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Department of Respiratory Medicine, Medical School, University of Edinburgh, Edinburgh EH8 9AG, United Kingdom
Glutathione (GSH), a ubiquitous tripeptide
thiol, is a vital intra- and extracellular protective antioxidant in
the lungs. The rate-limiting enzyme in GSH synthesis is
-glutamylcysteine synthetase (-GCS). The promoter
(5'-flanking) region of the human -GCS heavy and light
subunits are regulated by activator protein-1 and antioxidant response
elements. Both GSH and -GCS expression are
modulated by oxidants, phenolic antioxidants, and inflammatory and
anti-inflammatory agents in lung cells. -GCS is regulated at both
the transcriptional and posttranscriptional levels. GSH plays a key
role in maintaining oxidant-induced lung epithelial cell function and
also in the control of proinflammatory processes. Alterations in
alveolar and lung GSH metabolism are widely recognized as a central
feature of many inflammatory lung diseases including chronic
obstructive pulmonary disease (COPD). Cigarette smoking, the major
factor in the pathogenesis of COPD, increases GSH in the lung
epithelial lining fluid of chronic smokers, whereas in acute smoking,
the levels are depleted. These changes in GSH may result from altered
gene expression of
-GCS in the lungs.
The mechanism of regulation of GSH in the epithelial lining fluid in
the lungs of smokers and patients with COPD is not known. Knowledge of
the mechanisms of GSH regulation in the lungs could lead to the
development of novel therapies based on the pharmacological or genetic
manipulation of the production of this important antioxidant in lung
inflammation and injury. This review outlines
1) the regulation of cellular GSH
levels and -GCS expression under oxidative
stress and 2) the evidence for lung
oxidant stress and the potential role of GSH in the pathogenesis of COPD.
-glutamylcysteine synthetase; oxidants; antioxidants; activator
protein-1; antioxidant response element; smokers; lungs; chronic
obstructive pulmonary disease; airway epithelium
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