Oxidative stress and regulation of glutathione in lung inflammation

Abstract

Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

Effects of hexamethylene diisocyanate exposure on human airway epithelial cells: in vitro cellular and molecular studies.

“…Increases in thioredoxin reductase may thus not only signal HDI-induced thiolredox imbalance but also provide an "antigenreceptor-independent" mechanism by which epithelial cell responses to exposure may promote immunologic sensitization to HDI via either a) epithelial cell-derived cytokines/ chemokines under redox-dependent transcriptional regulation (13,14) or b) immunologically active thioredoxin (21)(22)(23)(24)(25). Interestingly, thioredoxin reductase contains selenium, which is thought to be crucial to its role as a cellular sensor of redox potential and which, based on its biochemical properties, should be highly susceptible to nucleophilic addition reactions with diisocyanates (10,28,31).…”

“…It remains unclear whether TDIinduced changes in glutathione levels are a direct effect of exposure or secondary to protective mechanisms such as oxidant injuryinduced protein glutathionylation (12). However, these data clearly demonstrate the potential for diisocyanates to alter airway epithelial cell thiol-redox homeostasis, an important modulator of numerous genes under the control of redox-sensitive transcription factors such as NFκB, Ref-1, and AP-1 (13,14).…”

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

“…Increasing GSH synthesis rates is an important adaptive response to oxidative stress throughout the body [46][47][48][49]. Synthesis of GSH can be increased by raising levels of glutamate cysteine ligase (GCL) [48][49][50], the rate-limiting enzyme in GSH synthesis.…”

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

“…The eosinophils and other leukocytes undergo respiratory burst activation with release of reactive oxygen species (ROS), including superoxide and its dismutation product, hydrogen peroxide (H 2 O 2 ) (2). Increased airway levels of ROS (3,4), coupled with decreased levels of antioxidants such as glutathione (5), may lead to an oxidant͞ antioxidant imbalance in the lungs of patients with asthma and activation of redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor B (NF-B). These transcription factors, in collaboration with Th2-specific transcription factors (i.e., c-maf, GATA-3, Stat6), control expression of Th2 cytokines (e.g., IL-4, IL-5, IL-13), the molecular hallmarks of asthma (6).…”