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

中性粒细胞、巨噬细胞和中性粒细胞弹性蛋白酶在急性肺损伤发生过程中的作用

• 批准号: 04670463
• 负责人: KUBO Keishi
• 金额: $ 1.79万
• 依托单位: SHINSHU UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670463/
• 关键词: Endotoxin; Air embolism; Acute lung injury; Sheep; Neutrophil; Elastase; Elastase inhibitor; エンドトキシン肺損傷; 好中球エラスターゼ阻害剤; 綿羊; エンドトキシン血症; 好中球; 特異的好中球エラスターゼ阻害剤

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.

在本项目中，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蛋白酶抑制剂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。E.coliETX，1ug/kg，给清醒绵羊输注30min以上，可引起一过性肺动脉高压、中性粒细胞减少和晚期肺通透性增加。组织学上，早期的中性粒细胞减少与中性粒细胞在肺部的聚集有关。ETX输注前1h持续输注ONO-5046 10 mg/kg/h可显著阻断上述功能障碍。持续输注ONO-5046，1 mg/kg/h，以剂量依赖的方式减轻上述功能障碍。ETX开始输注1h后，持续输注ONO-5046 10 mg/kg/h可减轻上述功能障碍。最后一项研究是观察ONO-5046对微气栓塞性急性肺损伤清醒绵羊肺功能障碍的影响。将1.25ml/h的微量空气通过插入肺动脉主干的弹性管(直径0.3 mm)注入2 h以上，可引起肺动脉高压和肺通透性增加。未发生中性粒细胞减少症。持续输注ONO-5046 10 mg/kg/h不能减轻空气栓塞所致的上述功能障碍。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致绵羊肺损伤中起重要作用，但与空气栓塞致肺损伤无关。

项目成果

Yanagidaira Y et al.: "The effects of prolonged exposure to cold on hypoxic pulmonary hypertension in rats." J.Wilderness Med. (in press).

Yanagidaira Y 等人：“长期暴露于寒冷对大鼠缺氧性肺动脉高压的影响。”

Kobayashi T et al: "The pulmonary circulation and acute lung injury Inhibitors of arachidonic acid metzbolism:In fluence on lung injury" Furuta Publishing Co.ed.by said SI, 521-542 (1991)

Kobayashi T 等人：“肺循环和急性肺损伤花生四烯酸代谢抑制剂：对肺损伤的影响”Furuta Publishing Co.ed.by 说 SI，521-542 (1991)

Matsuzawa, M.et al: "Cerebral edema in acute mountain sickness. In High-altitude Medicine eds by Ueda, G., Reeves, J.T., Sekiguchi, M." Shinshu Univ.Press. 300-304 (1992)

Matsuzawa, M.等人：“急性高山病中的脑水肿。高海拔医学编辑，作者：Ueda, G.、Reeves, J.T.、Sekiguchi, M.”

Nakagawa S et al: "High-altitude pulmonary edema with pulmonary thrombo enbolism" Chest. 103. 948-950 (1993)

Nakakawa S 等人：“高原肺水肿伴肺血栓栓塞”胸部。

Kub K et al: "Effects of ONO-5046,a specific neutrophil elartase inhibitor,on endotoxin-induced lung injury in sheep" J Appl Physiol. (発表予定).

Kub K 等人：“ONO-5046（一种特异性中性粒细胞弹性酶抑制剂）对绵羊内毒素诱导的肺损伤的影响”J Appl Physiol。