Original contributionOzone-induced increase in exhaled 8-isoprostane in healthy subjects is resistant to inhaled budesonide
Introduction
Ozone exposure in humans causes airway inflammation [1]. This response is characterized by decreased lung function [2], increased bronchial reactivity to methacholine [3], and increases in inflammatory cells and markers in both bronchoalveolar (BAL) fluid [4] and induced sputum [5]. We have recently demonstrated that lung inflammation induced by acute ozone exposure in healthy volunteers is not affected by pretreatment with budesonide, an inhaled corticosteroid [3]. We found decreased lung function, increased methacholine reactivity, and increased inflammatory markers in sputum (neutrophils, myoloperoxydase). There was no change in the exhaled markers such as nitric oxide (NO), carbon monoxide (CO), and nitrite [3].
Oxidative stress, which is an important pathogenetic component of lung inflammation, is also increased after ozone exposure in healthy volunteers as reflected by increased 8-isoprostane in airway lavage [1]. Isoprostanes are prostaglandin-like compounds produced by free radical peroxidation of arachidonic acid [6]. Measurements of these compounds in exhaled breath condensate (EBC), a new noninvasive method to sample secretions from the airways [7], has several advantages over other quantitative biomarkers of oxidant stress [8]. Isoprostanes (i) are chemically stable; (ii) are formed in vivo; (iii) are specific for lipid peroxidation, which is an important step in oxidative stress; (iv) exert biological activity, which may be relevant to the pathophysiology of lung diseases; (v) are used to define the clinical pharmacology of antioxidants; and, (vi) are measurable in EBC, which is likely to reflect oxidative stress in the lung [9].
We have previously shown that 8-isoprostane, a member of the F2 isoprostane class, is increased in EBC of patients with inflammatory airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, and in BAL fluid in patients with interstitial lung diseases 9, 10, 11, 12. Measurement of 8-isoprostane in EBC is potentially useful for noninvasive monitoring of ozone-induced oxidative stress in the lung. However, the effects of inhaled corticosteroids on 8-isoprostane are not clear. There is only one study showing that beclomethasone, an inhaled corticosteroid, reduces the 8-isoprostane increase in BAL in patients with asthma after antigen challenge [13]. However, in a previous study, we were unable to demonstrate any effect of pretreatment with inhaled budesonide on ozone-induced increase in inflammatory markers such as neutrophils and myeloperoxidase in sputum in healthy subjects [3].
The aim of this study was to investigate if oxidant stress, as reflected by exhaled 8-isoprostane, is affected by short-term ozone exposure and the effect of inhaled budesonide on free radical production after ozone exposure.
Section snippets
Subjects characteristics
Nine healthy subjects were studied (four men and five women; age: 30 ± 2.8 years, mean ± SEM). These subjects were previously enrolled in another study [3]. All had normal lung function (forced expiratory volume in 1 s [FEV1] 95.1 ± 3.2% predicted value, mean ± SEM), normal bronchial reactivity (screening provocative concentration of methacholine causing a 20% reduction in FEV1 [PC20] > 64 mg/ml), and were nonatopic on skin prick testing to common aeroallergens (cat, grass, pollen,
Exhaled 8-isoprostane
There was no difference between pre-exposure concentrations of exhaled 8-isoprostane in the two study groups (placebo: 16.9 ± 0.7 pg/ml; budesonide: 15.8 ± 0.3 pg/ml, p = .16). Compared with baseline values (15.8 ± 1.2 pg/ml, placebo and 15.3 ± 1.3 pg/ml, budesonide), there was no change after placebo (16.9 ± 0.7 pg/ml, p = .43) or budesonide treatment (15.8 ± 0.3 pg/ml, p = .71). 8-Isoprostane concentrations in EBC were increased 4 h after ozone exposure compared to pre-exposure values in both
Discussion
8-Isoprostane is formed in vivo by free radical peroxidation of arachidonic acid [6]. Measurement of this compound in biological fluid may provide a quantitative index of in vivo oxidative stress, which is an important component of airway inflammation [8].
In this study, we showed that short-term exposure to ozone causes an increase in lung oxidative stress that lasts up to 4 h as reflected by 8-isoprostane concentrations in EBC of healthy volunteers. These results are consistent with previous
Abbreviations
BAL—bronchoalveolar lavage
CI—confidence intervals
CO—carbon monoxide
EBC—exhaled breath condensate
EIA—enzyme immunoassay
FEV1—forced expiratory volume in 1 s
FVC—forced vital capacity
NO—nitric oxide
PC20—provocative concentration that causes 20% decrease in FEV1
ppb—parts per billion
SEM—standard error of the mean
Acknowledgements
This work was funded by Imperial College, National Heart and Lung Institute, London, England. This work was performed at Imperial College, School of Medicine at the National Heart and Lung Institute, Department of Thoracic Medicine, Dovehouse Street, London, England.
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