Infection & immunology Malcolm Watson COPD Treatment

Question 0

We can use muscarinic antagonists for BRONCHODILATION in COPD.
What is the name of the one licensed in the UK in 2013?

Answer 0

Aclidinium
A dry powder inhaler 
It has a fast M2 off time
Rapid systemic metabolism 
So it doesn't have horrible anticholinergic effects

Question 1

Can we use Beta 2 agonists in COPD?

Answer 1

No these often have limited effects

As bronchoconstriction isn’t really an issue in COPD, but we do use some muscarinic antagonists for broncho dilation

Question 2

We can use muscarinic antagonists for mucus hyper-secretion in COPD.
They bind to M3 receptors on goblet cells and stop acetylcholine released from Cholinergic nerves from binding to them and stimulating mucus to be released.
What are two examples?

Answer 2

Ipratropium

Tiotropium

Question 3

The EGF receptor is involved in mucus hyper secretion. How can this be ligand independent?

Answer 3

Ligand I depended through oxidative stress from cigarette smoke.
H2O2 effects the EGF receptor but not by binding at it’s binding site.

Question 4

EGF receptors stimulating mucus hypersecretion can be Ligand dependent. What’s the ligand and what can contribute to it’s binding?

Answer 4

soluble TGF alpha is the ligand
This TGFa needs to be cleaved from the cell surface first
Elastases can do this
Eosinophils and macrophages can secrete already soluble EGF alpha

Question 5

EGF receptors stimulate mucus hypersecretion by TGFa binding to an EGFR. What does this then cause?

Answer 5

Causes mucin gene transcription in the nucleus

There are trials of inhaled EGF kinase inhibitors for COPD

Question 6

Erlotinib is an EGF receptor inhibitor but also inhibits what?

Answer 6

MMP14

And Muc5AC

Question 7

Are corticosteroids much use in COPD?

Answer 7

Not really
More use in asthma
Some benefit in IV use for acute exacerbations

Question 8

What PDE selective inhibitor can be used in COPD? What does it inhibit?

Answer 8

Rofulimast
It inhibits PDEIV in leukocytes
This increases cAMP so stops constriction of bronchioles
Also inhibits TNFa release and chemotaxis
Improves lung function in patients on salmeterol and tiotropium

Question 9

What bacteria can cause acute exacerbations in COPD?

Answer 9

Haemophilis influenzae
Streptococcus pneumoniae

Treat with cephalosporins, penicillin, erythromycin

Question 10

What viruses are associated with acute exacerbation in COPD?

Answer 10

Rhinovirus
Influenza
Parainfluenza
Coronavirus

Question 11

What drug possibly prevents smoke induced emphysema?

Answer 11

Clarithromycin

Question 12

Would could retinoic acid possibly be used for?

Answer 12

To stimulate alveolar to grown
Seen in mice
This has also been seen with Recombinant Keratinocyte growth factor (Palifermin)

Question 13

Why aren’t inhaled glucocorticoids much use in COPD but they are in asthma?

Answer 13

They cause bronchodilation
This is beneficial in asthma
But not so much in COPD as it’s not down to bronchoconstriction more to do with mucus and tissue remodeling
Inflammation is not addressed in COPD

Question 14

What may cause glucocorticoids not to work in COPD?

Answer 14

Oxidative stress can interfere with how they work
From cigarette smoke
Causes decreased sensitivity to the glucocorticoids
Also the glucocorticoids inhibit neutrophil apoptosis here, less die, more inflammation, not good.
Glucocorticoids seem to take on complete different functions in asthma and COPD

Question 15

How do inflammatory stimuli interact with inflammatory genes?

Answer 15

Inflammatory stimuli lead to IkB phosphorylation
This leads to free NFkB
This moves into the nucleus and interacts with inflammatory genes
Production of inflammatory proteins begins

Question 16

What enzyme can suppress inflammatory gene expression?

Answer 16

Histone deacetylase (HDAC) 
This is a major pathway for glucocorticoid action 

This enzyme does the opposite job to histone acetyl transferase, it stops chromatin being unwound from the histone

Question 17

How does the histone modulate inflammatory gene transcription?

Answer 17

DNA wrapped tightly round histone
Histone acetylase enzyme unwinds it
DNA can then be accessed by RNA polymerase
Also helps NFkB Do it’s job, NFkB helps out with gene activation

Question 18

Corticosteroids can cause inflammatory gene suppression. They bind to glucocorticoid receptors in the cell nucleus and inhibit ____ and _____ co activators which cause gene activation. They activate HDAC (histone deacetylase) which causes _______ therefore gene repression.

Answer 18

Inhibit CBP and HAT (histone acetylase) co activators
Activate HDAC (histone deacetylase) which causes deacetylation and therefore gene repression

Question 19

Inflammatory stimuli mean increased HAT.

What does this mean?

Answer 19

Increased histone acetyl transferase.
This means more DNA unwinds from histones and can be transcribed into inflammatory proteins.
More inflammation

Question 20

Oxidative stress results in decreased HDAC. What does this mean?

Answer 20

Decreased in histone deacetylase
This means more DNA will unwind from histones as this enzymes not there to stop it
More DNA ready to be transcribed into inflammatory proteins
More inflammation

Question 21

What drug can promotes HDAC (histone deacetylase) activity and therefore decrease inflammation?

Answer 21

Theophylline

It enhances the anti- inflammatory effects of steroids