Chronic obstructive pulmonary disease

Abstract:

Chronic Obstructive Pulmonary Disease (COPD) is a term describing chronic bronchitis, emphysema or small airways disease. COPD is one of the greatest causes of disability and mortality in the twenty first century with future predictions painting an even graver story. Occupation, genome, and primarily smoking are the main causes of COPD. Symptoms are typical of a constant smokers cough which progresses into the debilitating palliative stage of the disease; the development of co-morbidities exacerbates these symptoms. COPD has a complex pathophysiology involving hyperinflation, excessive mucus production and airway remodelling; diagnosis is through lung function tests. COPD is poorly managed with few effective treatments and a poor prognosis.

Programmed ageing is seen in every human through telomere attrition, with non programmed ageing being an extrinsic factor. Accelerated telomere shortening through oxidative stress, DNA damage, and knockout of anti-ageing molecules all cause premature ageing. There is overwhelming evidence from research that COPD is a disease of accelerated ageing.

COPD is a long term inflammatory respiratory condition resulting in airflow obstruction. Recent theories suggest that COPD is a disease of accelerated lung ageing resulting from oxidative stress; this is based on the observation of shortened leukocyte telomeres and the knockout of anti-ageing genes in mice. In 2007, 3 million people died as a result of COPD, equating to a death every ten seconds as a result of COPD1. The risk of developing COPD is said to be related to the 'total burden of inhaled particles'2. The aetiology of COPD typically spans tobacco smoking, occupational causes and genetics.

Tobacco smoking is the best known cause of COPD; this includes cigars, cigarettes, pipes and various other cultural practices such as hookah smoking; not all smokers develop COPD. The age at which the person started smoking, the amount they smoke each day, in addition to how long they have smoked for are all important indicators for the risk of COPD. In England the adult smoking prevalence is estimated at 24%3 - a growing cause for concern based upon the relevance to COPD. In England, 87% of COPD deaths in men and 84% of COPD deaths in women are attributed to smoking4. The commonly quoted figure of 13% of deaths in smokers caused by COPD5 is misleading as the incidence of COPD in smokers is much greater. The risk of death from COPD increases thirteen fold in smokers compared to non smokers6. Passive smoking is attributed to COPD, with the importance of this being portrayed by public smoking bans; passive smoking causes a small number of deaths7.

In occupations where there is exposure to vapours, gas, dust or fumes there is an increased incidence of COPD7. Coal miners, construction workers, and individuals involved in the transport and cotton industry are typically at an increased risk of COPD8. Cadmium9 and Silica10 are agents which have good evidence for the cause of COPD. The Zutphen study concluded that occupational exposure in men had a relative risk of 1.48 for COPD11. Although this risk may seem large, it is not as significant as the link between smoking and COPD. General air pollution is also a risk factor for COPD, confirmed by 'The Air Pollution and Health: a European Approach project'12.

1-Antitrypsin is an enzyme made by the liver which blocks neutrophil elastase (a digestive enzyme of lung tissue), thus protecting the lung parenchyma. 1-Antitrypsin (AATD) deficiency is a disorder of genetic homozygotic origin characterized by reduced levels of functional1-Antitrypsin leaving the lung tissue exposed to neutrophil elastase during infection13. AATD is a known cause of familial emphysema14.

The key indicators of COPD are dyspnoea, chronic cough, chronic sputum production and history of exposure to key factors2. COPD patients have symptoms of dyspnoea (laboured or difficult breathing15) on exertion or at rest. The chronic cough and sputum production usually lasts in excess of three months in two consecutive years to be considered as chronic bronchitis-a component of COPD16. In addition to this, other symptoms can include shortness of breath, wheezing, chest tightness and fatigue17. Acute exacerbations of COPD present with a worsening of these symptoms in addition to reduced exercise tolerance, tachypnoea (shortness of breath), possible cyanosis (high levels of deoxygenated haemoglobin) and peripheral oedema17. COPD is a chronic progressive disease indicating that these symptoms become worse over time even with the best medical care2.

