Hybertson, Brooks M., Roger P. Kitlowski, Eric K. Jepson, and John E. Repine. Supercritical fluid-aerosolized vitamin E pretreatment decreases leak in isolated oxidant-perfused rat lungs. J. Appl. Physiol. 84(1): 263-268, 1998.We hypothesized that direct pulmonary administration of supercritical fluid-aerosolized (SFA) vitamin E would decrease acute oxidative lung injury. We previously reported that rapid expansion of supercritical CO₂ formed respirable particles of vitamin E and that administering SFA vitamin E to rats increased lung vitamin E levels and decreased neutrophil-mediated lung leak. In the present investigation, we found that pretreatment with SFA vitamin E protected isolated rat lungs against the oxidant-induced lung leak caused by perfusion with xanthine oxidase (XO) and purine, an enzyme system that generates superoxide anion () and hydrogen peroxide. SFA vitamin E droplets were 0.7-3 µm in diameter, and inhalation of the airborne droplets for 30 min deposited ~55 µg of vitamin E in rat lungs. Isolated rat lungs perfused with XO (0.02 U/ml) and purine (10 mM) gained more weight (1.75 ± 0.12 g, n = 8), retained more Ficoll (11.5 ± 1.2 mg/left lung, n = 7), and accumulated more Ficoll in their lung lavages (700 ± 146 µg/ml, n = 8) than control lungs [0.25 ± 0.06 g (n = 10), 6.2 ± 1.2 mg/left lung (n = 9), and 141 ± 31 µg/ml (n = 8), respectively, P < 0.05]. In contrast, isolated lungs from rats that were pretreated with SFA vitamin E had decreased (P < 0.05) weight gains (0.32 ± 0.06 g, n = 7), Ficoll retentions (3.3 ± 1.1 mg/left lung, n = 7), and lung lavage Ficoll concentrations (91 ± 26 µg/ml, n = 6) after perfusion with XO and purine compared with isolated lungs from control rats perfused with XO and purine. This protective effect was not observed in rat lungs given sham treatments (CO₂ alone or vitamin E acetate aerosolized with supercritical CO₂). Our results suggest that direct pulmonary supplementation of vitamin E decreases susceptibility to vascular leakage caused by XO-derived oxidants.