PREVENTION OF PHORBOL-MYRISTATE ACETATE-INDUCED ACUTE LUNG INJURY BY ALPHA-TOCOPHEROL LIPOSOMES

Phorbol myristate acetate (PMA) is commonly used to produce experiment al edema and other tissue injuries in the lung. Lung injuries induced by the administration of PMA has been shown to be mediated mainly by n eutrophils. Neutrophils recruited to the lower respiratory tract may d amage lung tissues by releasing reactive oxygen species, neutral prote ases, and lysosomal enzymes. The present study was conducted to invest igate whether alpha-tocopherol, entrapped in dipalmitoylphosphatidylch oline liposomes and delivered directly to the lung, could counteract s ome of the PMA-induced lung injuries. Plain liposomes or alpha-tocophe rol containing liposomes (8 mg alpha-tocopherol/kg body weight.) were intratracheally instilled into the lungs of rats 24 hr prior to PMA ex posure (25 mu g/kg) and treated rats were killed 3 hr later. Lungs of control animals exposed to PMA developed an increase in lung weight an d lipid peroxidation as well as a decrease in lung angiotensin convert ing enzyme (ACE) and alkaline phosphatase (AKP) activities. PMA treatm ent also caused an increase in myeloperoxidase (MPO) activity in the l ung, suggestive of neutrophil infiltration. Pre-treatment of PMA-treat ed 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 p ulmonary 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 appea r to demonstrate that the intratracheal administration of a liposome-a ssodated lipophilic antioxidant, such as alpha-tocopherol, can signifi cantly ameliorate the toxic effects of reactive oxygen species, putati vely released from PMA-stimulated pulmonary target cells and infiltrat ing neutrophils.