Flashcards in Infection & immunology Malcolm Watson COPD Treatment Deck (22):
Can we use Beta 2 agonists in COPD?
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
We can use muscarinic antagonists for BRONCHODILATION in COPD.
What is the name of the one licensed in the UK in 2013?
A dry powder inhaler
It has a fast M2 off time
Rapid systemic metabolism
So it doesn't have horrible anticholinergic effects
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?
The EGF receptor is involved in mucus hyper secretion. How can this be ligand independent?
Ligand I depended through oxidative stress from cigarette smoke.
H2O2 effects the EGF receptor but not by binding at it's binding site.
EGF receptors stimulating mucus hypersecretion can be Ligand dependent. What's the ligand and what can contribute to it's binding?
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
EGF receptors stimulate mucus hypersecretion by TGFa binding to an EGFR. What does this then cause?
Causes mucin gene transcription in the nucleus
There are trials of inhaled EGF kinase inhibitors for COPD
Erlotinib is an EGF receptor inhibitor but also inhibits what?
Are corticosteroids much use in COPD?
More use in asthma
Some benefit in IV use for acute exacerbations
What PDE selective inhibitor can be used in COPD? What does it inhibit?
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
What bacteria can cause acute exacerbations in COPD?
Treat with cephalosporins, penicillin, erythromycin
What viruses are associated with acute exacerbation in COPD?
What drug possibly prevents smoke induced emphysema?
Would could retinoic acid possibly be used for?
To stimulate alveolar to grown
Seen in mice
This has also been seen with Recombinant Keratinocyte growth factor (Palifermin)
Why aren't inhaled glucocorticoids much use in COPD but they are in asthma?
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
What may cause glucocorticoids not to work in COPD?
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
How do inflammatory stimuli interact with inflammatory genes?
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
What enzyme can suppress inflammatory gene expression?
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
How does the histone modulate inflammatory gene transcription?
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
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.
Inhibit CBP and HAT (histone acetylase) co activators
Activate HDAC (histone deacetylase) which causes deacetylation and therefore gene repression
Inflammatory stimuli mean increased HAT.
What does this mean?
Increased histone acetyl transferase.
This means more DNA unwinds from histones and can be transcribed into inflammatory proteins.
Oxidative stress results in decreased HDAC. What does this mean?
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