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

Abstract

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 gamma-glutamylcysteine synthetase (gamma-GCS). The promoter (5'-flanking) region of the human gamma-GCS heavy and light subunits are regulated by activator protein-1 and antioxidant response elements. Both GSH and gamma-GCS expression are modulated by oxidants, phenolic antioxidants, and inflammatory and anti-inflammatory agents in lung cells. gamma-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 gamma-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 gamma-GCS expression under oxidative stress and 2) the evidence for lung oxidant stress and the potential role of GSH in the pathogenesis of COPD.

Polymorphism in the 5′-Flanking Region of Human Glutamate-Cysteine Ligase Modifier Subunit Gene Is Associated With Myocardial Infarction

“…7,8 GCL is the rate-limiting enzyme in de novo GSH synthesis, whereas GSH synthetase apparently has no regulatory role. The GCLM gene has several putative oxidative stress-responsive elements in the promoter/enhancer region.…”

“…7 GSH is synthesized within most mammalian cells by the action of human glutamate-cysteine ligase (GCL) and GSH synthetase. 7,8 GCL catalyzes the ratelimiting step in de novo GSH synthesis. 7,8 GCL is a heterodimer composed of catalytic and modifier (GCLM) subunits.…”

“…7,8 GCL catalyzes the ratelimiting step in de novo GSH synthesis. 7,8 GCL is a heterodimer composed of catalytic and modifier (GCLM) subunits. 7,8 GSH production is paralleled with the induction of GCL gene expression, which is regulated primarily at the level of transcription.…”

“…7,8 GCL is a heterodimer composed of catalytic and modifier (GCLM) subunits. 7,8 GSH production is paralleled with the induction of GCL gene expression, which is regulated primarily at the level of transcription. 5,8 -11 Both genes have putative oxidative stress-responsive elements in their promoter/enhancer regions.…”

Antioxidant effect of diphenyl diselenide on oxidative stress caused by acute physical exercise in skeletal muscle and lungs of mice

“…NPSH play a role in protecting cells from oxidative stress by detoxifying exogenous and endogenous toxicants, and quenching ROS. 26 NPSH levels were determined by the method described by Ellman. 27 To determine NPSH, S 1 was mixed (1:1) with 10% trichloroacetic acid.…”