L6 - COPD Flashcards
COPD
chronic and progressive disease characterised by the development of airflow limitation that is not fully reversible and by an accelerated decline in lung function
COPD usually results from…
an abnormal inflammatory response of the lungs to noxious particles or gases
chronic bronchitis
usually seen in COPD
inflammation and excess mucus in the lung
Emphysema
usually seen in COPD
alveolar membrane breakdown
COPD established risk factors
smoking, occupational exposure, a1-antitrypsin deficiency, air pollution
smoking first degree relatives
increases risk 3 fold of COPD
Non-smoking first degree relatives
does not increase risk
COPD genetics
20+ genomic loci associated with lung function (FEV1 levels)
Several of these also associated with COPD susceptibility
a1-antitrypsin deficiency gene
SERPINA1
a1-antitrypsin deficiency genetics
autosomal recessive inherited disorder affecting 1 in 2000-5000 persons in eyrioe
a1-antitrypsin role
coats lungs, protecting from neutrophil elastase
neutrophil elastase
produced by white blood cells too break down harmful bacteria, potentially damaging to the lungs
a1-antitrypsin deficiency
lungs lack coating, so open to damage from neutrophil elastase - lung damage
a1-antitrypsin is trapped in the liver so there is liver damage
?% of COPD patients are or were smokers
90%
Smoking and emphysema mechanism
harmful particles trapped in alveoli
inflammatory response triggered
inflammatory chemicals dissolve the alveolar septum
large air cavity lined with carbon deposits formed
emphysema
COPD pathology
alveoli destruction, excess mucus, narrowed bronchiole, mucus hyper secretion, exudate, mucus inflammation and fibrosis, disrupted alveolar attachments
Airway inflammation
chronic inflammation affecting peripheral airways and lung parenchyma
inflammation increases with disease progression
Inflammatory process in epithelial cells
fibroblast then fibrosis formation
inflammatory process in macrophages
forms monocytes and Th1 cells.
Also Tc1 cells leading to alveolar wall destruction
neutrophil and proteases –> alveolar wall destruction
proteases to form mucus hypersecretion
Pattern recognition receptors
pro inflammatory cytokines and chemokines
reactive oxygen species
proteolytic enzymes –> neutrophil elastase, matrix metalloproteases
Oxidative stress
Increased by exogenous, i.e. cigarette smoke, and endogenous, i.e. inflammatory cell activation
Inflammation in oxidative stress
Increase in NK-kB and P38 MAPK, also autoantibodies
Ageing and cancer in oxidative stress
decrease in SIRT1 and DNA damage
Steroid resistance and oxidative stress
decreased MD2
fibrosis and emphysema in oxidative stress
decrease in antiproteases and increase in TGFB
Oxidative stress leads to…
telomere shortening, cellular senescence, DNA damage, mitochondrial dysfunction, decreased autophagy, stem cell exhaustion and decrease in anti-ageing molecules
Airway colonisation
bacterial pathogens that drive chronic airway and systemic inflammation
Healthy airway colonisation
bacterial clearance and resolution of inflammation
Airway colonisation in COPD
bacterial colonisation with defective phagocytosis and persistence of inflammation due to defective effercytosus
Defective phagocytosis leads to…
bacterial colonisation
Defective effercytosis leads to…
persistence of inflammation
Exacerbation trigger
viruses, bacteria or pollutants
Exacerbations
results in heightened inflammation –> oxidative stress, bronchoconstriction, oedema and mucus
Exacerbation treatment
antibiotics, steroids and bronchodilators
Exacerbations result in…
increased symptoms, hospitalisation, decreased quality of life, increased risk of future exacerbations, increased disease progression or death
Frequent exacerbations cause…
worse progress, faster disease progression, more hospital emissions and worse health status
Airway remodelling
development of specific structural changes in the airway wall in COPD accompanying long-standing and severe airway inflammation
airway remodelling through…
mucus hyper secretion, neutrophils in sputum, squamous metaplasia of epithelium, no basement membrane thickening, goblet cell hyperplasia, increased macrophages and CD8+ lymphocytes, mucus gland hyperplasia and little increase in airway smooth muscle
Asthma-COPD overlap syndrome
poorly-defined and understood, includes several phenotypes
COPD patients with increased eosinophil counts treatment
high dose ICS, Il-5, IL-13, IL-33 blocking antibodies
Asthmatic patients with severe disease or are current smokers with predominantly neutrophilic inflammation treatment
CXCR2 antagonists, phosphodiesterase-4-inhibitors, p38-MAPK inhibitors, IL-3 and IL-17 blocking antibodies, macrolides
Asthmatic patients who have had largely irreversible airway obstruction and might have increased inflammation treatment
inhaled combination therapy of corticosteroids, long-acting B2-agonist, long acting muscarinic antagonist
Management of stable COPD
reducing exposure to irritants and pulmonary rehabilitation
Relief of symptoms through bronchodilators and for long-acting muscarinic receptor antagonists
Reduces risk of exacerbations
management of exacerbations
Oral antibiotics and sometimes oral corticosteroids
bronchodilators
