EFFECT OF INHALATION OF LOW DOSES OF CROCIDOLITE AND FIBROUS GYPSUM ON THE GLUTATHIONE CONCENTRATION AND-GLUTAMYL TRANSPEPTIDASE ACTIVITY IN MACROPHAGES AND BRONCHOALVEOLAR LAVAGE FLUID

Abstract

Inhalation of asbestos can result in pulmonary fibrosis and in some cases the development of tumors, often many years after exposure. There is, however, an acute response by the lung, particularly the lower respiratory tract, which is part of the defensive mechanism for clearing the fibers. This is a process dominated by alveolar macrophages, which phagocytose the shorter fibers and release inflammatory products in attempting to deal with the longer ones. The result of this can be the production of active oxygen species that may lead to oxidative damage. To defend against such injury, the lung airways and parenchyma contain a number of antioxidants for their protection, of which the dominant one is glutathione (GSH). An alteration in levels of GSH as a result of toxic action could leave the lung vulnerable to damage. GSH is present at high concentration in Clara cells, type II pneumocytes, and alveolar macrophages, and there is also a high extracellular concentration of the compound. (-Glutamyl transpeptidase (-GT), the enzyme responsible for the breakdown of GSH prior to uptake, is found in the membranes of Clara and type II cells of the rat lung, although only negligible amounts are found in macrophages. This study investigated the effect of inhaled crocidolite asbestos on GSH concentration (in the form of nonprotein sulfydryl, NPSH) and-GT activity in macrophages and bronchoalveolar lavage (thought to represent the extracellular milieu). Calcined anhydrous gypsum was used as a putative control. We have previously studied similar endpoints using high exposure levels. This study, however, used dose levels closer to that seen in heavily industrially exposed individuals. We found that NPSH levels were significantly increased in both macrophages and acellular bronchoalveolar lavage fluid after 4 wk of exposure to crocidolite. The levels were still high after a 4-wk recovery period.-GT only altered significantly in lavage, but this occurred after exposure to both calcium sulfate and crocidolite. This response is contrary to that obtained in the previous investigation using high exposure levels. Both studies test the hypothesis that GSH would be mobilized by these cell types under a toxic insult. We conclude that exposure to lower levels of crocidolite causes a significant increase in intra- and extracellular NPSH. It is not possible to say from the present data whether the increase in extracellular NPSH has arisen from epithelial cell secretion or was caused by macrophage phagocytosis. However, the presence of such high amounts of antioxidant in the airways may prove to be pertinent to the mechanism of fiber toxicity.