Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lung tumor promoting process in mice

The induction of oxidative stress in pulmonary cells during the process of lung tumor promotion by dimethylarsinic acid (DMA), a main metabolite of inorganic arsenics in mammals, was examined by immunohistochemical analysis using a specific antibody against 4-hydroxy-2-nonenal (4HNE) adducts, which are major aldehydic metabolites of lipid peroxidation. We demonstrated that 4HNE-modified proteins existed specifically in the secretory granules in terminal bronchiolar Clara cells. Furthermore, the degree of positive staining increased with the duration of DMA administration. Transmission electron microscopy revealed morphological changes in the Clara cells of DMA-treated mice. These results suggest that Clara cells are the major target cell for DMA-induced oxidative stress and that the cells may play an important role in the lung tumor promotion process in mice.