NEUTROPHIL ELASTASE INHIBITION AMELIORATES ENDOTOXIN-INDUCED MYOCARDIAL INJURY ACCOMPANYING DEGRADATION OF CARDIAC CAPILLARY GLYCOCALYX
NEUTROPHIL ELASTASE INHIBITION AMELIORATES ENDOTOXIN-INDUCED MYOCARDIAL INJURY ACCOMPANYING DEGRADATION OF CARDIAC CAPILLARY GLYCOCALYX
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DOI：
10.1097/shk.0000000000001482
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发表时间：
2020-09-01
期刊：
影响因子：
3.1
通讯作者：
Ogura, Shinji
中科院分区：
文献类型：
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作者：
Fukuta, Tetsuya;Okada, Hideshi;Ogura, Shinji
脓毒症的心肌损伤可能是由几种炎症介质的爆发引起的，导致血管内皮损伤。然而，中性粒细胞弹性蛋白酶（NE）在脓毒症心肌损伤中的作用尚不清楚。我们的目的是评估内毒素血症引起的心肌损伤是否与NE相关。将脂多糖（LPS）以20 mg/kg的剂量腹腔注射中性粒细胞少的粒细胞集落刺激因子敲除小鼠（G-CSF-KO）和同窝对照小鼠。注射LPS后，G-CSF-KO小鼠的存活率显著高于对照组小鼠。G-CSF-KO小鼠血清肌钙蛋白I水平明显低于对照组。此外，LPS给药后6和12 h，炎性细胞因子白细胞介素-6 （IL-6）浓度较对照组显著降低。超微结构分析显示，G-CSF-KO小鼠血管内皮结构和内皮糖萼保存完好。接下来，小鼠在LPS给药后注射0.2 mg/kg的西维司他（NE抑制剂）。注射西司他的小鼠存活率明显高于对照组，血清肌钙蛋白I水平也明显低于对照组。此外，与对照组相比，LPS给药后6和12小时，IL-6水平显著降低。西维司他处理小鼠血管内皮结构和内皮糖萼在超微结构水平上被清晰保存。综上所述，NE与内毒素血症心肌损伤显著相关。抑制NE可能是内毒素血症治疗的有用工具。
Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.