Hagio Tetsuya, Matsumoto Shigeru, Nakao Shintaro, Abiru Taira, Ohno Hiroyuki, Kawabata Kazuhito
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Eur J Pharmacol. 2004 Mar 19;488(1-3):173-80. doi: 10.1016/j.ejphar.2004.01.037.
This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.
本研究检测了水合西维来司他钠（西维来司他）对中性粒细胞弹性蛋白酶的特异性抑制作用是否能降低仓鼠吸入盐酸（HCl）后与严重急性肺损伤相关的死亡。单次经气管内滴注HCl（0.2 N，200 μL）的动物会因气管被炎性渗出物阻塞而随时间推移死亡。在一项时间进程研究中，这些动物出现了严重的肺损伤，在HCl滴注后12至24小时达到峰值，表现为出血以及支气管肺泡灌洗液蛋白质浓度大幅增加。这些变化与支气管肺泡灌洗液中的中性粒细胞弹性蛋白酶活性密切相关。在HCl滴注后的前48小时内静脉输注西维来司他（0.01、0.1和1 mg/kg/h），能剂量依赖性地降低HCl滴注仓鼠的死亡率。在另一项实验中，对HCl滴注后8小时的支气管肺泡灌洗液参数和动脉血氧分压（PaO₂）进行分析，结果显示静脉注射1 mg/kg/h的西维来司他能显著改善支气管肺泡灌洗液参数和PaO₂水平，同时有证据表明支气管肺泡灌洗液中的中性粒细胞弹性蛋白酶活性受到抑制。这些结果表明，中性粒细胞弹性蛋白酶在这种导致呼吸衰竭死亡的严重急性肺损伤类型中起重要作用。
