A novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysema in rats
A novel oral neutrophil elastase inhibitor (ONO-6818) inhibits human neutrophil elastase-induced emphysema in rats
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DOI：
10.1164/rccm.2103118
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发表时间：
2002-08-15
影响因子：
24.7
通讯作者：
Yoshida, M
中科院分区：
文献类型：
--
作者：
Kuraki, T;Ishibashi, M;Yoshida, M
我们研究了一种新型的口服中性粒细胞弹性蛋白酶抑制剂（ONO-6818）对人中性粒细胞弹性蛋白酶（HNE）诱导的急性肺损伤和肺气肿的影响。雄性Wistar大鼠随机分为4组：（1）对照组（生理盐水）;（2）HNE组（HNE 200 U + 0.5%羧甲基纤维素[ONO-6818溶液]）;（3）低剂量ONO-6818组（4）高剂量ONO-6818组（HNE 200 U + ONO-6818 100 mg/kg）。使用微型喷雾器通过气管施用盐水和HNE。ONO-6818在HNE应用前1小时口服给药。应用HNE后6小时，测定支气管肺泡灌洗液中中性粒细胞计数和血红蛋白浓度以及肺组织髓过氧化物酶活性。应用后8周，估计FRC、TLC、肺顺应性和平均线性截距。ONO-6818剂量依赖性地减弱HNE诱导的肺髓过氧化物酶活性、血红蛋白和支气管肺泡灌洗液中中性粒细胞计数的增加。此外，它还显著减弱了HNE诱导的FRC、TLC、肺顺应性和平均线性截距增加。ONO-6818通过最小化肺出血和肺中嗜中性粒细胞的积累来抑制HNE诱导的急性肺损伤。ONO-6818还抑制HNE诱导的肺气肿变化的发展，包括肺过度充气、弹性回缩的降解和空域扩大。
We investigated the effects of a novel oral neutrophil elastase inhibitor (ONO-6818) on acute lung injury and pulmonary emphysema induced by human neutrophil elastase (HNE). Young male Wistar rats were divided into four treatment groups: (1) control group (saline); (2) HNE group (HNE 200 U + 0.5% carboxymethyl-cellulose [solution for ONO-6818]); (3) low-dose ONO-6818 group (HNE 200 U + ONO-6818 10 mg/kg); and (4) high-dose ONO-6818 group (HNE 200 U + ONO-6818 100 mg/kg). Saline and HNE were applied via the trachea using a microsprayer. ONO-6818 was administered orally 1 hour before HNE application. Six hours after HNE application, neutrophil counts and hemoglobin concentration in bronchoalveolar lavage fluid and lung tissue myeloperoxidase activity were determined. Eight weeks after the application, FRC, TLC, lung compliance, and mean linear intercept were estimated. ONO-6818 attenuated dose-dependently HNE-induced increases in lung myeloperoxidase activity, hemoglobin, and neutrophil count in bronchoalveolar lavage fluid. Furthermore, it significantly attenuated HNE-induced increases in FRC, TLC, lung compliance, and mean linear intercept. ONO-6818 inhibited acute lung injury induced by HNE by minimizing lung hemorrhage and accumulation of neutrophils in the lung. ONO-6818 also inhibited the development of HNE-induced emphysematous changes including lung hyperinflation, degradation of elastic recoil, and airspace enlargement.