Chest
Oxidants/Antioxidants and COPD
Section snippets
Oxidants in Cigarette Smoke
Cigarette smoke is a complex mixture of > 4,700 chemical compounds of which free radicals and other oxidants are present in high concentrations.4 Free radicals are present in both the tar and the gas phases of cigarette smoke. The gas phase of cigarette smoke contains approximately 1015 radicals per puff, primarily of the alkyl and peroxyl types. Nitric oxide (NO) is another oxidant that is present in cigarette smoke in concentrations of 500 to 1,000 ppm.4 NO reacts quickly with the superoxide
Cell-Derived Oxidants
The direct increase in the oxidative burden produced by inhaling cigarette smoke can be further enhanced in smokers' lungs by the release of oxygen radicals from inflammatory leukocytes, both neutrophils and macrophages, which are known to migrate into the lungs of cigarette smokers.8 Increased amounts of oxidants such as O2·− and hydrogen peroxide are released from the leukocytes of smokers, compared with those from nonsmokers.9
Iron is a critical element in many oxidative reactions. The
Oxidative Stress in the Airspaces
By virtue of its direct contact with the environment, the airspace epithelial surface of the lung is particularly vulnerable to the effects of oxidative stress. The respiratory tract lining fluid (RTLF) forms an interface between the epithelial cells and the external environment, and thus constitutes a first line of defense against inhaled oxidants. At least three processes may be responsible for oxidant injury to the respiratory tract epithelial cells from cigarette smoke: (1) a direct toxic
Oxidative Stress and Neutrophil Sequestration and Migration in the Lungs
The first step in the recruitment of neutrophils to the airspaces is the sequestration of these cells in the lung microcirculation.34 This occurs under normal circumstances in the pulmonary capillary bed, as a result of the size differential between neutrophils (average diameter, 7 μm) and pulmonary capillary segments (average diameter, 5 μm). Thus a proportion of the circulating neutrophils have to deform in order to negotiate the smaller capillary segments. Studies using a variety of
Evidence of Oxidative Stress in Smokers and Patients With COPD
There is now overwhelming evidence for the presence of increased oxidative stress in smokers and patients with COPD.50,51,52 Direct measurements of specific markers of oxidative injury resulting from excessive free radical activity can be made by electron spin resonance, which cannot be applied to the study of tissues at present. Most studies have therefore relied on indirect measurements of free radical activity in biological fluids. Although these markers suggest that oxidative stress has
Evidence of Systemic Oxidative Stress
There has recently been considerable interest in the systemic effects of COPD. One manifestation of a systemic effect is the presence of markers of oxidative stress in the blood in patients with COPD. This is reflected in the increased sequestration of neutrophils in the pulmonary microcirculation during smoking and during exacerbations of COPD which, as described above, is an oxidant-mediated event.37,38,39,40,46
Rahman and colleagues40 demonstrated increased production of superoxide anion from
Other Mechanisms Related to the Pathogenesis of COPD Involving Oxidants
The majority of the information that is available on the pathogenesis of COPD relates to the development of emphysema. COPD also includes the other conditions of chronic bronchitis and small airways disease. It is presumed that the factors that initiate inflammation and the effects of proteolytic and oxidant-induced damage are also relevant to these conditions, although much less information is available.
Animal models of elastase-induced emphysema also show features of airways diseases with
Evidence for a Relationship Between Oxidant/Antioxidant Balance and the Development of Airways Obstruction
The neutrophil appears to be a critical cell in the pathogenesis of COPD. Previous epidemiologic studies have shown a relationship between circulating neutrophil numbers and the FEV1,104,105 and indeed a relationship has been shown between the change in peripheral blood neutrophil count and the change in airflow limitation over time.105 Other studies have provided supportive evidence of a role for ROS released from circulating neutrophils and the development of airflow limitation. Richards and
Proinflammatory Genes
There is overwhelming evidence that COPD is associated with airway and airspace inflammation, as shown for example by recent biopsy studies.32 Numerous markers of inflammation have been shown to be elevated in the sputum of patients with COPD, such as interleukin (IL)-8 and tumor necrosis factor (TNF)-α.111
Genes for many inflammatory mediators, such as the cytokines IL-8, TNF-α, and nitric oxide (NO) are regulated by transcription factors such as TNF-κB). NF-κB is present in the cytosol in an
Oxidative Stress and Susceptibility to COPD
Since only a proportion (15 to 20%) of cigarette smokers appear to be susceptible to its effects and show a rapid decline in FEV1 and develop the disease,122 there has been considerable interest in identifying those who are most susceptible and the mechanisms of that susceptibility,123 since this may provide an important insight into the pathogenesis of COPD, as did the recognition of an association between α1-AT and COPD.
Polymorphisms of various genes have been shown to be more prevalent in
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