COPD Flashcards
What is COPD?
Chronic obstructive airway disease
- progressive airflow limitation that isn’t completely reversible
- associated with inflammation due to noxious gases
What is Chronic bronchitis?
Chronic bronchitis is a productive cough present over years and associated with excessive mucous production
Symptoms present as:
- overweight
- cyanosis
- increased haemoglobin
- peripheral oedema
- rhonchi and wheezing
What is emphysema?
Emphysema is associated with alveolar wall destruction resulting in a reduction in the surface areas of the lung
Symptoms present as:
- in older men
- skinny
- SOB
- Quiet chest
- Hyperinflation
- Flattened diaphragm
Risk factors that cause COPD?
Smoking Urban pollution Textile dust Industrial pollution Biomass
COPD vs Asthma
COPD has neutrophil rich sputum as opposed to eosinophil rich sputum
There is little variation in air flow
There is limited hyper-responsiveness
The t cells involved are Th1 and Tc1 cells (no Th2)
How are the airways obstructed in COPD?
Airways blocked by mucus
Airway walls are thickened due to:
- cell infiltrate
- thickened smooth muscle
- peribronchial fibrosis
Loss of elasticity due to emphysema
What is the cause of the mucus hypersecretion?
Mucous glands are enlarged
Goblet cell hyperplasia (lots of them) and metaplasia
Mucus production is controlled by neuronal impulses and inflammatory mediators
There is increased production but reduced clearance
Regulation of mucus production
Inhaled irritants stimulate sensory nerve
Signal sent to CNS via vagus nerve and signal sent back through cholinergic nerve
ACh released by nerve and acts on M3 receptor on mucus releasing cell
Local nerves release neuropeptides which act on NK1 receptors
Adrenaline suppresses mucus production
Inflammation in COPD
Leukocytes (macrophages and CD8+ cytotoxic cells) are sent in to clear up irritants
Elevated CD8+ counts indicate both this mechanism and also increased susceptibility to infection due to extra mucus
Neutrophils will release proteases that damage cells as well as IL-8 and LTB4 which attracts more leukocytes
Consequences of inflammation in COPD
Epithelium damaged:
cilia damaged: less mucus clearance
muscle hyperplasia
increased bronchial permeability
Increased stimulation of sensory nerves:
neurogenic inflammation
stimulates cough
What causes a cough?
A motor reflex initiated by irritants, chemicals and excessive mucus in the airway
Nerves are sensitised by inflammatory mediators
Treatments for a cough
High dose opioids effective
-OTC opioids are pretty ineffective, it does however cause the release of endogenous opioids which can suppress cough
The sugar in products can increase salivation which can also soothing cough
Placebo effect is pretty significant in cough suppression: can still be suppressed by opioid antagonists (naloxone)
Emphysema
Destruction of alveolar walls
Smoking can cause imbalance of protease/antiprotease where protease becomes higher
alpha1 anti-trypsin deficiency can exacerbate effects of COPD
What is elastase?
Protease most common in alveolar wall destruction
Comes neutrophils/macrophages
Degrades elastin, basement membrane and connective tissue in the airways
Levels of elastase increase after smoking
What are metallo proteinases?
Proteinases released by neutrophils and monocytes (collagenase is one example)
Inhibited by TIMP
TIMP decreased in emphysema and metallo proteinases are increased
Cytokines in COPD
TNF and IL-8 are increased in COPD
TNF increases mucin secretion and elastase production
Bronchodilators in COPD treatment
Since bronchoconstriction is not the biggest cause of constriction in COPD it’s effect is limited
How do muscarinic antagonists help?
Reduces parasympathetic stimulation of mucus secretion of mucus
Mucus associated with reduction in FEV and hospitilisations
eg. Ipratropium, Tiotropium and Aclidinium
Corticosteriods in COPD
I.V corticosteroids help in acute exacerbations
Steroids in maintenence have limited effect (but still help a little) on neutrophil counts, cytokine levels or proteases
PDE inhibitors
PDE 3/4 inhibition leads to bronchodilation
PDE 4 inhibition leads to reduced chemotaxis, granule release, respiratory release and TNFalpha release
Roflumilast is a PDE 4 selective inhibitor
Acute exacerbations of COPD
Usually involve infection of some sort
Bacerial; H. Influenza, S. Pneumoniae,
Viral: Rhinovirus, influenza, parainfluenza and coronavirus
What are Serpins?
Serine protease inhibitors
They are inactivated by oxidative stress
Protease inhibitors and antioxidants
alpha1 antitrypsin augmentation therapy can be used in patients who have a deficiency
Elastase inhibitors have not been great in trials
Anti oxidants have limited evidence for efficacy
-includes: Vit C/E, Omega 3 etc
Alondroate: How can it be used in COPD?
A bisphosphonate that acts by killing osteoclasts which are similar to macrophages
Could be used as an inhaled powder to kill macrophages in the airways
Shown to reduce symptoms of emphysema: alveolar enlargement, TNF production, macrophage production
Alternative treatments for COPD
High % O2
Physiotherapy
Mucolytics; N-acetyl cysteine breaks disulphide bonds in mucin
DNAse
Not useful in COPD but effective in CF
Why don’t ICS work in COPD?
Oxidative stress results in reduced steroid sensitivity
Steroids inhibit neutrophil apoptosis which are causative of COPD
Smoking reduces binding of glucocorticoids to the glucocorticoid receptor
What is histone acetylation?
Histone acetyltransferase (HAT) unpacks chromatin and allows RNA polymerase to bind to DNA
Allows for increased binding of transcription factors
This enhances inflammatory gene expression
Histone deacetylase (HDAC) does the exact opposite
- it wraps the DNA tightly on the nucleosome surface
- steroids inactivate HAT hence increasing amounts of HAT reduce sensitivity to steroids
How does smoking/irritants effect histone acetylation?
Infammatory stimulation increases HAT
Oxidative stress reduces HDAC
Mechanism for this might be inactivation via peroxynitrate made by reaction of NO with cigarette smoke and superoxide anions (O2-)
The peroxynitrate nitrates the tyrosine residue on HDAC2 blocking enzyme activity and marking it for destruction via protease
Combined effect of these increases inflammation
