Role of hydroxyl radicals derived from granulocytes in lung injury induced by phorbol myristate acetate.
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.
Kuroda
M
M
1st Department of Anatomy, Toho University School of Medicine, Tokyo, Japan.
Murakami
K
K
Ishikawa
Y
Y
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis / Q000166:cytology / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D005609:Free Radicals; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006651:Histocytochemistry; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism*; D017665:Hydroxyl Radical; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D005609:Free Radicals; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D013890:Thiourea; D013755:Tetradecanoylphorbol Acetate