Authors: Yuichiro Toda, Toru Takahashi, Kyoichiro Maeshima, Hiroko Shimizu, Kazuyoshi Inoue, Hiroshi Morimatsu, Emiko Omori, Mamoru Takeuchi, Reiko Akagi, Kiyoshi Morita

作者: 户田雄一郎, 高桥徹, 前嶋京一郎, 清水裕子, 井上和义, 森松浩志, 大森绘美子, 竹内守, 赤木玲子, 森田纪
Journal: International Journal of Molecular Medicine

期刊: 《国际分子医学杂志》
Publication Date: February 2007, Volume 19, Issue 2, Pages 237-243

出版日期: 2007年2月, 第19卷第2期, 237-243页

Abstract: This study evaluates the effects of sivelestat, a neutrophil elastase (NE) inhibitor, on acute lung injury (ALI) caused by hemorrhagic shock and resuscitation (HSR) in rats. The results show that sivelestat significantly mitigates lung injury by reducing pulmonary edema, neutrophil infiltration, and various markers of inflammation and oxidative stress.

摘要: 本研究评估了中性粒细胞弹性蛋白酶(NE)抑制剂Sivelestat对失血性休克复苏(HSR)导致的大鼠急性肺损伤(ALI)的影响。结果表明，Sivelestat显著减轻了肺损伤，降低了肺水肿、中性粒细胞浸润和多种炎症及氧化应激标志物。

Background: Hemorrhagic shock followed by resuscitation (HSR) is a critical condition that can lead to acute lung injury (ALI). Neutrophil elastase (NE) is a key enzyme involved in the inflammatory response and tissue damage seen in ALI. Sivelestat is a specific inhibitor of NE and has been proposed as a therapeutic agent to mitigate lung injury.

背景: 失血性休克复苏(HSR)是一种可能导致急性肺损伤(ALI)的危急情况。中性粒细胞弹性蛋白酶(NE)是参与ALI中炎症反应和组织损伤的关键酶。Sivelestat是一种特异性NE抑制剂，被提议作为缓解肺损伤的治疗剂。

Methods:
- Subjects: Male Sprague-Dawley rats.
- Procedure: Rats were subjected to hemorrhagic shock by maintaining a mean arterial blood pressure of 30±5 mm Hg for 60 minutes, followed by resuscitation with the shed blood. During resuscitation, animals received a bolus injection of sivelestat (10 mg/kg) followed by continuous infusion (10 mg/kg/h) for 60 minutes.
- Assessment: Lung injury was evaluated through pulmonary histology, lung wet-to-dry weight ratio (W/D), myeloperoxidase (MPO) activity, gene expression of TNF-α and iNOS, NF-κB DNA binding activity, and ICAM-1 expression.

方法:
- 对象: 雄性Sprague-Dawley大鼠。
- 程序: 通过保持平均动脉压为30±5 mm Hg持续60分钟使大鼠经历失血性休克，随后用流失的血液进行复苏。在复苏期间，动物接受Sivelestat（10 mg/kg）的静脉注射，随后连续输注（10 mg/kg/h）60分钟。
- 评估: 通过肺组织学、肺湿重/干重比（W/D）、髓过氧化物酶（MPO）活性、TNF-α和iNOS的基因表达、NF-κB的DNA结合活性以及ICAM-1表达评估肺损伤。

Results:
- Lung Histology: HSR induced significant lung injury characterized by pulmonary edema and neutrophil infiltration.
- Inflammation Markers: There was an increase in lung W/D ratio, MPO activity, TNF-α and iNOS expression, NF-κB activity, and ICAM-1 expression in HSR-treated rats.
- Sivelestat Treatment: Sivelestat significantly ameliorated lung injury, reducing all measured indices of inflammation and tissue damage.

结果:
- 肺组织学: HSR引起显著的肺损伤，表现为肺水肿和中性粒细胞浸润。
- 炎症标志物: HSR处理的大鼠肺W/D比、MPO活性、TNF-α和iNOS表达、NF-κB活性和ICAM-1表达均增加。
- Sivelestat治疗: Sivelestat显著缓解了肺损伤，降低了所有测量的炎症和组织损伤指标。

Conclusion: The study concludes that sivelestat reduces HSR-induced lung injury by inhibiting the inflammatory signaling pathway and directly inhibiting NE activity. This suggests potential clinical applications for sivelestat in treating ALI caused by similar mechanisms.

结论: 研究得出结论，Sivelestat通过抑制炎症信号通路和直接抑制NE活性来减轻HSR引起的肺损伤。这表明Sivelestat在治疗由类似机制引起的ALI方面具有潜在的临床应用价值。