Chronic Obstructive Pulmonary Disease Biology Essay

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The American Thoracic Society (ATS) has defined COPD as "a disease state characterized by the presence of airflow limitation due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible." The European Respiratory Society (ERS) defined COPD as "reduced maximum expiratory flow and slow forced emptying of the lungs, which is slowly progressive and mostly irreversible to present medical treatment." The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classified COPD as "a disease state characterized by airflow limitation that is not fully reversible. It is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

Chronic obstructive pulmonary disease (COPD) has become one of the rapidly increasing global cause for morbidity and mortality worldwide and therefore should be a major health concern4. COPD is the fourth leading cause of death worldwide5 and is estimated to be ranked 3rd in 2020 in Global Burden of Disease, recognised in 4-10% adult male population prevalence of 4.1% of 35295 subjects and male to female ratio of 1.56:12. In India the male to female ratio had varied from 1.32:1 to 2.6:1 in different studies with a median ratio of 1.6:1.

Disease severity has typically been determined using the degree of impairment of the lung function The staging of severity for COPD offered by GOLD is as followed

Stage 0 ;

At risk characterised by normal FEV1 and FEV1/FVC. Chronic respiratory symptoms like cough, sputum production is often present.

Stage I: Mild Copd

Characterized by mild airflow limitation (FEV1/FVC < 0.70, FEV1 80% predicted). Symptoms of chronic cough and sputum production may be present, but not always. At this stage, the individual is usually unaware that his or her lung function is abnormal.

Stage II: Moderate Copd

Characterized by worsening airflow limitation (FEV1/FVC < 0.70, 50% FEV1 < 80% predicted), with shortness of breath typically developing on exertion and cough and sputum production sometimes also present. This is the stage at which patients typically seek medical attention because of chronic respiratory symptoms or an exacerbation of their disease.

Stage III: Severe COPD:

Characterized by further worsening of airflow limitation (FEV1/FVC < 0.70, 30% FEV1 < 50% predicted), greater shortness of breath, reduced exercise capacity, fatigue, and repeated exacerbations that almost always have an impact on patients' quality of life.

Stage IV: Very severe COPD

Characterized by severe airflow limitation (FEV1/FVC < V0.70, FEV1 < 30% predicted or FEV1 < 50% predicted plus the presence of chronic respiratory failure).




Existing impaired lung function

Increasing age

Male gender

Occupational hazards (gold and coal mining, silica exposure in glass or cotton industry, cotton or grain dust, toluene disocyanate, asbestos etc)

AAT deficiency (genetic disorder contributing to the risk factor of copd, especially Emphysema)


Air pollution : unclear whether there is a risk of copd however air pollution worsens conditions in existing pulmonary dysfunction

Bronchial reactivity

Family history

Nutritional status


Respiratory tract infection

Socioeconomic status


COPD is characterised by chronic inflammation of the airways, lung tissue and pulmonary blood vessels as a result of exposure to inhaled irritants such as tobacco smoke or other risk factors. The inhaled irritants cause inflammatory cells such as neutrophils, CD8+ T-lymphocytes, B-Cells, macrophages and dendritic cells to accumulate. These cells,when activated causes initiation of an inflammatory cascade triggering the release of inflammatory mediators such as tumour necrosis factor (TNFα), interferon γ (IFNγ), matrix-metalloproteinases (MMP-6, MMP-9), C-reactive protein (CRP), Interleukins (IL-1, IL-6, IL-8) and fibrinogen. The inflammatory markers sustain the inflammatory process leading to tissue damage as well as a range of systemic effects. The chronic inflammation is present from the outset of the disease and this leads to various structural changes in the lung which further leads to perpetuation of airflow limitation.

Structural changes

Airway remodelling in COPD is a direct result of the inflammatory response associated with COPD and leads to narrowing of the airways. Three main factors contribute to this: peribronchial fibrosis, build up of scar tissue from damage to the airways and over-multiplication of the epithelial cells lining the airways.The main site of airflow obstruction occurs in the small conducting airways that are < 2 mm in diameter. This is because of inflammation and narrowing (airway remodelling) and inflammatory exudates in the small airways. Other factors contributing to airflow obstruction include loss of the lung elastic recoil (due to destruction of alveolar walls) and destruction of alveolar support (from alveolar attachments).

Emphysema is also associated with loss of lung tissue elasticity, which occurs as a result of destruction of the structures supporting and feeding the alveoli. This means that the small airways collapse during exhalation, impeding airflow, trapping air in the lungs and reducing lung capacity.

Smoking and inflammation enlarge the mucous glands that line airway walls in the lungs, causing goblet cell metaplasia and leading to healthy cells being replaced by more mucus-secreting cells. Additionally, inflammation associated with COPD causes damage to the mucociliary transport which is responsible for clearing mucus from the airways. Both these factors contribute to excess mucus in the airways which eventually accumulates, blocking them and worsening airflow.

Mucus hypersecretion

Mucous hypersecretion results in a chronic productive cough. This is characteristic of chronic bronchitis but not necessarily associated with airflow obstruction, and not all patients with COPD have symptomatic mucous hypersecretion. The hypersecretion is due to squamous metaplasia, increased numbers of goblet cells, and increased size of bronchial submucosal glands in response to chronic irritation by noxious particles and gases. Ciliary dysfunction is due to squamous metaplasia of epithelial cells and results in an abnormal mucociliary escalator and difficulty in expectorating.

