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A Review of the GOLD Guidelines for the Diagnosis and Treatment of Patients With COPD: Pathogenesis

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Pathogenesis

Chronic obstructive pulmonary disease is an insidious and progressive disease: there are no characteristic symptoms in the early stages of the disease; in later stages, the symptoms are partially, but not fully, reversible. COPD usually occurs in mid-life following long-term exposure to noxious particles or gases when the normal protective and repair functions in the lungs are overwhelmed or functioning suboptimally. Smoking continues to be the leading cause of COPD.[1] Evidence suggests that cigarette smoking is directly toxic to cells within the lungs and also impairs the mechanisms responsible for the repair of lung tissue. However, not all cases of COPD are caused by smoking, and not all smokers develop COPD. The risk of COPD is dependent on the total burden of particles inhaled over time. Long-term inhalational exposure to occupational dusts and chemicals, indoor pollution from heating and cooking with biomass fuels, and outdoor pollution all increase the risk of COPD.[1]

Chronic obstructive pulmonary disease is associated with a significant inflammatory component, where the cascade of inflammatory events ultimately leads to the tissue damage that characterises this condition. The inflammation seen in the respiratory tract of patients with COPD is actually an exaggeration of inflammatory responses normally seen in the respiratory tracts of individuals who smoke, but do not have COPD.[15] In patients with COPD, there is an increase in the lungs and circulation in the levels of several inflammatory markers, including C-reactive protein, tumour necrosis factor-alpha, interleukin (IL)-8, IL-6 and monocyte chemoattractant protein-1. Serum levels of many of these markers correlate with measurements of COPD including forced expiratory volume in 1s (FEV1), dyspnoea levels (measured by the BODE index, a multidimensional scale of Body-mass index, airway Obstruction, Dyspnoea, and Exercise capacity), and exacerbation rates.[16] There is also a characteristic increase in the levels of leucocytes in various parts of the lung, including neutrophils, macrophages and T-lymphocytes (particularly CD8+).[1,15] An imbalance of proteases (such as elastase, which degrades connective tissue in the lungs) and antiproteases (such as alpha1-antitrypsin) is thought to contribute to the irreversible lung damage seen in COPD, particularly in patients with emphysema.[15] Protease/antiprotease imbalance may be caused by worsening lung inflammation or by environmental or genetic factors.[1] Oxidative stress is also thought to be an important component of COPD pathogenesis. Cigarette smoke, inflammation, respiratory infections, genetic factors and dietary factors can all have an effect on oxidant/antioxidant balance.[17] Several adverse reactions can occur in the lung in response to oxidative stress, including increased inflammation, increased mucus secretion and inactivation of protective antiproteases.[1]

Alpha-1 antitrypsin (AAT) deficiency is an important genetic factor for the development of COPD. AAT is an antiprotease which exerts a protective effect on lung tissue by inhibiting the elastase that breaks down lung connective tissue.[18] Approximately 3% of COPD patients have this deficiency.[19] Onset of COPD in AAT-deficient individuals often occurs earlier in life than in those without the deficiency; however, some patients can benefit from AAT augmentation therapy in addition to standard COPD treatments.

As COPD progresses, worsening lung inflammation and tissue damage result in the characteristic pathologic changes of COPD, which are found primarily in the proximal and peripheral airways, lung parenchyma and pulmonary vasculature.[1] Imbalance between the lung's repair and defense mechanisms results in small airway fibrosis. When injured, normal lungs undergo tissue-repair processes that return the tissue to normal or near normal functioning. However, in the presence of the tissue destruction associated with emphysema, these repair processes are altered, and the balance between destruction and repair is affected. Eventually, the destruction of the parenchymal tissue in the lungs results in emphysema, which is characterised by enlarged alveolar sacs and structural damage to the respiratory bronchioles.[20]

Remodelling of the small airways is a key factor in the development of the irreversible airflow limitation characteristic of COPD. Airway remodelling describes the persistent changes that occur within the structural components of the airways in response to inflammation and occurs in patients with either COPD or asthma.[21] Because of the structural changes in the airway walls, the resistance in the peripheral airways increases, resulting in the major sites of obstruction. Additionally, oedema and hypersecretion of mucus contribute to airway narrowing. These changes all contribute to the air trapping and progressive airflow limitation seen in patients with COPD.[1]

Importantly, it needs to be stressed that the inflammatory changes seen in COPD are not the same as those that occur in asthma,[15,22] and this probably explains the different responses to pharmacotherapy, for example, inhaled corticosteroid (ICS) responses, seen in the two diseases.[23] However, it has also been suggested that airway remodelling in asthmatic patients may be related to the development of COPD symptoms with non-reversible airway obstruction and accelerated decline in FEV1, suggesting functional and pathologic overlap between the two diseases.[24,25] It should be noted, however, that the nature of this association is not yet fully understood, and the correlation between asthma airway remodelling and an increased risk of developing COPD requires further investigation.[24]

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