Airway Mucus Production & Pharmacotherapy of Overproduction Flashcards

1
Q

Vestbo et al studied the risk of mortality of COPD paitents with or without mucus hypersecretion in the Copenhagen Heart Study. Interpret the data from the study.

A
  1. As FEV1 decreases, RR increases (i.e. increased COPD severity, increased death). Overall mortality in COPD is bad, but COPD with CMH is worse than without.
  2. There is a greater excess in decline of lung function in COPD with CMH. There is greater excess decline in men with CMH than in women with CMH.
  3. INcreased risk of death if COPD with CMH and infection.
  4. Greater risk of hospitalisation of COPD with CMH than without CMH. Women with CMH are at greater risk of hospitalistion copmared to men with CMH
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Mucus is made of mucin (from goblet cells and submucosal glands) and the watery compnonent of plasma exudates (can include proteins too). Describe the changes seen in the airway when there is inflammation in regards to cells involved in mucus production.

A
  1. Goblet cell hyperplasia (differentiation of basal/ciliated cells) - new goblet cells resist apoptosis
  2. Submucosal gland hypertrophy
  3. Increased plasma exudate leakage (due to remodelling)

The factors above lead to decreased mucociliary clearance.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Briefly outline the cascade leading to a hypersecretory phenotype.

A

Stimulus (allergens, pathogens, cigarette smoke), lead to inflammation and nerve activation (nAChR by nicotine in CS). This leads to the ↑secretion of mucus and ↑MUC expression via secretagogue activation. This is linked with secretory (goblet) cell hyperplasia/hypertrophy leading to mucus hypersecretion and the pathophysiology and clinical symptoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Name some potential treatments for airway mucus hypersecretion

A

Anti-inflammatory, anti-cholinergics

Mediator antagonists (leukotrienes?)

Anti-exocytosis, EGFR antagonists (MAPK, MEK/ERK inhibitors; MUC antisense oligomers; hCLCA1 inhibitors; RAR-a antagonists)

Pro-apoptotic factors

Mucus hydrators, mucolytic, mucoactive drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

EGFR involved in in vitro airway mucin synthesis and in rat models of goblet cell hyperplasia and mucin synthesis. EGFR inhibitor (BIBX1522, Nadel 1999) inhibited mucin synthesis, decreased hyperplasia and mucus secretion.

This can be explained by the:

  1. ↑ErbB-R in smokers, COPD and asthma
  2. ↑ErbB ligands (EGF, TGFa) in COPD and asthma

Describe the signalling cascade of the EGFR ErbBR and how it leads to mucus secretion.

A
  1. Ligand binds to ErbB-R and homo-/hetero-dimerises
  2. Auto-phosphorylation occurs in the cytoplasmic domain of ErbB-R
  3. Adaptor proteins (Grb2, Shc, Sos) bind to the phosphorylated domains
  4. Activation of the Ras/Raf/MEK/ERK pathway through GTP
  5. ↑Sp1 (TF) which binds and upregaultes expression of MUC5AC gene
  6. Mucin synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

EGR tyrosine kinase inhibitors inhibit what part of the cascade?

A

The auto-phosphorylation of the cytosolic domain, therefore no adaptor protein binding and no activatio of the Ras/Raf/MEK/ERK pathway.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

EGF-R inhibtors have shown promise in in vitro and animal studies observing mucin expression and synthesis. Name one factor that could affect the efficacy of this therapy.

A

EGF-R inhibitors are derived from drugs used in anit-cancer treatment/studies. This is relevant as goblet cells (mucus secreting) do not proliferate but instead are derived from the differentiation of basal cells.

This is seen in clinical trials of EGF-R in this context: ineffective reduction in mucus production, poorly tolerated in patient population

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Name three genes coding for mucin and indicate which is relevant in respiratory tract.

A

MUC5AC

MUC5B

MUC2 - GI tract?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Exocytosis of Mucin: ________ and _______ code for ________ mucin monomers. They ________ each other due to their _______ charge and are therfore highly _______ occupying. These monomers form long mucin chains via ________ bond formation. _________ ions allow for the condensation of the mucin chains. When at the _______ profiling stage, the influx of ______ dilutes calcium causing the increase of mucin size (_________) and exits the vesicle.

A

MUC5AC and MUC5B code for glycosylated mucin monomers. They repel each other due to their negative charge and are therfore highly space occupying. These monomers form long mucin chains via disulphide bond formation. Calcium ions allow for the condensation of the mucin chains. When at the omega profiling stage, the influx of water dilutes calcium causing the increase of mucin size (decondensation) and exits the vesicle.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Clostridium botulinium causes botulism by the prevention of neurotransmitter secretion at the NMJ. There are 7 serotypes (A to G) that target the NMJ. Describe the structure of a C. botulinium toxin and how it prevents NT secretion by naming the enzyme involved.

A

Toxin has three domains: X (neuronal binding), Y (translocation) and Z (catalytic) domains. The toxin translocates to the pre-synaptic bouton and cleaves the SNARE complex vie endopeptidase enzymes. This leads to the prevention of NT secretion.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Describe how modifications of the botulinium neurotoxins can be used as anti-exocytotic therapy for mucus. Describe how it leads to its anti-exocytotic effects.

A

The X domain is replaced with EGF making EGF-YZ.

EGF-YZ binds to the EGF-R which gets endocytosed.

Protons move into the lysosome and degrade the EGF, allowing the dissociation of YZ.

YZ translocates and cleaves SNARE complex (syntaxin)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Anti-exocytosis therapy with EGF-YZ worked. Howeer, describe one theoretical problem with this therapy

A

Inhibiting the secretion of mucin will lead to intracellular mucin granule build-up and this may lead to complications (perhaps cell death, inappropriate defense to pathogens)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Name another potential target for anti-exocytosis therapy.

A

MARCKS - a chaperone protein that traffics mucin granules to the cell sruface for exocytosis.

Observed but no clinical benefit

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe the mechanism of hypertonic saline as a mucus hydrator in cysitc fibrosis by comparing, normal CFTR, CF and CF with HTS

A

Normal CFTR: Cl is pumped out of the peithelial cell. CFTR also downregulates the activity of ENaC leading to reduction of Na absoprtion into cell. Water moves to the airway lumen, hydrating the mucus.

CF: CFTR not funcitoning, therefore, Na influx into cell by ENaC. Water follows into the cell down the osmotic gradient, thickening the mucus. Leads to decreased mucociliary clearance.

CF with HTS: HTS creates an osmotic gradient which allows water to move out into the airway to hydrate the mucus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the classification of CFTR gene mutations (I to VI)

A

I: No protein synthesis

II: Protein synthesis but no trafficking

III: Trafficking but non-functional

IV: Trafficking but decreased function

V: Functional but decreased protein synthesis

VI: Functional but decreased stability (degraded too quickly)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly