Brief Communication
Reduced Superoxide Dismutase in Lung Cells of Patients with Asthma

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Abstract

Lung cells recovered from symptomatic patients with asthma generate increased amounts of reactive oxygen species (ROS). Animal and in vitro studies indicate that ROS can reproduce many of the features of asthma. The ability of ROS to produce the clinical features of asthma may depend on an individual's lung antioxidant defenses. Patients with asthma are reported to have reduced antioxidant defenses in peripheral blood, but little is known about the antioxidant defenses of their lung cells. To define lung cell antioxidant defenses in asthma, the glutathione concentration and the glutathione reductase, glutathione peroxidase, catalase, and superoxide dismutase (SOD) activities were measured in cells recovered by bronchoalveolar lavage (BAL cells) and by bronchial brushing (bronchial epithelial cells, HBEC) from normal subjects and patients with asthma. Superoxide dismutase activity was reduced 25% in BAL cells (p < .05) and nearly 50% in HBEC (p < .02) from patients with asthma. Alterations in the other antioxidants were not identified. A direct relationship was found between airway reactivity to methacholine, measured as PC20FEV1, and HBEC SOD activity (r2 = 89; p < .005), but not between airway reactivity and the other antioxidants. The finding of reduced SOD activity in lung cells of patients with asthma suggests that diminished SOD activity serves as a marker of the inflammation characterizing asthma. Alternatively, it may play a role in the development or severity of the disease. © 1997 Elsevier Science Inc.

Introduction

Although the pathogenesis of asthma remains incompletely defined, a key observation in patients is an increased number and activity of inflammatory cells in the lung.1, 2, 3 The inflammatory cells, which include alveolar macrophages (AM), neutrophils, eosinophils, lymphocytes, and mast cells, as well as the epithelial cells lining the airways, have the capacity to generate reactive oxygen species (ROS).4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Reactive oxygen species can reproduce the pathophysiological features of asthma including enhanced arachidonic acid release, airway smooth muscle contraction, increased airway reactivity and secretions, increased vascular permeability, increased synthesis of chemoattractants, and impaired beta-adrenergic responsiveness (reviewed in [14]). Cells obtained from the peripheral blood and the lungs of patients with asthma generate increased amounts of ROS and the increase correlates with disease severity.6, 7, 9, 12

The lungs possess a host of antioxidant defenses (reviewed in [15]), including the glutathione redox cycle (glutathione peroxidase, glutathione reductase), superoxide dismutase and catalase, plus vitamins C and E. In several studies, whole blood and peripheral blood cells (monocytes, neutrophils) obtained from patients with asthma have exhibited reduced antioxidant defenses including reduced glutathione peroxidase and superoxide dismutase activities.11, 16, 17, 18, 19 Also, a decrease in non-specific airway reactivity has been reported following vitamin C supplementation.[20] These findings suggest that asthma is characterized by reduced antioxidant defenses. Consequently, augmenting these defenses could prove to be beneficial. Experience with sarcoidosis, an inflammatory disease in which the abnormalities in the lung may be opposite those found in peripheral blood,[21] demonstrates the need for directly analyzing lung antioxidant defenses.

We recently reported increased levels of glutathione in the bronchoalveolar lavage (BAL) fluid from patients with asthma and demonstrated an inverse relationship between glutathione levels and airway reactivity to methacholine.[20] However, the fluid bathing the lungs and the airways is only one source of antioxidants. Cells recovered by BAL (mostly AM) and bronchial epithelial cells also have the capacity to detoxify ROS.13, 23, 24 They can defend the airways against inhaled and locally generated ROS by providing the initial interface with environmental oxidants and they are near the oxidants generated by locally recruited and activated inflammatory cells. Yet, remarkably little is known about lung cell antioxidant defenses in patients with asthma.

In the present study we examined antioxidant defenses in lung cells obtained from normal subjects and patients with asthma. We found decreased superoxide dismutase activity, but no change in either catalase or the enzymes of the glutathione redox cycle, in BAL cells, and bronchial epithelial cells (HBEC) recovered from patients with asthma. The potential implications of these observations are discussed.

Section snippets

Study Design

Two separate groups of subjects were studied at different times. Each group consisted of normal subjects and patients with asthma. The first group (group 1) underwent bronchoscopy and had bronchoalveolar lavage (BAL) performed. The BAL cells recovered were used to measure total glutathione (GSH + GSSG) concentration as well as glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase activities. The second group (group 2) underwent bronchoscopy and had bronchial

Results

The patients with asthma in Group 1 had slightly but not significantly lower FEV1 values than the normal subjects and a higher percentage of peripheral blood eosinophils (p < .05) (Table 1). There were no differences in the BAL fluid protein concentration, the percentage of BAL fluid recovered, the total number of BAL cells, or the BAL differential cell count. At least 85% and usually more than 90% of the BAL cells recovered in both the normal subjects and the patients with asthma were AM.

The

Discussion

This study was designed to characterize the antioxidant defenses of cells obtained from the lungs of patients with asthma. We analyzed cells recovered by BAL (mostly AM) and bronchial brushing (HBEC) for glutathione concentration and glutathione peroxidase, glutathione reductase, catalase, and SOD activities. We considered characterization of these local antioxidant defenses to be important for several reasons. First, asthma is an inflammatory disease,1, 2, 3 the inflammatory cells obtained

Acknowledgements

This work was supported in part by grants from the Department of Veterans Affairs, National Institutes of Health (RR-00048 and AI-11403), and the Northwestern University Crane Asthma Center.

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