Smoking and COPD
• In 2010 around 13% of adults over 15 smoke; this is in steady decline especially in Westernised countries but increasing in developing countries
• Despite high prices, there are still high rates of smoking in:
o Low SES and country/rural/Indigenous communities o Expensive on personal health as well as economy
• There has been a decline in Australian smoking rates since 1990 due to government initiatives and community campaigns
o This includes advertising bans in print, National Tobacco Campaigns, Warnings, plain packaging, point of sale advertising pans and plain packaging
• People still smoke because nicotine is highly addictive, affecting the CNS dopamine pleasure/reinforcement and executive centres
o It binds nicotinic Ach receptors in the brain (NAc and VTA)
• Nicotine is a major appetite suppressant and many smokers continue to smoke in order to control body weight
• Therapeutic intervention to combat nicotine addiction including:
o NRT (patches and spray)
o Nicotine receptor blockers (Bupropion) o Partial agonist (Varencline)
▪ These increase the probability of quitting by 2-fold in addition to psychological and behavioural modification
o Quitting is the only intervention to reverse the health consequences of smoking
• COPD causes the largest number of deaths of LRT diseases
o It affects males and females equally (around 7000) in total per year, but this could be under- estimated because patients do not die of respiratory disease (rather dying from CVD) o COPD is also under recognised and under treated
o It is the third leading cause of disease burden in Australia o It affects 1 in 5 Australians aged over 40
o It costs $900 mill of direct health care costs
o It is almost entirely preventable but completely incurable (because you cannot grow back a lung with stem cell therapy)
• There is also a stigma around this because it is caused by smoking; brought it upon themselves so may cause a lack of sympathy in some. But smoking was depicted as glamorous in the past, celebrities did it etc.
• It is considered a disease of aging because it takes years for the patients to develop symptoms so there is a lag in number despite decline in smoking
o There are increased public health measures, better drugs/treatment options for COPD yet incidence is rising because of this lag
• There is natural decline in FEV1 with age
o Patients with COPD are stratified into mild to severe according to their lung function o Smoking accelerates the decline in lung
function but the rate plateaus when you stop o If you stop smoking at the age of 45, you lung function will never reach of point of disability
COPD
• It is a group of disorders characterised by airway inflammation and airflow limitations that is not fully reversible
• A progression condition associated with an abnormal inflammatory response of the lungs to noxious stimuli and gases
• The major risk factor is smoking (it causes 80-90% of cases)
o It can also be caused by occupational dust and chemicals or environmental tobacco smoke (lots of legislation to stop this) and indoor and outdoor air pollution (biomass including open wood fires)
• There is also an interaction with genes; not everyone who smokes develops COPD; some can be susceptible
• Recurrent viral/bacterial infection can exacerbate and worsen lung function
• COPD encompasses:
o Chronic bronchitis (mucus plugging, productive cough due to hypersecretion/hypertrophy of mucus glands)
o Chronic obstructive bronchitis due to fibrosis and obstruction o Emphysema
▪ This is enlargement of the airspaces (without the alveolar units, you do not have recoil; the airways are held open by alveolar unit so if these are destroyed, they collapse because there is no cartilage)
▪ Destruction of lung parenchyma
▪ Loss of lung elasticity
▪ Closure of small airways
o Most patients have all three conditions
• In COPD, there is loss of elasticity and alveolar attachment as well as thickening of the airways so the lumen is smaller o When expiring the airways should constrict slightly
to force air out but they still remain open o In COPD, there can be airway closure so air can
become trapped causing hyperinflation so you cannot get oxygenated air in the periphery of the lung.
o This will cause messages to be sent to the brain to breathe; this leads to breathlessness
o This can finally lead to dyspnoea (a feeling of tightness/lungs are burning) and decreased exercise tolerance (cannot do normal daily taks because of breathlessness; you may need O2 mask is hypoxic)
• The severity of COPD is determined by the amount of inflammation in the lungs
o All smokers have increased inflammation in the lungs; it is initally probably a protective mechanism but there is also increased mucous production
o Prolonged smoking will increase proteases (destroy elastin), inflammatory mediators, cytokines, neutrophils and macrophages (the last two engulg phagocytic debris (dead
cells/bacteria/virus/smoke)
o Macrophages are bigger in the smoker; there are also vacuolated and brown bc of tar etc.
o When smoke is removed, inflammation decreases slightly but sustained elevation persists for a very long time
• Epithelial cell and macrophages are stimulated by smoke to release growth factors
• Macrophages release a cocktail of mediators (chemokines and cytokines) which stimulate T cellss, neutrophils and monocytes to differentiate into macrophages in the lung
• As the disease progresses, it becomes more of a problem because there is a release of proteases by Tc1 cell, neutrophils and macrophages which tip the balance against the anti-proteases (which are also reduced) and they destroy the parenchyma leading to emphysema
• The activation of fibroblasts by TGFB leads to fibrosis in the small airways
• Proteases also cause mucous hypersecretion (and hypertophy of the glands)
• There is lots of OXIDATIVE STRESS which is increased, also because the cigarette smoke is full of antioxidants by the macrophages, neutrophils and structural cells like epithelial cells release oxidants as a protective mechanism against bacteria and viruses (can be quite damaging)
• The cellular and environmental triggers of ROS can cause the mitochondria to also release ROS
o ROS cause lipid peroxidation (post- translational modification of proteins) which, if not repaired, you get a long term changes in cell function, signalling and DNA damage
• The carbonyl stress can cause autoimmunity, tissue remodelling, impaired phaygocytic function etc.
• It can also lead to impaired steroid function which is important in COPD because the only anti- inflammatories available are GCs (which are not very effective in COPD and have been shown to increase risk of pneumonia in patients)
Proposed method of GC resistance in COPD
• GCs are generally effective in asthma; used as an adjunct to B-agonists; they are overused in COPD but do not control inflammation
• Usually corticosteroids will bind GR (receptor) and increase HDAC2 which will decrease histone acetylation (it does the reverse to inhibit production of inflammatory genes)
o This will stop the production of TNF-a and IL-8 which are the predominant inflammatory cytokines in COPD
o The stimuli causing inflammation stimulates the macrophage and causes activation of the NFKB pathway which causes histone acetylase to be activation which works on DNA to help transcribe inflammatory genes for IL-8 and TNF-a
• Chronic smoking causes chronic NFKB activation so there will be elevated inflammatory gene transcription (and MMP-9 which is a protease)
o Also the oxidative stress and oxidants released by structural/inflammatory cells causes the formation of peroxynitrite which decreases the activity of HDAC2 and even promote its destruction
o Corticosteroids are less effective because there is less HDAC so there is a marked increase in inflammatory cytokines translated
• It is thought that they inflammation of the lungs spills over into systemic inflammation; so in COPD, patients may have low grade systemic inflammation which is thought to contribute to muscle wasting and CVD and diabetes. So exacerbations will also worsen the co-
morbidities.
• Bacteria, viruses and pollutants amplify the processes occurring so there is increased inflammation/mucus hypersecretion and constriction of airways (also worse dyspnoea and worse functional capacity)
• This requires modification of maintenance treatment/increased GCs or other treatment
