Chest
Volume 117, Issue 5, Supplement 1, May 2000, Pages 303S-317S
Journal home page for Chest

Oxidants/Antioxidants and COPD

https://doi.org/10.1378/chest.117.5_suppl_1.303S-aGet rights and content

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. Oxidative stress is thought to play an important role in the pathogenesis of a number of lung diseases, not only through direct injurious effects, but by involvement in the molecular mechanisms that control lung inflammation. A number of studies have shown an increased oxidant burden and consequently increased markers of oxidative stress in the airspaces, breath, blood, and urine in smokers and in patients with COPD. The presence of oxidative stress has important consequences for the pathogenesis of COPD. These include oxidative inactivation of antiproteinases, airspace epithelial injury, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of proinflammatory mediators. With regard to the latter, oxidative stress has a role in enhancing the inflammation that occurs in smokers and patients with COPD, through the activation of redox-sensitive transcriptions factors such as nuclear factor-κB and activator protein-1, which regulate the genes for proinflammatory mediators and protective antioxidant gene expression.

The sources of the increased oxidative stress in patients with COPD are derived from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Antioxidant depletion or deficiency in antioxidants may contribute to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants, and hence dietary supplementation may be a beneficial therapeutic intervention in this condition. Antioxidants that have good bioavailability or molecules that have antioxidant enzyme activity may be therapies that not only protect against the direct injurious effects of oxidants, but may fundamentally alter the inflammatory events that play an important part in the pathogenesis of 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

References (144)

  • GG Duthie et al.

    Effects of smoking and vitamin E on blood antioxidant status

    Am J Clin Nutr

    (1991)
  • British Thoracic Society

    Guidelines for the management of chronic obstructive pulmonary disease

    Thorax

    (1997)
  • T Church et al.

    Free-radical chemistry of cigarette smoke and its toxicological implications

    Environ Health Perspect

    (1985)
  • WA Pryor et al.

    Oxidants in cigarette smoke: radicals hydrogen peroxides peroxynitrate and peroxynitrite

    Annals N Y Acad Sci

    (1993)
  • KY Zang et al.

    Detection of free radicals in aqueous extracts of cigarette tar by electron spin resonance

    Free Radic Biol Med

    (1995)
  • CK Chow

    Cigarette smoking and oxidative damage in the lung

    Ann NY Acad Sci USA

    (1993)
  • GW Hunninghake et al.

    Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers

    Am Rev Respir Dis

    (1983)
  • D Morrison et al.

    Epithelial permeability inflammation and oxidant stress in the air spaces of smokers

    Am J Respir Crit Care Med

    (1999)
  • F Mateos et al.

    Iron metabolism in the lower respiratory tract

    Thorax

    (1998)
  • AB Thompson et al.

    Lower respiratory tract iron burden is increased in association with cigarette smoking

    J Lab Clin Med

    (1991)
  • LJ Wesselius et al.

    Increased release of ferritin and iron by iron loaded alveolar macrophages in cigarette smokers

    Am J Respir Crit Care Med

    (1994)
  • A Cantin et al.

    Oxidants, antioxidants and the pathogenesis of emphysema

    Eur J Respir Dis

    (1985)
  • P Laurent et al.

    Cigarette smoke blocks cross-linking of elastin in vitro

    Am Rev Respir Dis

    (1983)
  • CE Cross et al.

    Oxidants antioxidants and respiratory tract lining fluids

    Environ Health Perspect

    (1994)
  • JA Dye et al.

    Effects of cigarette smoke on epithelial cells on the respiratory tract

    Thorax

    (1994)
  • S Lannan et al.

    Effects of cigarette smoke and its condensates on alveolar cell injury in vitro

    Am J Physiol

    (1994)
  • XY Li et al.

    An investigation of the role of glutathione in the increased epithelial permeability induced by cigarette smoke in vivo and in vitro

    Am J Respir Crit Care Med

    (1994)
  • XY Li et al.

    Mechanisms of cigarette smoke induced increased airspace permeability

    Thorax

    (1996)
  • I Rahman et al.

    Cigarette smoke glutathione metabolism and epithelial permeability in rat lungs

    Biochem Soc Trans

    (1995)
  • XY Li et al.

    The role of tumour necrosis factor in increased airspace epithelial permeability in acute lung inflammation

    Am J Respir Cell Mol Biol

    (1995)
  • D Morrison et al.

    Epithelial permeability, inflammation and oxidant stress in the air spaces of smokers

    Am J Respir Crit Care Med

    (1999)
  • K Kilburn et al.

    Leukocyte recruitment to airways by cigarette smoke and particle phase in contrast to cytotoxicity of vapor

    Science

    (1975)
  • GW Hunninghake et al.

    Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers

    Am Rev Respir Dis

    (1983)
  • T Schaberg et al.

    Superoxide anion release induced by platelet-activating factor is increased in human alveolar macrophages from smokers

    Eur Respir J

    (1992)
  • GA Richards et al.

    Spirometric abnormalities in young smokers correlate with increased chemiluminescence responses of activated blood phagocytes

    Am Rev Respir Dis

    (1989)
  • WB Davis et al.

    Enhanced cytotoxic potential of alveolar macrophages from cigarette smokers

    J Lab Clin Med

    (1988)
  • PW Ludwig et al.

    Alterations in leukocyte oxidative metabolism in cigarette smokers

    Am Rev Respir Dis

    (1982)
  • JR Hoidal et al.

    Altered oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic cigarette smokers

    Am Rev Respir Dis

    (1981)
  • PK Jeffery

    Structural and inflammatory changes in COPD: a comparison with asthma

    Thorax

    (1998)
  • W MacNee et al.

    Neutrophil traffic in the lungs, the role of hemodynamics, cell adhesion and deformability

    Thoxax

    (1993)
  • C Selby et al.

    In vivo neutrophil sequestration within the lungs of man is determined by in vitro ‘filterability’

    J Appl Physiol

    (1991)
  • JC Hogg

    Neutrophil kinetics and lung injury

    Physiol Rev

    (1987)
  • W MacNee et al.

    The effect of cigarette smoking on neutrophil kinetics in human lungs

    N Engl J Med

    (1989)
  • EM Drost et al.

    Changes in neutrophil deformability following in vitro smoke exposure: mechanism and protection

    Am J Respir Cell Mol Biol

    (1992)
  • E Drost et al.

    Decreased leukocyte deformability following acute cigarette smoking in smokers

    Am Rev Respir Dis

    (1993)
  • I Rahman et al.

    Systemic oxidative stress in asthma COPD, and smokers

    Am J Respir Crit Care Med

    (1996)
  • ME Klut et al.

    Activation of neutrophils within pulmonary microvessels of rabbits exposed to cigarette smoke

    Am J Respir Cell Mol Biol

    (1993)
  • C Nathan et al.

    Cytokine-induced respiratory burst of human neutrophils dependence on extracellular matrix proteins and CD11/CD18 integrins

    J Cell Biol

    (1989)
  • C Selby et al.

    Inhibition of neutrophil adherence and movement by acute cigarette smoke exposure

    Exp Lung Res

    (1992)
  • C Selby et al.

    Neutrophil retention in the lungs of patients with chronic obstructive pulmonary diseases

    Am Rev Respir Dis

    (1991)
  • Cited by (376)

    View all citing articles on Scopus
    View full text