Prevention of phorbol myristate acetate-induced acute lung injury by alpha-tocopherol liposomes

Phorbol-myristate acetate (PMA) is commonly used to produce experimental edema and other tissue injuries in the lung. Lung injuries induced by the administration of PMA has been shown to be mediated mainly by neutrophils. Neutrophils recruited to the lower respiratory tract may damage lung tissues by releasing reactive oxygen species, neutral proteases, and lysosomal enzymes. The present study was conducted to investigate whether alpha-tocopherol, entrapped in dipalmitoylphosphatidylcholine liposomes and delivered directly to the lung, could counteract some of the PMA-induced lung injuries. Plain liposomes or alpha-tocopherol containing liposomes (8 mg alpha-tocopherol/kg body weight) were intratracheally instilled into the lungs of rats 24 hr prior to PMA exposure (25 micrograms/kg) and treated rats were killed 3 hr later. Lungs of control animals exposed to PMA developed an increase in lung weight and lipid peroxidation as well as a decrease in lung angiotensin converting enzyme (ACE) and alkaline phosphatase (AKP) activities. PMA treatment also caused an increase in myeloperoxidase (MPO) activity in the lung, suggestive of neutrophil infiltration. Pretreatment of PMA-treated rats with plain liposomes had no effect on PMA-induced injuries. In contrast, pretreatment of rats with liposomal alpha-tocopherol, 24 hr prior to PMA administration, resulted in a significant elevation of pulmonary alpha-tocopherol concentration, accompanied by a concomitant reduction in MPO activity and reversal of PMA-induced changes in lung edema, lipid peroxidation, ACE and AKP activities. These results appear to demonstrate that the intratracheal administration of a liposome-associated lipophilic antioxidant, such as alpha-tocopherol, can significantly ameliorate the toxic effects of reactive oxygen species, putatively released from PMA-stimulated pulmonary target cells and infiltrating neutrophils.