Very severe COPD can develop into respiratory failure. There are two extreme stereotypical patients of respiratory failure. One is the 'pink puffer' (emphysematous type18), someone who has dyspnoea but no resting cyanosis. The other is nicknamed the 'blue bloater' (bronchitic type18); a patient with cyanosis at rest, cor pulmonale and oedema17. Cor pulmonale is a condition of right ventricular hypertrophy as a result of the COPD.

When a patient presents with the key indicators of COPD, diagnosis of the disease should be a strong consideration. The most common form of confirming this diagnosis is by spirometry, testing pulmonary function. In the UK the National Institute for Health and Clinical Excellence (NICE) recommends the use of the European Respiratory Society (ERS) Spirometry predicted normal values19. It is suggested that a bronchodilator is also used for the diagnosis and assessment of the severity of COPD by spirometry. The patient's spirometry result is compared to the predicted value for their height and age allowing COPD diagnosis. Under-diagnosis is a frequent occurrence in the elderly using this method; the ERS 1993 values are also not applicable to some populations such as Asians20.

The best known and internationally recognised criteria for COPD are that from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The lung function test results can be graded by the GOLD criteria into different categories of severity of COPD. The figure below indicates the different stages of COPD and the treatment indicated in each stage.

The forced expiratory volume1 (FEV1) is the maximum volume of air (in litres at body temperature and ambient pressure) one can expel from their lungs in one second. The forced vital capacity (FVC) is the maximum volume of air one can expel from their lungs upon expiration. The FEV1/FVC is the Forced Expiratory Ratio (FER); if the FER is below the normal value of 0.75-0.9 this result helps to ascertain an obstructive pulmonary defect such as COPD17.

Further testing can be done; the extent of breathlessness can be measured using the Medical Research Council Dyspnoea Scale. A chest radiograph using computer tomography (CT scan) can be used to rule out differential diagnoses. A full blood count test can be administered to exclude the differential diagnoses of anaemia. Cyanosis can be detected by pulse oximetry, and an Electrocardiogram can show indications of cor Pulmonale20.

Chronic bronchitis is characterised by goblet cell hypertrophy, chronic mucosal inflammation, bronchospasm, and increased mucus secretion17. Goblet cell hypertrophy and chronic inflammation of the mucosa is evident from the histopathological chronic bronchitis specimen (figure 2). As the disease progresses to its latter stages the bronchi themselves exhibit inflammation with pus in the lumen21. There is an inverse relationship between FEV1 decline in COPD and eosinophil, neutrophil and CD8+ T lymphocyte accumulation in the respiratory tract22. Infiltration of the epithelium by neutrophils is seen throughout the bronchial tree, along with eosinophil accumulation in the lamina propria23. Widespread scarring and remodelling follows the inflammation resulting in thickened airway walls resulting in lumen narrowing particularly affecting the small airways. Changes in the epithelial morphology are seen (squamous metaplasia), coupled with sub epithelial fibrosis causing exacerbation of airflow limitation21.

Senile emphysema can be defined as the naturally occurring physiological ageing of a lung, characterised by inflammation and structural changes leading to deterioration in pulmonary function24. Senile emphysema can be differentiated from the emphysematous lung by the lack of alveolar wall damage25.

Emphysema is characterised by permanent 'dilation and destruction' of lung parenchyma distal to the terminal bronchiole21. Centri-acinar (or centrilobular) is the most frequent of emphysema; this begins in the respiratory bronchioles, rarely affecting the alveolar portions of the lungs. Panacinar emphysema is another major form of emphysema associated with AATD affecting the entire acinar structure21. Loss of elastin results in reduced lung elastic recoil. This loss of recoil aids the collapse of airways which is exacerbated by reductions in interstitial supporting tissue. The collapse of airways causes air to get trapped and hyperinflate alveoli resulting in bullae formation17.

