Kuroda M, Murakami K, Ishikawa Y
1st Department of Anatomy, Toho University School of Medicine, Tokyo, Japan.
Am Rev Respir Dis. 1987 Dec;136(6):1435-44. doi: 10.1164/ajrccm/136.6.1435.
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.
佛波醇肉豆蔻酸酯乙酸酯（PMA）诱导的肺损伤与活化粒细胞释放的毒性氧化剂密切相关。但导致肺损伤的主要毒性氧化剂尚不清楚。因此，我们使用了各种氧自由基清除剂进行研究。向静脉注射PMA的家兔静脉内给予二甲基硫脲（DMTU，一种有效的羟自由基清除剂）、超氧化物歧化酶（SOD，一种超氧阴离子清除剂）加过氧化氢酶（一种过氧化氢清除剂），可防止肺灌洗中显示肺损伤的生化数据和细胞数量变化。形态学上，注射PMA的家兔肺显示轻度间质水肿、间质毛细血管内粒细胞聚集以及肺泡腔内粒细胞增多。此外，有肺内皮细胞破坏的直接形态学证据。在用DMTU或SOD加过氧化氢酶治疗的家兔中，没有肺内破坏性改变的证据。用SOD治疗的家兔未显示出对PMA诱导的肺损伤有保护作用。过氧化氢酶治疗仅提供了一点保护。此外，在用于检测过氧化氢（H2O2）生成的超微细胞化学研究中，过氧化氢酶治疗的家兔肺灌洗中产生H2O2的粒细胞数量显著减少，但肺内观察到了破坏性改变。相比之下，尽管DMTU治疗的家兔肺灌洗中产生H2O2的粒细胞数量没有减少，但用DMTU治疗可预防肺损伤。这些数据表明，来自受刺激粒细胞的毒性氧化剂羟自由基在PMA诱导的肺损伤发病机制中起重要作用。
