Cigarette smoking is undoubtedly the most important factor in the development of chronic obstructive pulmonary disease (COPD). The pathologic changes characteristic of COPD are found in the trachea, bronchi, bronchioles, respiratory bronchioles, alveoli, and pulmonary vasculature. These changes include chronic inflammation, and structural changes that result from repeated injury and repair.1
An overview of the pathogenesis of COPD is shown in Figure 1. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airways disease (obstructive bronchiolitis) and parenchymal destruction (emphysema).1
The following processes have been shown to be involved in the pathogenesis of COPD, but their relative importance to, and interaction within the characteristic COPD disease state is still unclear.
The chronic inflammation seen in the respiratory tract of patients with COPD seems to be an amplification of the normal inflammatory response to the inhalation of irritants and noxious particles, such as cigarette smoke.1 COPD is characterised by a specific pattern of inflammation involving neutrophils, macrophages, and lymphocytes,1,2,3 the pathologic roles of which are summarised in Table 1.
Table 1. Inflammatory cells involved in the pathogenesis of COPD.
A number of studies have indicated that oxidative stress has a significant role in the pathogenesis of COPD.4,5 Biomarkers of oxidative stress are increased in the breath and sputum of COPD patients.1 Free radicals are secreted by certain inflammatory cells, and are introduced during the inhalation of cigarette smoke.5,6 Oxidative stress in the lungs amplifies the inflammatory response, inactivates protease inhibitors and stimulates mucus production.1,4
Within the lungs of patients with COPD, the normal balance between proteases, which degrade connective tissue, and protease inhibitors, which prevent this destruction, is disrupted.1,6 This imbalance is at least partly due to the secretion of proteases by macrophages and neutrophils.1 Protease-mediated destruction of elastin in lung parenchyma reduces lung elasticity, and is likely to be irreversible.1 Damage due to the increase in protease production is further compounded by the reduction or inhibition of protease inhibitors.1,6
In addition to eliciting an inflammatory response and inducing oxidative stress, cigarette smoke causes direct damage to airways.7 The continued inhalation of smoke damages cilia, reducing their ability to clear mucus. Consequently, thick plugs of mucus can accumulate in the airways, intensifying the inflammatory response and increasing the risk of infection. The scarring and remodelling due to bronchiolitis thickens airway walls, leading to widespread narrowing (peripheral airways obstruction), which progressively traps air during expiration and increases the amount of air remaining in the lungs following expiration (hyperinflation).1 Figure 2 illustrates the causes of small airway obstruction seen in patients with COPD.7
Reduced elastic recoil of the lungs further reduces the driving pressure that forces air out of the lungs, leading to greater air trapping and hyperinflation.8 As a result, these patients use a large amount of energy to exhale, which contributes to fatigue.
Irreversible destruction of gas-exchanging airspaces (i.e. respiratory bronchioles, alveolar ducts and alveoli)9 reduces the surface area of respiratory membrane available for gas transfer, and as a consequence the amount of gas that can transfer across in a given time, resulting in hypoxaemia (decreased oxygen in the blood) and hypercapnia (elevated CO2 in the blood) (Figure 3).1
In COPD patients, the development of certain systemic features can have a major impact on quality of life and survival. The inefficient respiration associated with advanced COPD places enormous stress on the respiratory and circulatory systems, resulting in the development of several co-morbid conditions. Reduced pulmonary function limits physical function, including lower limb function, exercise performance, skeletal muscle strength, and basic physical actions,10 consistent with the activity limitation reported by many patients with COPD.12
Mild-to-moderate pulmonary hypertension may develop as pulmonary vascular resistance is increased due to pulmonary vasoconstriction (caused by hypoxia) and the destruction of pulmonary vascular tissue associated with emphysema.13 Progression of pulmonary hypertension can lead to cor pulmonale (enlargement of the right ventricle of the heart). As resistance in pulmonary vascular tissue increases, the right ventricle has to eject blood against a greater pressure gradient, and a sustained increase in pulmonary vascular resistance may eventually lead to right ventricular failure.13
Weight loss, weakness and fatigue, due to the loss of skeletal muscle through increased apoptosis and/or muscle disuse, further reduce the exercise capacity and health status of patients with severe COPD.14
Patients with COPD frequently have a variety of comorbidities. These commonly include cardiovascular disease, chronic renal failure, type 2 diabetes and asthma.15,16,17 Comorbidities may share common causes with COPD (such as smoking, which is associated with ischemic heart disease and lung cancer), arise as complications of COPD (e.g. pulmonary hypertension and heart failure), or occur concurrently due to factors such as old age (e.g. hypertension, diabetes mellitus, depression and osteoarthritis).18 It has also been suggested that several comorbidities (such as musculoskeletal wasting, metabolic syndrome and depression) that are unlikely to be attributable to smoking may be linked to COPD by a common underlying inflammatory mechanism.19
The presence of comorbidities increases the likelihood of adverse outcomes, including mortality, in patients with COPD.20 Comorbid cardiovascular disease has also been shown to increase the risk of COPD-related hospitalisations and accident and emergency visits and to greatly increase medical costs.21