In COPD, emphysema and chronic bronchitis often co-exist resulting in various functional consequences. Loss of lung recoil with resulting hyperinflation causes elevated total lung capacity, functional residual capacity and residual volume. Ventilation-Perfusion mismatching occurs because of mucus blocking smaller airways (chronic bronchitis effect) and loss of recoil (emphysema effect). Ventilation-Perfusion mismatching results in a reduced partial pressure of oxygen in arterial blood, explaining the tachypnoea seen in the 'Pink Puffer'. Carbon dioxide content is unaffected due to the tachypnoea facilitating excretion at a rate to suffice the central chemoreceptor (responsible for 80% of the ventilatory response), which is receptive to carbon dioxide and not oxygen17. However, failure to maintain the ventilatory response results in central chemoreceptor insensitivity to high carbon dioxide levels. This outcome of this is a hypoxaemic, oedematous, cyanosed state seen in the 'blue bloater' COPD patient. Commonly these patients experience polycythaemia to counteract the hypoxaemia21.

COPD is not curable but the progression of the disease can be slowed with effective management. Treatment aims to alleviate chronic symptoms and prevent acute exacerbations. The first and foremost management is to reduce the risk factors to COPD -the cause of the disease. Smoking cessation is the most important factor to slow the progression of COPD in smokers. Smoking cessation is the only intervention that can slow the progression of the COPD. There is a large amount of help one can get when deciding to quit smoking; examples include behavioural therapy, and pharmacological intervention (Nicotinic replacement therapy or Bupropion26). The government pushes education, training and public campaigns to raise awareness of smoking too26.

Oral corticosteroids such as prednisolone courses can be prescribed for acute exacerbations of COPD but with a little effect, theoretically working by inflammatory reductions. Sometimes COPD patients may not be able to stop taking these corticosteroids after the acute exacerbation is over, resulting in use for 'maintenance' 27. Long term use of oral corticosteroids is not encouraged and should be kept at a minimum dose due to the risks of osteoporosis. Inhaled corticosteroids are not encouraged or licensed for use alone in COPD treatment. Studies have shown that inhaled corticosteroids do not reduce inflammation judged by sputum analysis28. Corticosteroids are generally not used in COPD patients due to insensitivity causing a very poor response. Only 25% of patients will show a response to this treatment27.

There are various ways of preventing acute exacerbations. Pneumococcal and influenza vaccinations can help to reduce respiratory infections. Staying away from cold weather aids this in addition to reducing bronchospasm (and the resulting breathlessness) by staying warmer. Prompt treatment with an antibiotic course will shorten the acute exacerbation of COPD21. Oxygen is important during acute exacerbations too.

Bronchodilators are commonly used in the management of COPD, delivered by inhalers or nebulisers. 2 adrenergic receptoragonists relax smooth muscle, dilating the bronchial pathways in the lung. The Short acting 2 agonist Salbutamol is often used, improving lung function, dyspnoea, and exercise limitation 27. Muscarinic receptor antagonists can be used to relax smooth muscle by blocking parasympathetic bronchial constriction. Short term Ipatropium can be used, which when combined with a 2 agonist has the greatest effect. When short acting bronchodilators are ineffective, long-acting 2 agonists such as salmeterol27, and longer term muscarinic antagonists such as Tiotropium are used in conjunction for greatest effects. There are adverse cardiovascular outcomes associated with bronchodilators29.

Theophylline is a type of Xanthine which acts by inhibiting phosphodiesterase. This inhibition potentiates cyclic AMP production in the lung, consequently inducing smooth muscle relaxation. In addition to this it causes mast cell stabilisation and reduces eosinophil survival. The effects upon spirometry are negligible, but it can improve blood gasses and exercise tolerance17. Theophylline has recently been shown to potentiate the action of corticosteroids, thus being more effective when co-administered30. In the UK theophylline is only used after the unsuccessful use of bronchodilators29.

