The Mitochondria-Targeted H2S-donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma.
The Mitochondria-Targeted H2S-donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma.
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DOI：
10.1097/shk.0000000000001210
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发表时间：
2019-08
期刊：
影响因子：
3.1
通讯作者：
M. Wepler;T. Merz;U. Wachter;J. Vogt;E. Calzia;A. Scheuerle;Peter Möller;M. Gröger;Sandra Kress;Marina Fink;Britta Lukaschewski;Grégoire Rumm;B. Stahl;M. Georgieff;M. Huber-Lang;R. Torregrossa;M. Whiteman;O. McCook;P. Radermacher;C. Hartmann
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文献类型：
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作者：
M. Wepler;T. Merz;U. Wachter;J. Vogt;E. Calzia;A. Scheuerle;Peter Möller;M. Gröger;Sandra Kress;Marina Fink;Britta Lukaschewski;Grégoire Rumm;B. Stahl;M. Georgieff;M. Huber-Lang;R. Torregrossa;M. Whiteman;O. McCook;P. Radermacher;C. Hartmann
失血性休克（HS）占创伤性死亡率的30-40%，这是由于低氧血症和组织缺血引发的全身性高炎症引起的多器官衰竭。缓释的线粒体靶向H2S供体AP39在多种I/ r损伤和急性炎症模型中发挥了有益作用。因此，我们在合并钝性胸外伤（TxT）和HS并随后复苏的小鼠模型中测试了ap39治疗的效果。方法在冲击波诱导TxT或假手术后，麻醉和器械化小鼠进行1小时出血，然后进行4小时复苏，包括静脉注射100或10nmol kg AP39或对照物，再输出血血，液体复苏和去甲肾上腺素。评估肺力学和气体交换、血流动力学、代谢和酸碱状态。分析血液和组织样本的细胞因子和趋化因子水平、免疫印迹、免疫组织化学、线粒体耗氧量（JO2）和组织学变化。结果大剂量AP39可减轻全身炎症反应，降低肺组织诱导型一氧化氮合酶（iNOS）表达和i - κ b α表达。在联合创伤组（TxT + HS）中，高剂量AP39治疗的动物平均动脉压（MAP）最低，因此去甲肾上腺素需求量最高，死亡率更高。低剂量AP39对血流动力学没有影响，导致去甲肾上腺素需求量和死亡率不变。结论AP39是一种全身抗炎药。在我们的创伤伴HS模型中，由于其强大的血管扩张特性，可能存在狭窄的剂量和时间窗口，这可能导致或促成循环休克相关性低血压的加重。
Hemorrhagic shock (HS) accounts for 30-40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H2S donor AP39 exerted beneficial effects in several models of I/R-injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation. METHODS After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 hour of hemorrhage followed by 4 hours of resuscitation comprising an i.v. bolus injection of 100 or 10nmol kg AP39 or vehicle, re-transfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO2) and histological changes. RESULTS High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure (MAP) and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates. CONCLUSION AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.