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Diminished Immunoreactivity of -Glutamylcysteine Synthetase in the Airways of Smokers' Lung

Departments of Internal Medicine and Pathology, University of Oulu, Oulu University Hospital; and Biocenter of Oulu, Oulu, Finland

Correspondence and requests for reprints should be addressed to Professor Vuokko L. Kinnula, Department of Internal Medicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland. E-mail: vuokko.kinnula{at}oulu.fi

Glutathione (GSH) plays a major role in protecting the airways against oxidative stress. The rate-limiting enzyme in de novo GSH synthesis is -glutamylcysteine synthetase (-GCS), which is induced by acute exposure to GSH-depleting cytokines and oxidants, but downregulated by transforming growth factor ß and prolonged oxidant exposure, at least in vitro. Cell-specific expression or regulation of -GCS may play an important role both in the defense against oxidants and in the pathogenesis of oxidant-associated airway diseases. In this study, the localizations of -GCS heavy (-GCS-HS) and light (-GCS-LS) subunits were investigated by immunohistochemistry in 22 patients with chronic obstructive pulmonary disease (COPD), 20 smokers without COPD, and 13 lifelong nonsmokers. The ultrastructural distributions of both -GCS subunits were assessed by immuno–electron microscopy. Both subunits were expressed most prominently in the large airways, and their ultrastructural localization was both cytoplasmic and along the plasma membrane. The expression of -GCS-HS was stronger in the central bronchial epithelium than in the peripheral bronchioli (p = 0.020), or in alveolar macrophages (p = 0.008). The expression of -GCS-HS in the central bronchial epithelium showed a tendency to be higher in nonsmokers compared with all smokers (p = 0.052). Alveolar macrophages of nonsmokers had higher levels of -GCS-HS (p = 0.001) and -GCS-LS (p = 0.001) than did smokers. The expression of -GCS-HS in the central bronchial epithelium was more marked in nonsmokers than in patients with COPD (p = 0.015), the difference between smokers and patients with COPD was not significant. In conclusion, the heavy and light subunits of -GCS are mainly expressed in the large airways. Their tendency to decrease in cigarette smokers may further predispose lung cells to ongoing oxidant stress, which contributes to the progression of lung injury.

Key Words: -glutamylcysteine synthetase • smoking • chronic obstructive pulmonary disease • oxidant • glutathione

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