The importance of pulmonary rehabilitation is often overseen. Pulmonary rehabilitation is a multidisciplinary programme aimed at exercise for patients with COPD. The programme is tailored to suit the individual based on the severity of their impairment. The programme aims to increase exercise tolerance and build accessory respiratory muscle strength. Ultimately it aims to improve the physical and psychosocial aspects of a COPD patient's life.

Oxygen therapy can be used in acute exacerbations of COPD and end-stage COPD. It aims to prolong the life of patients with a resting daytime hypoxaemia, helping to slow the rate of progression of cor pulmonale. The more oxygen is typically used the better the outcome, however this is a controversial relationship in AATD. Oxygen therapy can be helpful overnight and during exercise17. COPD is a chronic disease which cannot be cured making it terminal in its latter stages. As a result the importance of palliative care as part of management cannot be underestimated.

In COPD sufferers with a forced expiratory volume 1 (FEV1) less that 0.8L, there is a yearly mortality rate of 25%17. Patients with complications such as ongoing infections, hypercapnia, cor pulmonale, or even those who still smoke have a significantly worse prognosis. COPD patients die from complications such as respiratory failure, pneumonias or cardiac arrhythmias, not COPD itself17. COPD is accountable for over 70% of respiratory disease mortality; it is the 6th greatest cause of mortality in the UK31. The prevalence of COPD is estimated at 3.7 million people in the UK22. In 2009 it was estimated that 428 men and 288 women per million population died1. The international prevalence of stage 2 COPD or higher is estimated at 10.1%32. In Europe alone the direct cost of COPD is 38.6 billion Euros33. COPD is the thirteenth leading cause of burden of disease in terms of disability, weighing in at 30.2 million disability-adjusted-life-years (DALYs) 34. It is expected that by 2020 that COPD will be the fifth leading cause of burden of disease in terms of disability35.

COPD is a complex disease which has various co-morbidities. Weight loss is gradually seen, which worsens the prognosis of the disease. Peripheral muscle dysfunction and general weakness exacerbates exercise intolerance; osteoporosis, atherosclerosis, diabetes mellitus and malignant pulmonary neoplasms are also other complications36. The most significant co-morbidities are cardiovascular events; the increase in relative risk of cardiac arrhythmia is 2.4 for COPD sufferers36. Similarly heart failure and ischaemic heart disease are much more common in the COPD population than the general population. COPD patients are 1.3 times more prone to affective disorders than the general population36.

From figure 3 we can see the changing rates of mortality in certain diseases. Since 1970 the deaths as a result of COPD have doubled. Cardiovascular disease and accident mortality has rapidly fallen since 1970, with steadier rates in cancer and diabetes mellitus. As a result, COPD has rapidly become a disease with one of the highest mortality rates. By 2020 COPD is predicted to be the third greatest cause of death35.

Ageing is the proliferation of changes after the reproductive phase of life, characterised by homeostatic imbalance increasing the risk of death or disease24. There are different perceived forms of ageing; programmed ageing and non-programmed ageing. Programmed ageing is a natural, instinctive process by which senescence occurs in eukaryotic cells. Senescence is when cells lose the ability to multiply37, resulting in cell death; the main mechanism behind this is telomere shortening. Non-programmed ageing is an extrinsic process; methods of non-programmed ageing include loss of anti-ageing molecules and oxidative stress. It is known that oxidative stress causes accelerated telomere shortening38, suggestive of the COPD and ageing link.

Telomeres are repeating sequences of DNA found capping the ends of chromosomes, they do not code for a gene, and their function is to ensure complete replication at the end of each cell cycle. During DNA replication there is an issue with the lagging strand because DNA polymerase a must work in the 5'-3' direction, attaching beyond the end of the sequence in question which is being replicated during the S-phase. This is known as the 'end replication problem' which during embryogenesis, in germ cells, and certain stem cells is solved by an extension of the lagging strand provided by Telomerase, a DNA synthetic enzyme39. The problem arises in the fact that postnatally telomerase is suppressed in most somatic tissues. As a result each cell cycle causes the telomere length at the ends of chromosomes to shorten, limiting proliferation to a finite amount (Hayflick limit37).

The cell cycle is a series of phases in a cell's life ranging from division to quiescence. The interphase consists of the G1, S and G2 phases, whilst the mitotic phase (M phase) is when mitosis (cell division) occurs15. The G1 checkpoint is of great importance with regards to DNA damage being the first checkpoint in the new diploid cell following mitosis. The other significant DNA checkpoint is the G2 checkpoint which checks that DNA replication has been successfully completed39.

Human fibroblast telomeres have been discovered to shorten by 50-100 base pairs for each progression through the cell cycle (each division) 41. The G1 checkpoint contains the first mortality stage (M1) which detects excessively shortened telomeres, preventing progression to the S-phase and resulting in cellular senescence (G0)42. This entails arrest from the cell cycle, leading to the inability to proliferate. The tumour suppressor P53 is a protein which the G1 phase is dependent of. Increased P53 activity stimulates transcription of p21 which consequently binds to the cyclin-CDK complex preventing the cell to progress to the S-phase in the cell cycle. When telomere shortening is critical, p53 activity increases causing the arrest from the cell cycle39. In human fibroblasts it is estimated that after 50-70 cycles the telomeres become critically short and dysfunctional, resulting in replicative senescence41. In some cells however mutant tumour suppressor p53 genes result in the M1 stage(first mortality as part of the G1 checkpoint inducing senescence) being bypassed in light of the extensively shortened telomeres42. The telomere continues to undergo attrition as it goes through the cell cycle each time, inducing a second 'crisis' checkpoint. This checkpoint M2 (second mortality stage within the G2 checkpoint) is p53 independent. At this checkpoint the chromosome lacks stability which results in cellular apoptosis42.

These intrinsic mechanisms act as a tumour suppressor; they prevent uncontrollable cellular proliferation. However the drawback is that this mechanism causes cellular senescence after a finite amount of rounds in the cell cycle, resulting in reduced organ repair which is a component of ageing. Thus telomere attrition and cell cycle checkpoints can be perceived as a method of programmed cellular ageing. This is attributable to senile emphysema where lung function declines in older age.

Studies have highlighted the clinically significant fact that smokers and furthermore COPD patients express shorter circulating leukocyte telomere lengths than normal patients43. It has been shown that chronic oxidative stress such as seen in COPD increases the rate of telomere shortening44. There are increased tumour suppressor protein p53 and p21 levels earlier in a cells life. Studies show that oxidative stress causes a cell to enter senescence, or an 'aged state' in fewer cell cycles than normal44.

Theories have been put forward that COPD is a disease of accelerated lung ageing; the paper entitled 'Shortened Telomeres in Circulating Leukocytes of Patients with Chronic Obstructive Pulmonary Disease' proposes this43. The study was conducted in France with 136 stable COPD patients, and 155 healthy control subjects (113 of which smoked but did not have COPD). Telomere length was assessed using a polymerase chain reaction (PCR) based assay of blood samples. Figure 5 shows the results of the study. The shaded box indicates females, and the box not shaded is representative of males. The results depicted that the median telomere length ratio in patients with COPD was 0.57, 0.79 in smokers without COPD and 0.85 in non smokers without COPD. Using a 95% confidence interval, the P values comparing COPD and controls is smaller than 0.001, illustrating the clinical significance of the findings. Inferences made from the study are that smoking does reduce telomere length, but sufferers of COPD have an even shorter telomere length than control non-smoking non-COPD suffering subjects.

The telomere shortening in COPD patients maybe be questioned due to the fact that many diseases exhibit telomere shortening which could be the cause of the shortening seen in the study. Chronic HIV infection and Alzheimer's disease reduces lymphocyte telomere length, whilst intestinal epithelium telomere lengths are reduced in chronic inflammatory bowel disease45. However the study has excluded COPD sufferers with known malignancy, inflammatory and metabolic conditions. The study matched the age and sex of the control and smoking subjects which reduces variation in telomere length ratios based on these two characteristics. Another strength of the method is that telomere length was assessed in real time preventing variations in telomere length if they were left to be assessed later on. The study uses more than 60 people in each of the COPD and control categories; the large sample size means that telomere lengths are closer to the true subpopulation, reducing variation. This study provides a solid foundation to base the connection between telomere shortening and COPD. However the paper only studies peripheral leukocytes; COPD is a pulmonary disease and therefore a study investigating lung parenchyma would be a more accurate illustration of telomere shortening in COPD. The paper entitled 'Alveolar Cell Senescence in Patients with Pulmonary Emphysema46' studies telomere lengths in alveolar type 2 and endothelial cells. This study was on a much smaller scale with 13 emphysema patients and 21 control subjects, 10 who were smokers. Specimens were collected during lung volume reduction surgery and pulmonary resections (for lung cancer in the control subjects). Telomere lengths were assessed using immunostaining and counterstaining followed by digital video imagery calculating telomere signal intensities. Emphysema patients had significantly shorter telomeres than non-smokers, and shorter telomeres than asymptomatic smokers. In addition to this, the level of senescence markers such as (cyclin-dependent kinase inhibitor) p21 were studied between COPD patients and asymptomatic control patients. P21 as discussed before is directly involved in senescence downstream of p53, thus higher levels of p21 confers a higher level of cellular senescence. Greater levels of p21 were found in alveolar cells in COPD sufferers than control subjects implying greater cellular senescence.

The importance of the findings are somewhat blurred due to the shortcomings of the study itself. The number of test subjects is so low that the telomere lengths may not be realistic of the true subpopulation due to variation. The control subjects who are asymptomatic have pulmonary neoplasms which could affect the results. The biggest downfall of this study is that the results are not of telomere length itself, but of telomere signal intensity.

The implications of both studies are very important. It is known that emphysema is associated with alveolar and endothelial cell apoptosis47. The loss of alveolar parenchyma contributes to pulmonary destruction characteristic of emphysema47. As a result it could be judged that telomere shortening plays a vital role in the pathogenesis of COPD.

Telomere shortening is not the only method that induces a cell into a state of senescence. Failure to protect DNA from oxidative damage can lead to premature ageing on a cellular level. The disposable soma theory by Kirkwood48 relates ageing to an energy imbalance, preventing protection of DNA against oxidative insults. Reactive oxygen species (ROS) contain oxygen with a very reactive unpaired set of valence shell electrons. Failure to eliminate ROS can directly damage DNA which is highlighted at the G1 or G2 checkpoints. Failure to repair the damaged DNA is also detected by these checkpoints resulting in early senescence. In addition to causing premature senescence by DNA damage, Oxidative insults have also been proven to contribute to telomere shortening (due to smoking) resulting in chromosome instability and cell death49

Anti-ageing molecules are novel molecules in vivo which reduce the rate of ageing on a cellular level, which if 'knocked' out increases susceptibility to COPD, implying that COPD is caused by ageing. One such molecule is encoded by the klotho gene, which is a membrane protein attaching to fibroblast growth factors50. The study 'Disruption of theklothoGene Causes Pulmonary Emphysema in Mice' depicts how knocking out the klotho gene results in premature ageing and emphysema (a constituent of COPD) 51. The investigation used mice with the homozygous and heterozygous mutant klotho genes in addition to a normal control mouse to consider the effects without this anti-ageing molecule. The mice's lung volume was measured post mortally through pulmonary function testing. The results show that the homozygous mutant mice had larger lung volumes indicative of lung hyperinflation. The histological results show that after 10 weeks the homozygous mutant mice and after 120 weeks the heterozygous mice displayed typical signs of ageing: kyphosis, hair loss, ectopic calcifications in addition to emphysema51. These results show that a mutant anti-ageing molecule leads to emphysema, indicating the importance of COPD as a disease of accelerated ageing. The strengths of the study make this inference more credible. The size of mice was considered in the results, the same species were used, and emphysema was noted after 4 weeks of development thus ruling out developmental defects. Limitations of the study are that it is carried out in mice, a whole different species to humans preventing the results from having direct implications for COPD in humans. The range of the homozygous mutant mice lung capacity is 703306l as opposed to the control homozygous klotho mice which was 663122l51. As one can see the difference is only 40l, and with a p value above 0.05 the increased lung capacity is clinically insignificant, thus questioning the true extent of emphysema in mice51.

Senescence marker protein-30 (SMP30) is an anti-ageing molecule decreasing with age, which was initially found in rat liver52. SMP30 is expressed in multiple tissues such as the brain, kidney and bronchial epithelium52. The study entitled 'Senescence Marker Protein-30 Protects Mice Lungs from Oxidative Stress, Ageing, and Smoking'53 adopted a similar style to the klotho study51 of 'knocking' the gene of this molecule out. SMP30 was knocked out in male mice only due to the X-linked nature of SMP30 allowing mice which either had (SMP30Y/+) or didn't have (SMP30Y/-) SMP30 in its' cells. The mice were exposed to smoke from cigarettes for eight weeks following which lung and histopathological evaluations occurred53. It was shown that in the SMP30Y/- mice there was significantly enlarged airspaces and parenchymal destruction compared with the SMP30Y/+53. In the comparison of lung enlargement and parenchymal destruction results, the p value was less than 0.05 indicating clinical significance. With a lack of SMP30, there is increased susceptibility to noxious agents. This study further signifies the importance of lung ageing in smoking induced emphysema53. The main limitation of this study like the klotho study51 is that it is conducted in mice and not humans. It is clear that COPD is quickly becoming a disease of great importance due to morbidity and mortality, currently and in the future. Many studies in recent years have tried to ascertain whether COPD is a disease of accelerated lung ageing. Accelerated telomere attrition in COPD patients is of great importance to this debate. It may seem clear that COPD is a disease of accelerated lung ageing in light that telomere shortening is a measure of biological ageing. However I feel that this simple conclusion is much more complex; with the only scientifically reliable data coming from leukocytes, the accelerated shortening cannot be definitive. There is a study on alveolar and epithelial telomere lengths but the small scale and questionable measuring methods do not make this study comprehensive and reliable. It is appreciable that these factors can be related to difficulties in obtaining lung tissue samples on a larger scale. Further investigations into lung parenchymal telomere lengths, and getting around the method of sample collection would provide a clearer picture in regards to telomere length and the role of accelerated ageing in COPD.

The knockout of anti-ageing molecules in mice studies provides an exciting new prospect of COPD being a disease of accelerated lung ageing, from a different perspective. There is overwhelming evidence showing that COPD is associated with ageing in mice. This is an area which research would be very difficult to extend into human beings. The ethical injustice of knocking out molecules leading to disease and premature death in humans is not a viable option.

Research shows that ageing does play a significant role in COPD, however I believe that COPD cannot be defined as a disease of accelerated lung ageing at this point in time. All the research conducted currently points to this conclusion, but there is yet to be a definitive study. Some therapeutic implications can be drawn out from these studies even if the evidence is not fully comprehensive. It has been shown that without certain anti-ageing molecules, accelerated ageing occurs accompanied by COPD characteristics. With COPD set to be one of the top causes of mortality by 2020, the multifaceted phenomenon of ageing and it's role in COPD requires even greater input from the scientific community35.

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