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.