期刊
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
卷 579, 期 1-2, 页码 58-80出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2005.02.025
关键词
glutathione; oxidants; AP-1; ARE; Nrf-2; glutamylcysteine ligase; lungs
资金
- NIEHS NIH HHS [ES01247] Funding Source: Medline
Oxidant/antioxidant imbalance, a major cause of cell damage, is the hallmark for lung inflammation. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and extra-cellular protective antioxidant against oxidative stress, which plays a key role in the control of signaling and pro-inflammatory processes in the lungs. The rate-limiting enzyme in GSH synthesis is glutamylcysteine ligase (GCL). GSH is essential for development as GCL knock-out mouse died from apoptotic cell death. The promoter (5'-flanking) region of human GCL is regulated by activator protein-1 (AP-1) and antioxidant response element (ARE), and are modulated by oxidants, phenolic antioxidants, growth factors, inflammatory and anti-inflammatory agents in various cells. Recent evidences have indicated that Nrf2 protein, which binds to the erythroid transcription factor (NF-E2) binding sites, and its interaction with other oncoproteins Such as c-Jun, Jun D, Fra1 and Maf play a key role in the regulation of GCL. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many chronic inflammatory lung diseases. Knowledge of the mechanisms of GSH regulation could lead to the pharmacological manipulation of the production and/or gene transfer of this important antioxidant in lung inflammation and injury. This article describes the role of AP-1 and ARE in the regulation of cellular GSH biosynthesis and assesses the potential protective and therapeutic role of glutathione ill oxidant-induced lung injury and inflammation. (c) 2005 Elsevier B.V All rights reserved.
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