Regulation of redox glutathione levels and gene transcription in lung inflammation: Therapeutic approaches

Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH), is a vital intra- a nd extracellular protective antioxidant. Glutathione is synthesized from it s constituent amino acids by the sequential action of gamma-glutamylcystein e synthetase (gamma-GCS) and GSH synthetase. The rate-limiting enzyme in GS H synthesis is gamma-GCS, Gamma-GCS expression is modulated by oxidants, ph enolic antioxidants, and inflammatory and anti-inflammatory agents in vario us mammalian cells. The intracellular GSH redox homeostasis is strictly reg ulated to govern cell. metabolism and protect cells against oxidative stres s. Growing evidence has suggested that cellular oxidative processes have a fundamental role in inflammation through the activation of stress kinases ( JNK, MAPK, p38) acid redox-sensitive transcription factors such as NF-kappa B and AP-1, which differentially regulate the genes for proinflammatory me diators and protective antioxidant gents such as gamma-GCS, Mn-SOD, and hem e oxygenase-1. The critical balance between the induction of proinflammator y mediators and antioxidant genes and the regulation of the levels of GSH i n response to oxidative stress at the site of inflammation is not known. Kn owledge of the mechanisms of redox GSH regulation and gene transcription in inflammation could lead to the development of novel therapies based on the pharmacological manipulation of the production of this important antioxida nt in inflammation and injury. This FORUM article features the role of GSH levels in the regulation of transcription factors, whose activation and DNA binding leads to proinflammatory and antioxidant gene transcription. The p otential role of thiol antioxidants as a therapeutic approach in inflammato ry lung diseases is also discussed. (C) 2000 Elsevier Science Inc.