Gas exchange abnormalities

These occur in advanced disease and are characterised by arterial hypoxaemia with or without hypercapnia. An abnormal distribution of ventilation-perfusion ratios is the main mechanism of abnormal gas exchange in COPD . An abnormal diffusing capacity of carbon monoxide per litre of alveolar volume correlates well with the severity of the emphysema.

The underlying disease process in COPD leads to the characteristic physiologic abnormalities and symptoms. Decreased FEV1 primarily results from inflammation, narrowing of peripheral airways and a dynamic airway collapse in a more severe emphysema, whereas decreased gas transfer arises from the parenchymal destruction of emphysema. The extent of inflammation, fibrosis, and luminal exudates in small airways is correlated with the reduction in FEV1 and FEV1/FVC ratio, and probably with the accelerated decline in FEV1 in COPD. Gas exchange abnormalities result in hypoxemia and hypercapnia, and have several mechanisms in COPD. In general, gas transfer becomes worse as the disease progresses. 4

Pulmonary hypertension

This occurs late in the course of COPD, normally after the development of severe gas exchange abnormalities. Factors contributing to pulmonary hypertension in COPD include vasoconstriction (mostly of hypoxic origin), endothelial dysfunction, remodelling of pulmonary arteries and destruction of the pulmonary capillary bed. This combination of events may eventually lead to right ventricular hypertrophy and dysfunction (cor pulmonale).


Cough :

Cough may be intermittent (early morning) at the beginning, progressively becoming present throughout the day, but is seldom entirely nocturnal [4]. Chronic cough is usually productive and is very often discounted as it is considered an expected consequence of smoking. Cough syncope or cough rib fractures may occur. Sputum initially occurs in the morning but later will be present all day long. It is usually tenacious and mucoid and in small quantities [2]. Production of sputum for ≥3 months in 2 consecutive years is the epidemiological definition of chronic bronchitis. A change in sputum colour (purulent) or volume suggests an infectious exacerbation.

Dyspnoea :

Dyspnoea is usually progressive and over time it becomes persistent. At the onset it occurs during exercise (climbing up stairs, walking up hills) and may by avoided entirely by appropriate behavioural changes (e.g. using an elevator). However, as the disease progresses, dyspnoea is elicited even during minimal exertion or at rest.


An exacerbation of COPD may also be defined as a sustained worsening of respiratory symptoms that is acute in onset and usually requires a patient to seek medical help or alter treatment

Another symptom-based definition of COPD exacerbation used in large controlled clinical trials is characterized by an increase in baseline dyspnea, cough, or associated with a change in quality and quantity of sputum that led the patient to seek medical attention and lasts for at least 3 days. Unlike asthma, patients with COPD do not experience

Clinical Heterogeneity of the Cause of COPD Exacerbations

The causes of COPD exacerbations vary greatly. Most COPD exacerbations are thought to be caused by infections, although the type of infection is often unclear.Virus-associated COPD exacerbations treated with antibiotics and glucocorticoids have longer recovery periods than nonviral COPD exacerbations.

Both bacterial and viral infections are increased during COPD exacerbations. Infectious exacerbations have longer hospitalizations and greater impairment of several measures of lung function than noninfectious exacerbations. The purulence of the sputum color during COPD exacerbations has been proposed in the past as a marker of bacterial infection and is a reason for starting antibiotic treatment in the GOLD and CTS guidelines. COPD exacerbations with purulent sputum production have been associated with a large bacterial load in some, but not all, studies.

In a small portion of severe COPD exacerbations, there is no evidence of infection; environmental triggers, such as air pollutants or changes in airway temperature, are thought to be the initiating factors. COPD exacerbations have seasonal variation, which is important to realize when analyzing the relevance of short-term clinical trials (lasting <12 months) investigating the effect of drugs in preventing COPD 3exacerbations./03000/Clinical_Definition_of_COPD_Exacerbations_and.18.aspx#P100"46


A substantial proportion of COPD patients have found to have extra-pulmonary symptoms and signs. Patients with COPD, particularly when the disease is severe and during exacerbations, have evidence of systemic inflammation, measured either as increased circulating cytokines, chemokines and acute phase proteins, or as abnormalities in circulating cells. The common extrapulmonary manifestations include :


Cardiovascular events

Normocytic anaemia

Oxidative stress


Cachexia and nutritional abnormalities



Lung cancer

Obstructive sleep apnoea

Skeletal muscle weakness

[Sin et al. 2006a].

The severity of the underlying COPD modifies the risks of these extra-pulmonary manifestations. For example, According to Broekhuizen et al and Sin and Man et al in mild to moderate COPD, cardiovascular co-morbidities and cancer predominate, however, in more advanced disease, osteoporosis, cachexia, and peripheral muscle weakness become the leading extra-pulmonary complications of COPD [The presence of these extra-pulmonary manifestations of COPD increases morbidity and mortality of COPD patients.

Cardiovascular disorders

COPD and CAD are both highly prevalent and share common risk factors, such as exposure to cigarette smoke, older age and sedentarism. It has become increasingly evident that patients with airflow limitation have a significantly higher risk of death from myocardial infarction and this is independent of age, sex and smoking history

In patients with mild to moderate COPD (forced expiratory volume in one second, FEV1, >60%of predicted), cardiovascular events are the leading cause of hospitalization and the second leading cause of mortality]. Among patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD)

stages 0 to 2 disease (i.e. FEV1 >50% of predicted), cardiovascular disorders account for approximately 50% of all hospitalizations and nearly a third of all deaths [Anthonisen et al. 1994]. In more advanced disease, cardiovascular events account for 20-25% of all deaths in COPD . Rapid decline in FEV1 is one of the independent risk factor of Cardiovascular events in COPD.

Thus reduced FEV1 as well as reduced FEV1 to FVC ratio, COPD symptoms and a

clinical diagnosis of COPD are all independent risk factors for cardiovascular events. Antothesin et al stated that even relatively small reductions in lung function increases the risk for coronary events, ventricular arrhythmias, and cardiovascular mortality by twofold. In patients with mild to moderate COPD, cardiovascular diseases are the leading cause of hospitalization, accounting for 40 to 50% of all hospital admissions. They are the second leading cause of mortality,. In general, a 10% decrease in FEV1 among COPD patients increases the cardiovascular event rate by ∼30% . It is postulated that in COPD, persistent pulmonary inflammation promotes the release of pro-inflammatory chemokines and cytokines into the circulation. These mediators then stimulate various endorgans including the liver, adipose tissues, and the bone marrow to release excessive amounts of acute-phase proteins, inflammatory cells, and secondary cytokines into the general circulation, resulting in a state of persistent low-grade systemic inflammation. The systemic inflammation in turn adversely impacts the blood vessels, contributing to plaque formation and, in certain cases, to plaque instability and rupture. During exacerbations, systemic inflammation increases even further causing further increasing risk of cardiovascular events. Arterial stiffness is increased in patients with COPD as compared to the normal smokers and nonsmokers and is unrelated to disease severity or circulating CRP concentrations. The increased arterial stiffness may predispose patients to systemic hypertension along with an increased risk of cardiovascular disease in COPD patients. Arterial stiffness may reflect common pathological mechanisms, such as abnormalities in connective tissue or inflammation, or may be a response to the systemic inflammation associated with COPD. One of the mechanism for reduced arterial stiffness is impaired endothelial NO production. COPD patients with emphysema have impaired flow-mediated vasodilatation, which may reflect a generalised impairment in endothelial function, possibly in response to systemic inflammation . The defect in endothelial function may reflect a reduction in circulating endothelial progenitor cells that repair endothelial injury and maintain normal function .

Normocytic Anaemia

Contrary to common teaching, recent studies have shown that there is a high prevalence of anaemia in COPD patients, ranging 15-30% of patients, particularly in patients with severe disease, whereas polycythaemia (erythrocytosis) is relatively rare (6%). The level of haemoglobin is strongly and independently associated with increased functional dyspnoea and decreased exercise capacity, and is therefore said to be an important contributor to functional capacity and a poor quality of life. In some studies, anaemia is an independent predictor of mortality. The anaemia is usually of the normochromic normocytic type characteristic for diseases of chronic inflammation and appears to be due to resistance to the effects of erythropoietin, the concentration of which is elevated in these patients. Whether the treatment of anaemia will result in improvement in functional outcome measures remains to be determined.


Several studies have shown a very high prevalence of osteoporosis and low bone mineral density (BMD) in patients with COPD, even in milder stages of disease . Over half of patients with COPD recruited for the large TORCH (Towards a Revolution in COPD Health) trial (6,000 patients) had osteoporosis or osteopenia as determined by dual-energy radiograph absorptiometry (Dexa) . In a cross-sectional study the prevalence of osteoporosis was 75% in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV disease and was strongly correlated with reduced FFM . Interestingly, the prevalence is high for males and even higher for females. The incidence of traumatic and nontraumatic fractures is similar for both sexes. The relationship between osteoporosis and functional limitation is uncertain but likely to be important as fractures remain a daunting problem in the elderly. Vertebral compression fractures are relatively common among COPD patients and the resultant increased kyphosis may further reduce pulmonary function.

COPD patients have several risk factors for osteoporosis, including advanced age, poor mobility, smoking, poor nutrition, low BMI and high doses of inhaled corticosteroids as well as courses of oral steroids. Low BMD is correlated with reduced Free Fat Mass in COPD patients . However, COPD itself may be a risk factor for osteoporosis and this may be related to systemic inflammation. Using computed tomography (CT) to determine bone density of thoracic vertebrae, there is a significant correlation between CT-measured emphysema and bone density, supporting the view that osteoporosis is related to emphysema. There is some evidence that osteoporosis is also associated with an increased risk of atherosclerosis and heart disease in patients without COPD . The association between osteoporosis and increased arterial wall stiffness as well as between these variables and the systemic level of IL-6 suggests a common association with the degree of systemic inflammation. Regardless of sex, patients with COPD attending clinics should be treated with a bisphosphonate, as recommended by current guidelines . A trial of alendronate in patients with COPD showed some improvement in BMD in the lumbar spine but not the hip over 1 yr of therapy .

Oxidative stress

The oxidative burden is increased in COPD. include cigarette smoke and reactive oxygen and nitrogen species released from inflammatory cells are the sources of oxidants. This creates an imbalance in oxidants and antioxidants of oxidative stress. Many markers of oxidative stress are increased in stable COPD which are further increased in exacerbations. Oxidative stress can lead to inactivation of antiproteases or stimulation of mucous production. It can also increase inflammation by enhancing transcription factor activation (such as nuclear factor κB) and hence gene expression of pro-inflammatory mediators. Oxidative stress induces endothelial dysfunction . Oxygen-derived free radicals like superoxide anions impair endothelial vasomotor function [Cai and Harrison, 2000]. Oxidative stress can impair vasodilation, endothelial cell growth, and promote plaque build-up and rupture [Sugiyama et al. 2004]. Leukocytes, can generate a large amount of oxidative stress through the induction of enzymes such as NADPH oxidase, superoxide dismutase, nitric oxide synthase, and myeloperoxidase, when activated . When the oxidant load exceeds the antioxidant capacity of the organ, proteins, lipids, carbohydrates, and DNA materials in the local milieu may be modified through oxidation, resulting in tissue injury. Oxidants can also induce inflammation. Inflammation, in turn, can generate more oxidant species, creating a positive feedback loop. COPD patients experience more oxidative stress than control subjects. The load is further increased in patients who continue to smoke and in patients who experience frequent exacerbation. Local oxidative stress in the peripheral muscles of COPD patientsis associated with reduced muscle strength. The etiology of the oxidative burden in COPD is probably multifactorial. Hypoxemia, poor nutrition, inflammation, infection, and smoking have all been implicated.

Cachexia and nutritional abnormalities

Cachexia is defined as excessive weight loss in the setting of ongoing disease, associated with disproportionate muscle wasting [Owen, 2005].Weight loss related to starvation, on the other side, is associated with a disproportionate reduction in fat mass. Cachexia and weight loss are observed frequently in patients with COPD. It is associated with poor functional capacity, reduced health status, and increased mortality. The prevalence of weight loss in COPD increases with COPD disease progression. Only 10 to 15% of patients have significant weight loss in mild to moderate COPD. However, in severe COPD, nearly 50% of patients have significant weight loss [Creutzberg et al. 1998]. Although cachexia of COPD affects all body compartments, skeletal muscle mass appears to be especially vulnerable. According to Augusti et al most patients with moderate to severe COPD have significantly reduced fat-free mass. This change in body composition can also occur in the early stages of the disease and even in the absence of any reduction in the total body weight. Accordingly, while total body weight is a useful surrogate measure to monitor patients for COPD-related cachexia, in certain circumstances, it can be misleading; measurement of fat-free mass may be a more sensitive marker of disease activity and outcomes of COPD patients. COPD-related cachexia is an independent risk factor for morbidity and mortality. In a recent study, Hallin and colleagues found that in a group of patients who were hospitalized due to an exacerbation of COPD, a history of weight loss during a 12 month follow-up period and the initial weight of the patients were both independently associated with a higher risk of experiencing new exacerbation. In a study by Schols and colleagues, mortality risk increased significantly once the body mass index (BMI) of patients reached 25 kg/m2 or less .

The mechanisms responsible for cachexia in COPD are not well understood. In health, protein degradation and replacement is carefully regulated and controlled. Any significant perturbations in protein degradation and replacement balance can result in cachexia and wasting. Nutritional status and body hormones play significant roles in maintaining this homeostasis. For instance, growth factors such as human growth hormone, insulin-like growth factor-1, and anabolic steroids promote protein synthesis, whereas glucocorticoids and catecholamines favor catabolism. Low testosterone levels have also been found to be associated with COPD cachexia as testosterone promotes myoblastic activity and inhibits the synthesis of proinflammatory cytokines such as TNF-α. More recently, cytokines and chemokines have been implicated in the pathogenesis of cachexia. When patients become clinically ill from an inflammatory or infectious insult, there is a rapid rise in the circulating levels of pro-inflammatory cytokines such as IL-1, interferon-γ (IFN-γ ) and TNF-α. These cytokines especially TNF-α, and INF-γ can act synergistically to inhibit messenger RNA expression for myosin heavy chain, leading to decreased muscle protein synthesis. These cytokines may also directly or indirectly stimulate proteolysis of myosin heavy chains as stated by Acharya et al. In COPD, the hormonal balance is shifted towards catabolism, especially in the severe to very severe stages of the disease. Schols et al stated that patients have reduced testosterone levels, and increased proinflammatory cytokine expression both in the muscles as well as systemically, and increased catecholamine synthesis presumably related to the underlying inflammatory and oxidative processes in the airways. Even the frequent intake of inhaled or systemic glucocorticoids by COPD patients contribute to a catabolic state.


Patients with COPD are frequently isolated and unable to engage in many social activities due to their physical impairment,.Anxiety and depression are very frequent in patients with COPD and appear to be more prevalent than in other chronic diseases. Anxiety and depression symptoms may be confused with symptoms of COPD, so these psychiatric problems are often undiagnosed and untreated in clinical practice. Depressive symptoms that are clinically relevant are estimated to occur in 10-80% of all patients. The mechanisms responsible for depression in patients with COPD are unknown and likely to be multifactorial . Depression may precede the development of COPD and there might be shared genetic factors but smoking is more frequent in patients with anxiety and depression. "Reactive" depression associated with declining health status is more common. The effects of ageing, smoking and hypoxaemia on brain function are likely to contribute to its genesis. There is growing evidence that systemic inflammation may result in depression and IL-6 appears to play a particularly important role in humans and in animal models of depression . Whatever the cause, untreated depression increases the length of hospital stay, frequency of hospital admissions, and leads to impaired quality of life and premature death.


Patients with COPD are three to four times more likely to develop lung cancer than smokers with normal lung function lung cancer is a common cause of death in COPD patients, particularly those with severe disease. There is an increased risk of small cell and squamous cell cancers to a greater extent than adenocarcinomas. Smoking cessation does not appear to reduce the risk of lung cancer . Females may have a greater risk of COPD and lung cancer, possibly due to hormone-stimulated metabolism of carcinogens in tobacco smoke. The increased prevalence of lung cancer in COPD patients is probably linked to the increased inflammation and oxidative stress in COPD (fig. 2/5/1165.full#F2#F2"⇓) . NF-κB activation may provide a link between inflammation and lung cancer . Pro-inflammatory cytokines may also promote tumour angiogenesis, which accelerates cell growth and metastases. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates multiple antioxidant and detoxifying genes, is functionally defective in COPD lungs /5/1165.full#ref-146#ref-146"146 and may contribute to the increased susceptibility of COPD patients to lung cancer, since Nrf2 plays an important role in defence against certain carcinogens in tobacco smoke by regulating the expression of several detoxifying enzymes . Epidermal growth factor receptors (EGFR), which promote epithelial proliferation, show an increased expression in COPD patients . Increased lung cancer in chronic obstructive pulmonary disease (COPD). Inflammation and increased oxidative stress in COPD may enhance the growth and metastasis of lung cancer. In addition, increased expression of epidermal growth factor receptors (EGFR) may accelerate cancer growth.


A study on large population has shown that there is an increased prevalence of diabetes among COPD patients (relative risk 1.5-1.8), even in patients with mild disease.It is unlikely to be explained by high doses of inhaled corticosteroids, since patients with mild disease who are steroid-naïve also have an increased risk of diabetes. Pro-inflammatory cytokines, including TNF-α and IL-6, induce insulin resistance by blocking signalling through the insulin receptor and increase the risk of type 2 diabetes. The metabolic syndrome also appears to be common among COPD patients, reflecting the concurrence of diabetes and cardiovascular disease with airway obstruction .


Epidemiological studies have shown that ∼20% of patients with obstructive sleep apnoea (OSA) also have COPD, whereas ∼10% of patients with COPD have OSA independent of disease severity. Obstructive Sleep Apnoea patients share several of the comorbidities of COPD like endothelial dysfunction, cardiac failure, diabetes and metabolic syndrome .Recent evidence shows that OSA patients have local upper airway inflammation, as well as systemic inflammation and oxidative stress .


Skeletal muscle weakness is one of the main systemic effects of COPD. It is often accompanied by loss of fat-free mass (FFM). However, muscle weakness may precede general cachexia. Skeletal muscle protein turnover is a dynamic process balancing protein synthesis and breakdown. In chronic illnesses like COPD, loss of muscle mass occurs at a slower rate. Data from human studies clearly indicate that atrophy of skeletal muscles is apparent in COPD and is specific to muscle fibre type IIA/IIx. Furthermore, these abnormalities are related to respiratory function, exercise intolerance, health status, mortality and healthcare resource utilisation. Muscle wasting is associated with loss of muscle strength, which in turn is a significant determinant of exercise capacity in patients with COPD independent of disease severity.


Inactivity appears to be an important factor, as muscles that are active, such as the diaphragm and adductor pollicis, are not usually weak in contrast to inactive muscles, such as quadriceps and vastus lateralis.. Patients with COPD are very immobile which is further reduced around the time of exacerbation. COPD patients loose quadriceps strength rapidly around the time of acute exacerbation and it has found to be deteriorating with the number of execerbations. Muscle disuse or muscle myopathy has been observed in COPD patients which may be the effect of muscle deconditioning, detraining, inactivity or heightened inflammation

Protein degradation in skeletal muscle occurs through several proteolytic systems, including the lysosomal pathway, calcium-dependent proteases, calpain and the 26S ubiquitin proteasome pathways. Loss of muscle mass is a complex process involving changes in the control of substrate and protein metabolism as well as changes in muscle cell regeneration, apoptosis and differentiation. Impaired protein metabolism may result in muscle atrophy when protein degradation exceeds protein synthesis. Increased myofibrillar protein breakdown has been demonstrated in cachectic COPD patients. There is increased apoptosis of skeletal muscle cells in severely underweight COPD patients. Systemic inflammation has found to be an important factor in several studies in the pathogenesis of weight loss and wasting of muscle mass.

In addition to inflammation, the development and progression of skeletal muscle dysfunction in COPD has also been strongly associated with enhanced oxidative stress, with increased reactive oxygen species (ROS) production and/or reduced antioxidant capacity. Oxidative stress may be enhanced in skeletal muscle of COPD patients as peroxidation products are elevated in the plasma of COPD patients at rest, after sub-maximal exercise and during exacerbations of the disease. ROS can increase muscle proteolysis, inhibit muscle-specific protein expression and increase muscle cell apoptosis

Muscle Strength and Endurance; It has been found from the recent evidences that approximately 70% of patients with chronic lung disease had lower quadriceps strength than the mean value obtained in normal subjects of similar age. The reduction in peripheral muscle mass contributes to peripheral muscle weakness in patients with COPD but it is unclear whether this muscle weakness attributes to muscle atrophy

As compared to normal subjects of similar age, the upper limb strength and endurance is relatively preserved compared to that of the lower limbs. This uneven distribution of muscle weakness between upper and lower limbs could be related to the differences in accustomed level of activity between the different muscle groups. The upper limb muscles are probably more normally involved in activities of daily living when compared with lower limb muscles

Oxygen Delivery and Utilization;. Patients with COPD characteristically show poor exercise performance which is indicated by a marked reduction in both peak pulmonary O2 uptake and work rate at peak exercise. Central pulmonary factors such as inability to adequately increase total ventilation because of the elevated work of breathing and disturbances of arterial respiratory blood gases (PaO2 and PaCO2) have been found related to the exercise intolerance in these patients . Recently, other evidence suggests that skeletal muscle dysfunction plays an important role in the limitation of exercise tolerance in COPD. Since the total ventilation, cardiac output, and exercise intensity remain closely coupled in COPD, the inability to raise ventilation appears to be the principal governor of the O2 transport process: a low ceiling on ventilation means a low ceiling on cardiac output and thus on systemic O2 delivery.


Several studies have reported the potential contributions of different mechanisms, principally being steroid use, inflammation and hypoxaemia

Corticosteroid use

Since patients with COPD are usually treated with either "short-burst" therapy for acute exacerbations or as long-term, low-dose "maintenance" corticosteroids therapy, several researchers have investigated the probability that COPD peripheral muscles experience a toxic myopathy called as "steroid-induced myopathy". Evidence was shown that long-term high doses of steroids mediates A significant reduction in quadriceps strength being strongly associated with quadriceps atrophy, was reported in COPD patients who received chronically low doses of steroids i.e the average daily dose of prednisolone amounted to 5 mg in the 6-month period as compared with patients unexposed to this medication. Decramer et al. reported severe quadriceps weakness that was significantly correlated with the average daily dose, mostly as a short-burst therapy of steroids taken by patients during acute exacerbations over the preceding 6 months. Evidences shows that the myopathic effects of repetitive bursts of steroid therapy might be greater than those of continuous low-dose therapy.

Systemic inflammation

Evidences have clearly indicated that COPD is associated with both an abnormal inflammatory response of the lung and with systemic inflammation which is characterised by the enhanced activation of circulating inflammatory cells (neutrophils and lymphocytes), greater expression of surface adhesion molecules in circulating neutrophils, and increased plasma levels of cytokines (interleukin (IL)-6 and IL-8, tumour necrosis factor (TNF)-α and its receptors tumour necrosis factor receptor (TNFR)-55 and TNFR-75) and acute phase reactant proteins (C-reactive proteins, lipopolysaccharide-binding protein (LBP), FAS and FAS ligands). Various studies have shown that systemic inflammation may trigger a catabolic/anabolic imbalance that ultimately results in skeletal muscle wasting and reduced muscle strength. Inflammation can have a negative impact on muscle protein catabolism via different cytokine-mediated pathways, particularly TNF-α. First, inflammation increases the demand for amino acids to synthesise acute phase proteins in the liver and reduces muscle protein stores. Secondly, TNF-α activates the adenosine triphosphate (ATP)-ubiquitin-dependent proteolytic system, through which muscle proteins are degraded and repair systems are inhibited. Thirdly, TNF-α stimulates apoptosis via fragmentation of DNA and/or interaction with the TNF-α receptor present on muscle cells It is further important to specify that TNF-α may also have a direct inhibitory effect on myofilaments and may alter muscle contractility, irrespective of changes in protein degradation or synthesis.

Peripheral muscle wasting and weakness have been convincingly assgociated with increased levels of serum acute phase reactant proteins (C-reactive proteins and LBP) and inflammatory cytokines (IL-8, and TNF-α receptors) in these patients. The levels of glutamic acid and glutamate in the vastus lateralis, as well as the sum of plasma amino acids (mainly alanine, glutamine and glutamic acid), have also been reported to be significantly decreased and inversely correlated with serum levels of LBP in COPD, suggesting that amino acids are indeed redirected from muscle to liver in these patients.


Chronic hypoxia adversely affects skeletal muscles. With prolonged exposure to high-altitude hypoxia, glycolytic enzyme (which is active in anaerobic metabolism) activity increases, whereas oxidative enzyme activity decreases . Hypoxia also increases oxidative stress, which can adversely affect muscle performance. Because of the shift to glycolytic metabolism, the oxidative capacity of skeletal muscle decreases . Muscle fiber cross-sectional area is decreased in mountain climbers undergoing prolonged hypoxia (greater than 6 weeks). In conclusion, adaptation to hypoxia makes muscle tissue more vulnerable to oxidative stress, which in turn leads to a malfunction in ATP generation and increases the accumulation of inosine monophosphate (IMP) in skeletal muscles. Inosine monophosphate has been detected in the resting skeletal muscles of patients with COPD .

Hypercapnia ;

Short-term exposure to hypercapnia results in skeletal muscle weakness, but no change in fatigability . In acute hypercapnic respiratory failure marked derangements in energy metabolism are seen, with marked reductions in ATP and phosphocreatine concentrations . Acute hypercapnia also contributes to intracellular acidosis in patients with acute respiratory failure. The effects of chronic hypercapnia need to be delineated.


In contrast to the effects of hypoxia, hypercapnia, and inflammation, the effects of nutritional depletion and muscle wasting on peripheral skeletal muscle function in COPD is reasonably well documented. Prolonged nutritional depletion is associated with proportionate reductions in muscle mass, whereas the mechanical effectiveness of the residual myofibrillar material remains unaffected . The effects of nutritional depletion on type II fibers are of greater magnitude than on type I fibers; greater atrophy of type II fibers ensures that a greater percentage of the remaining total muscle area will be composed of slow oxidative fibers whose resistance to fatigue is greater than that of fast fibers. Therefore the tension of the muscles generated during basal activities is well preserved, but the maximum power output may be impaired as progressively greater number of fast fibers are recruited. The high oxidative capacity of type I fibers can be considered as a metabolic adaptation to a process of glucose sparing by a greater reliance on fat as an energy substrate. It has been demonstrated in healthy men that the predominence of fat combustion during exercise is related to the percentage of slow-twich fibers in the quadriceps femoris muscle .

Effect of skeletal muscle dysfunction on exercise tolerance and functional performance :

The importance of peripheral skeletal muscle dysfunction in the impairment of exercise capacity in patients with COPD was suggested by Killian and colleagues . They observed that both patients with COPD and normal subjects frequently reported that the sensation of leg fatigue limited exercise. Impaired peripheral skeletal muscle function and (upper and lower extremity) exercise limitation can be discussed from the point of view of reduced strength and reduced endurance capacity of these muscles.

1. Peripheral Muscle Strength

Reduced strength is observed in peripheral muscles of patients with COPD. Quadriceps force correlates significantly with 6-min walking distance and maximal oxygen uptake . Muscle strength was also significantly correlated with symptom intensity during incremental exercise testing . Since these findings do not allow conclusions on a causal relationship, two additional observations make a causal relationship more likely. Firstly, changes in muscle strength have been demonstrated to correlate significantly with change in exercise capacity . Secondly, peripheral muscle strength training has been shown to improve maximal muscle strength, exercise endurance capacity, and quality of life . Reduced walking distance was shown to correlate significantly with the creatinine-height index in underweight patients with COPD, implying correlation with reduced fat-free body mass available for exercise . Recently, depletion of fat-free body mass was also found to correlate with reduced O2max in COPD .

2. Peripheral Muscle Endurance

Deterioration of endurance capacity of peripheral muscles is also likely to contribute to reduced exercise capacity. Low intensity endurance muscle training has been shown to significantly improve limb muscle endurance, but not muscle strength . It is also now well established that an early onset of anaerobic muscle metabolism during incremental exercise contributes to exercise limitation in COPD . Maltais and colleagues found a significant relationship between muscle aerobic enzyme levels and maximal oxygen uptake. In lung transplant patients, maximal oxygen uptake was significantly reduced and significantly correlated with abnormalities of skeletal muscle oxidative capacity . During constant work rate exercise, the contribution of aerobic and anaerobic metabolism to total muscle metabolism can be studied in the steady state. In patients with both mild and severe COPD, improved aerobic capacity is reflected by showing that, for a given level of exercise, the levels of lactate and ventilation are lower . This also reflects the link between skeletal muscle function and exercise capacity in COPD.

Reduced exercise capacity and muscle weakness render patients with COPD disabled and are associated with high utilization of health care resources . Poor exercise capacity and peripheral muscle weakness have also been shown to contribute to mortality. Moreover, patients with COPD and respiratory muscle myopathy and weakness have a higher mortality rate than do control patients with COPD.

Fatigability :

When normal individuals exercise vigorously the exercising muscle develops contractile fatigue. With contractile fatigue, the force generated by the muscle for a given neural input decreases. Patients with COPD become breathless when they exercise, and may stop exercise because of breathlessness before they stress the exercising muscle sufficiently to develop fatigue. This limits the exercise performance in Copd patients

Jeffery et al measured quadriceps twitch force (a measure of fatigue) before and after high-intensity cycle exercise to the limits of tolerance in a group of patients with moderately severe COPD and found a significant reduction in twitch force after exercise in 11 out of 19 patients. Thus, the majority of patients displayed contractile fatigue of the quadriceps muscle (the primary working muscle during stationary cycling) despite their having a severely reduced exercise capacity (the peak oxygen consumption [VO2] averaged 51% of predicted). In a subsequent study they measured potentiated quadriceps twitch force (a more sensitive index of contractile fatigue in a group of patients with COPD of varying severity. Potentiated twitch force fell in 17 out of 21 patients after exercise . Thus, most patients with COPD will develop contractile fatigue of the exercising muscle after exercise to the limits of tolerance. Patients with severe disease (FEV1 <40% of predicted) were as likely to develop exercise-induced quadriceps fatigue (seven out of nine) as those with milder disease (10 out of 12). According to Mador et al, healthy elderly individuals also develop exercise-induced quadriceps fatigue after cycle exercise to the limits of tolerance. The degree of exercise-induced quadriceps fatigue was not significantly different between the healthy elderly and the patients with COPD, even though the patients with COPD exercised at a significantly lower workload. These results suggest that the quadriceps muscle is more fatigable in patients with COPD than in healthy elderly persons.

Quadriceps myopathy in copd :

As evidenced from the above discussions Quadriceps myopathy is a feature of COPD which along with exertional dyspnea substantially reduce exercise performance. The magnitude of quadriceps weakness is related to disease severity, but there is wide variation for a given forced expiratory volume in 1 second (FEV1). The most straightforward suggestion is that the muscle changes are simply a local result of inactivity. This explanation is favoured by the preferential involvement of lower limb muscle (generally less active in COPD) over upper limb muscle, as well as the sparing of the diaphragm which shows increased activity. This argument is further supported by the observation that exercise training,9 and possibly externally applied nerve stimulation, can reverse disease induced changes in the muscle. Another explanation is that muscle wasting is the result of a systemic inflammatory response. The other possibility, which is consistent with the known histological myopathy in stable patients with COPD, is that the weakness is due to an acute myopathy. If so, the contractile properties of the muscle could have been directly impaired by inactivity, but the acute inflammatory response recognised to accompany acute exacerbations may also be relevant if an acute exacerbation could be shown to result in local skeletal muscle damage. It is now recognised that patients with frequent exacerbations of COPD have a more rapid rate of decline in lung function, and the study by Spruit et al raises the intriguing hypothesis that frequent exacerbators might have a more rapid decline in quadriceps strength.

Exertional dyspnoea

Patients with advanced COPD complain of breathlessness with activities of daily living and, in most of them, dyspnea is reported as a reason for limitation during exercise testing. The argument is made that during exercise, the ratio of inspiratory muscle pressure to maximal inspiratory muscle strength is increased due to the increased load and to the decreased capacity of the respiratory muscles to generate inspiratory pressures. This imbalance is thought to contribute to the sense of effort and exertional dyspnea. Patients with COPD are often limited in daily activities due to breathlessness. Exertional dyspnea, however, is not always related to the severity of airway obstruction. It has been reported that in COPD, limb effort or leg fatigue may be an important symptom associated with exercise limitation. Killian and Campbell/5/1293.full#ref-6#ref-6"6 hypothesized that breathlessness may be due to the perception of inspiratory muscle effort. As COPD progresses, respiratory muscles have to generate increased pressures to maintain an adequate V̇e. Also, because respiratory muscle strength decreases with disease progression, the ratio of inspiratory muscle pressure to inspiratory muscle strength during tidal breathing increases, both at rest and during exercise. Increasing values of this ratio are associated with development of respiratory muscle fatigue. Therefore, it was appealing to postulate that dyspnea is associated with this increased demand of the ventilatory muscles.

Andrea et al explained the major limitation to exercise performance in copd along with dynamic hyperinflation and lack of oxidative capacity of skeletal muscles, is inadequate energy supply to the respiratory and locomotor muscle caused due to Increased energy demands during exercise in COPD. Decreased energy supplies during exercise with expiratory flow limitation.this can be better explained by the following loop diagram

Effect of COPD on physical activity and functional performance.

Physical activity and Functional performance are profoundly affected in COPD patients which have an impact on their activities of daily life.

Sandland et al recorded daily activity using an activity monitor for 7 consecutive

days in 4 groups of 29 COPD patients. He demonstrated that patients with COPD have a significantly reduced level of spontaneous domestic activity compared with healthy controls. This activity is further compromised in patients receiving LTOT compared with non-LTOT COPD patients despite similar disease severity.

Mark et al performed the FLOW (Function, Living, Outcomes, and Work) cohort study of adults with COPD (n=1,202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery, SPPB), submaximal exercise performance (Six Minute Walk Test, SMWT), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). He found out that COPD was related to a broad array of physical functional limitations compared to a matched referent group without the disease, including lower extremity functioning, exercise performance, skeletal muscle strength, and self-reported limitation in basic physical actions.


The treatment for COPD is palliative, not curative.2 It is probable that longevity cannot be significantly improved with any treatment, except in patients with hypoxemia who benefit from supplemental oxygen therapy.2

Smoking Cessation: Smoking cessation, including cigarettes, cigars, and pipes, is the most important step in the treatment of COPD, since smoking is the most common cause.3,12 Smoking cessation can revert the decline in lung function to values of nonsmokers.14 In fact, an aggressive smoking intervention program has been shown to significantly reduce the age-related decline in FEV1 in middle-aged smokers with mild airway obstruction.14 Continuation of smoking essentially ensures that symptoms will worsen.12

Pharmacologic Interventions: Medication intervention usually consists of life-long chronic therapy with dosage adjustments and additional agents when exacerbations present. According to the American Lung Association, bronchodilators (oral or inhaled) are central to the symptomatic management of COPD. Additional treatment includes antibiotics, oxygen therapy, and systemic glucocorticosteroids.15 Inhaled glucocorticosteroids continue to be studied.

Chronic systemic steroid treatment poses the risk of serious side effects and is therefore usually reserved for acute exacerbations. Patients with COPD should receive pneumonia and influenza vaccines. Lung transplantation or lung volume reduction surgery may be an option for certain individuals. In addition, treatments for alpha-1 antitrypsin (AAT) deficiency emphysema, including AAT replacement therapy (a life-long process) and gene therapy, are being evaluated.