Lung injury induced by
phorbol myristate acetate (PMA) is closely associated with toxic
oxidants released from activated granulocytes. But the major toxic
oxidant causing lung damage is not really known. We have, therefore, conducted investigations using various
oxygen radical scavengers. The
intravenous administration of
dimethylthiourea (
DMTU), a potent
hydroxyl radical scavenger, or of
superoxide dismutase (SOD), a
superoxide anion scavenger, plus
catalase, a hydrogen peroxide scavenger, to rabbits intravenously injected with PMA prevented biochemical data and cellularity indicative of lung damage in lung lavages. Morphologically, the lungs of PMA-injected rabbits revealed mild interstitial
edema, aggregates of granulocytes within the interstitial capillaries, and the increase of granulocytes in alveolar spaces. Furthermore, there was direct morphologic evidence of pulmonary endothelial cell disruption. In rabbits treated with
DMTU or SOD plus
catalase, there was no evidence of destructive changes in the lungs. SOD-treated rabbits did not show evidence of protection from PMA-induced
lung injury. Only a little protection was provided by
catalase treatment. Moreover, in the ultracytochemical study for examination of
hydrogen peroxide (H2O2) generation, the number of H2O2-generated granulocytes remarkably decreased in lung lavages of
catalase-treated rabbits, but destructive changes were observed in the lungs. In contrast, though the number of H2O2-generated granulocyte was not decreased in lung lavages of
DMTU-treated rabbits, treatment with
DMTU could afford protection from
lung injury. These data indicate that the
hydroxyl radical, a toxic
oxidant derived from stimulated granulocytes, is deeply involved in the pathogenesis of PMA-induced
lung injury.