functional protein

  • only need 15-20% of CFTR protein present for normal function
  • why is recessive conditions
28
Q

what mutation classes are the most severe in CF?

A

Classes 1-3 are most severe and usually have pancreatic unsufficiency (and around 100mM sweat [Cl-]

29
Q

what happens when carbachol (CCH) added to Cl- secreting cells?

A

Activates Ach, increases Ca2+ IC, this stimulates Cl- secretion

30
Q

What happens when indomethacin is added to Cl- secreting cells?

A

Indomethacin inhibits prostoglandin production - cAMP levels decrease - CFTR not stimulated - Cl- secretion is reduced

31
Q

What happens when IBMX is added to Cl- secreting cells?

A

IBMX inhibits phosphodiesterase (degrades cAMP)

- when IBMX levels added, cAMP levels rise - Cl- secretion is stimulated via CFTR activation

32
Q

what happens when forskolin is added to Cl- secreting cells?

A

activates adenylate cyclase levels (cAMP levels rise), this stimulates CFTR and increases Cl- secretion

33
Q

what balance determines the water content of the faeces?

A

balance between Na and Cl

34
Q

what are the channels in the alveolar cell model?

A 
apical - CFTR (Cl- absorption)
apical - ENaC (Na+ absorption)
basolateral - Na/K+ ATPase
basolateral - K+ channel - out of cell
basolateral - K and Cl out of cell
35
Q

what are the channels on the distal sweat glands cell model?

A

apical - CFTR (Cl- absoption) (Why in CF - high sweat chloride)
apical - ENaC - Na absorption
basolateral - Na/K ATPase
basolateral - Cl out of cell via basolateral membrane

36
Q

what is the difference in the effect that CFTR has on ENaC in the upper airways and lower airways

A

In upper airways CFTR inhbits ENaC

in lower airways, CFTR stimultaes ENaC

37
Q

what happens when PG are inhibited but IBMX/fsk added?

A

IT doesnt matter is Pg is inhibited, as cAMP is increased anyway by IBMX and fsk - bypasses Pg

epithelial (8 decks)

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