A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats.
A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats.
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DOI：
10.3892/ijmm.19.2.237
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发表时间：
2007-02
影响因子：
5.4
通讯作者：
Y. Toda;Toru Takahashi;K. Maeshima;H. Shimizu;Kazuyoshi Inoue;H. Morimatsu;E. Omori;M. Takeuchi;R. Akagi;K. Morita
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文献类型：
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作者：
Y. Toda;Toru Takahashi;K. Maeshima;H. Shimizu;Kazuyoshi Inoue;H. Morimatsu;E. Omori;M. Takeuchi;R. Akagi;K. Morita
失血性休克后复苏（HSR）导致中性粒细胞在肺中隔离，从而导致急性肺损伤（ALI）。神经弹性蛋白酶（NE）被认为在ALI的发病机制中起关键作用。本研究探讨了NE特异性抑制剂西维来司对HSR诱导的大鼠ALI的保护作用。通过抽取血液使雄性Sprague-Dawley大鼠失血性休克，以维持平均动脉血压30+/-5mmHg 60分钟，然后用流出的血液复苏。HSR处理的动物在复苏开始时静脉内推注西维来司他（10 mg/kg），然后在复苏阶段连续输注60 min（10 mg/kg/h）或溶剂。通过肺组织学、肺湿重/干重（W/D）比、髓过氧化物酶（MPO）活性、肿瘤坏死因子（TNF）-α和诱导型一氧化氮合酶（iNOS）基因表达、核因子（NF）-kappaB的DNA结合活性和细胞间粘附分子（ICAM）-1的免疫组织化学分析来评估肺损伤。HSR处理诱导肺损伤，表现为肺水肿伴中性粒细胞浸润，肺W/D比、MPO活性、TNF-α和iNOS的基因表达、NF-κ B的DNA结合活性增加，以及ICAM-1的表达增加。相反，西维来司治疗显著改善了HSR诱导的肺损伤，如通过所有这些指标的显著改善所判断的。这些结果表明，除了对NE的直接抑制作用之外，西维来司他至少部分地通过抑制炎症信号通路来减轻HSR诱导的肺损伤。
Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30+/-5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-kappaB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-alpha and iNOS, and DNA-binding activity of NF-kappaB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.