Cellular glutathione turnover in vitro, with emphasis on type II pneumocytes

The most important extracellular antioxidant in the lung is glutathione (GSH). The epithelial lining fluid of normal lungs contains very high concentrations of this tripeptide, about 100 times higher than that found in the extracellular fluid of many other tissues. How these high extracellular GSH levels are established and the mechanisms for increases (e.g. smokers) or decreases (e.g. lung fibrosis) are still unknown, but more insight into the regulation of GSH turnover in type II pneumocytes has recently become available. The purpose of this review is to give an overview of the literature concerning cellular GSH turnover for different cell types in vitro, with an emphasis on alveolar type II epithelial cells. The main messages of this review are that: 1) GSH is, in fact, an important vehicle for stabilizing, detoxifying and transferring cysteine; 2) cysteine is the rate-limiting substrate for GSH synthesis, especially under conditions of oxidative stress; 3) various transport systems exist for the uptake of the constituents of GSH, of which gamma-glutamyltransferase appears to be important; 4) intracellular GSH levels of the type II cells are governed by different factors, including, probably, the extracellular redox state; and 5) a more reduced extracellular redox state appears to favour GSH efflux, whilst an oxidized state leads to retention of GSH inside the cell. These concepts should lead to reconsideration of some of the conventional approaches to increasing intracellular glutathione levels.