THE ROLE OF NEUTROPHIL, MACROPHAGE AND NEUTROPHIL ELASTASE IN THE DEVELOPMENT OF ACUTE LUNG INJURY

在这个项目中进行了四项研究。第一项研究是观察特异性中性粒细胞弹性酶抑制剂ONO-5046对内毒素（ETX）诱导的绵羊急性肺损伤肺功能障碍的影响。在清醒的绵羊体内注射大肠杆菌ETX超过30分钟，可导致短暂性肺动脉高压、中性粒细胞减少和后期肺通透性增加。组织学上，早期中性粒细胞减少与肺中中性粒细胞的积累有关。在ETX输注前1小时，持续输注ONO-5046, 10mg/kg/h，可显著阻断上述功能障碍。二是ONO-5046以1 mg/kg/h持续输注，呈剂量依赖性地减弱上述功能障碍。第三，在ETX开始注射后1h，继续注射ONO-5046，剂量为10mg/kg/h，可减弱这些功能障碍。最后观察ONO-5046对醒羊微空气栓塞急性肺损伤肺功能障碍的影响。通过插入肺动脉主干的弹性管（径0.3 mm）注入微量空气，1.25 ml/h，持续2h，导致肺动脉高压，肺通透性增加。未发生中性粒细胞减少。持续输注ONO-5046 （10mg/kg/h）不能减轻空气栓塞所致的这些功能障碍。这些研究表明，中性粒细胞和中性粒细胞弹性蛋白酶在内毒素诱导的绵羊肺损伤中起重要作用，但与空气栓塞诱导的肺损伤无关。

In this project four stuies were performed. First study was to see the effects of specific neutrophil elastase inhibitor, ONO-5046, on lung dysfunction in endotoxin (ETX)-induced acute lung injury in sheep. E.coli ETX, lug/kg, infusion over 30 min into awake sheep resulted in transient pulmonary hypertension, neutropenia and in increased pulmonary permeability during the late phase. Histologically the early neutropenia was associated with the accumulation of neutrophils in the lungs. Continuous infusion of ONO-5046, 10mg/kg/h, 1h before ETX infusion remarkably blocked these dysfunctions. Second, continous infusion of ONO-5046,1 mg/kg/h, attenuated these dysfunctions with dose dependent manner. Third, continuous infusion of ONO-5046, 10mg/kg/h, 1h after the start of ETX infusion attenuated these dysfunctions. Last study was to see the effects of ONO-5046 on lung dysfunction in microair-embolism-induced acute lung injury in awake sheep. Microair, 1.25 ml/h, over 2 h, was infused through elastic tube (ID 0.3 mm) inserted in the main trunk of the pul monary artery resulted in pumlmary hypertension during air infusion and in increased pulmonary permeability. Neutropenia did not occur. Continuous infusion of ONO-5046, 10mg/kg/h, did not attenuated these dysfunctions induced by air embolism. From these study neutrophil and neutrophil elastase plays an important role of endotoxin-induced lung injury in sheep, but does not relate to air-embolism-induced lung injury.