The oxidant-antioxidant balance in the airspaces of the lungs may be critical in protecting the lungs from the effects of cigarette smoke. We studied the effect of cigarette smoke and its condensates on the detachment, attachment, and proliferation of the A549 human alveolar epithelial cell line, in an in vitro model of cell injury and regeneration and the protective effects of antioxidants. Whole and vapor phase cigarette smoke decreased 51Cr-labeled A549 cell attachment, increased cell detachment, and decreased cell proliferation, as assessed by [3H]thymidine uptake. Freshly isolated rat type II alveolar epithelial cells showed an enhanced susceptibility to smoke-induced cell lysis when compared with the A549 cell line. Reduced glutathione (GSH) (400 microM) protected against the effects of cigarette smoke exposure on cell attachment, proliferation, and detachment. Depletion of intracellular GSH with buthionine sulfoxamine enhanced the epithelial cell detachment injury produced by smoke condensates. We conclude that cigarette smoke and its condensates cause an oxidant-induced injury to A549 human type II alveolar epithelial cells. Both intra- and extracellular GSH have important roles in protecting epithelial cells from the injurious effects of cigarette smoke.