Regulation of glutathione in inflammation and chronic lung diseases.
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 in oxidant-induced lung injury and inflammation.
Rahman
Irfan
I
Department of Environmental Medicine, Division of Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY 14642, USA. irfan_rahman@urmc.rochester.edu
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002908:Chronic Disease; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005721:Glutamate-Cysteine Ligase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
D000975:Antioxidants; D006133:Growth Substances; D016877:Oxidants; D010636:Phenols; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione