Regulation of glutathione in inflammation and chronic lung diseases

Mutat Res. 2005 Nov 11;579(1-2):58-80. doi: 10.1016/j.mrfmmm.2005.02.025. Epub 2005 Jul 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Chronic Disease
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Genetic Predisposition to Disease
  • Glutamate-Cysteine Ligase / drug effects
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism*
  • Glutathione / metabolism*
  • Glutathione / pharmacology
  • Growth Substances / metabolism
  • Growth Substances / pharmacology
  • Humans
  • Lung Diseases / genetics
  • Lung Diseases / metabolism*
  • Lung Diseases / pathology
  • Oxidants / metabolism
  • Phenols / pharmacology
  • Pneumonia / genetics
  • Pneumonia / metabolism
  • Smoking / adverse effects


  • Antioxidants
  • Growth Substances
  • Oxidants
  • Phenols
  • Glutamate-Cysteine Ligase
  • Glutathione