The inhalation of inorganic dusts and fibers is associated with chronic inflammatory processes in the lower respiratory tract dominated by alveolar macrophages, which release, inter alia, increased amounts of inflammatory products and cytokines. The effect of these various mediators on other cells may be important in asbestos-related epithelial cell injury. To defend against such injury the lung airways and parenchyma contain a number of antioxidant species for their protection, of which the dominant one is glutathione. This compound can be regarded as a paradigm for the antioxidant protection system of the lung, and a decrease in its level as a result of any toxic action would leave the lung vulnerable to damage. Intracellular glutathione tends to be located in Clara cells, type II pneumocytes, and alveolar macrophages and can be secreted under stress or lost by cell damage.-Glutamyl transpeptidase (-GT) is found in the Clara and type II pneumocytes of the rat lung, but almost none is found in macrophages. The hypothesis that glutathione will be mobilized by these cell types under a toxic insult has been tested in a study of the effect of inhaled UICC crocidolite asbestos on glutathione concentration and-GT activity in type II cells, macrophages, and bronchoalveolar lavage (thought to represent the epithelial lining fluid). Calcined anhydrous gypsum was used as a putative control. It was expected that inhaled crocidolite would alter glutathione concentrations in the lungs more than fibrous gypsum, in some degree proportional to the relative toxicity of the fibers. In fact the greatest change occurred with milled and fibrous gypsum, which both produced a two- to threefold increase in glutathione levels in cell-free bronchoalveolar lavage (cBAL), compared to air control animals.-GT activity was altered by exposure to crocidolite and, to a lesser extent, fibrous gypsum in both type II cells and macrophages. In type II cells for both fibers no significant change was observed at the end of the exposure period, although levels had nearly doubled with the milled calcium sulfate, suggesting an effect due to increased calcium levels. We conclude that there is a cellular response to the presence of fibers or particles characterized by an increase in-GT levels. The reason for this is to encourage increased uptake of glutathione (GSH), which, in part, is consumed, purging the lungs of the insult.