Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease

Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and ext racellular protective antioxidant in the lungs. The rate-limiting enzyme in GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS). The promot er (5'-flanking) region of the human gamma-GCS heavy and light subunits are regulated by activator protein-1 and antioxidant response elements. Both G SH and gamma-GCS expression are modulated by oxidants, phenolic antioxidant s, and inflammatory and anti-inflammatory agents in lung cells. gamma-GCS i s regulated at both the transcriptional and posttranscriptional levels. GSH plays a key role in maintaining oxidant-induced lung epithelial cell funct ion and also in the control of proinflammatory processes. Alterations in al veolar and lung GSH metabolism are widely recognized as a central feature o f many inflammatory lung diseases including chronic obstructive pulmonary d isease (COPD). Cigarette smoking, the major factor in the pathogenesis of C OPD, 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 gamma-GCS in the lungs. The mechani sm of regulation of GSH in the epithelial lining fluid in the lungs of smok ers 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 b ased on the pharmacological or genetic manipulation of the production of th is important antioxidant in lung inflammation and injury. This review outli nes 1) the regulation of cellular GSH levels and gamma-GCS expression under oxidative stress and 2) the evidence for lung oxidant stress and the poten tial role of GSH in the pathogenesis of COPD.