Cigarette smoking increases the alveolar epithelial permeability to small solutes, as assessed by the pulmonary clearance of aerosolized 99mTc-labeled diethylenetriaminepentaacetate. The involvement of lipid peroxidation in this increased clearance was tested in eight asymptomatic young smokers by investigating the effects of a 3-wk supplementation with oral vitamin E (1,000 IU/day) on pulmonary clearance according to a protocol designed as a single-blind crossover study. Indexes of acute tobacco intoxication (exhaled CO, carboxyhemoglobin, and urinary cotinine) and lung function parameters [including Krogh factor (KCO)] were also studied. Under control conditions, pulmonary clearance was abnormally increased (2.93 +/- 0.78%/min), whereas KCO was in the normal range. Pulmonary clearance correlated strongly with expired CO (P < 0.04), HbCO (P < 0.005), urinary cotinine (P < 0.003), and KCO (P < 0.004). Supplementation with vitamin E, a highly efficient antioxidant, neither decreased the pulmonary clearance nor altered the above correlations. However, the strong correlations observed between pulmonary clearance and indexes of acute tobacco intoxication, which reflect the amount of inhaled smoke and the resultant oxidant stress, do not allow exclusion of the involvement of lipid peroxidation in the pulmonary clearance increase observed in smokers.