1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. 2Emergency Medical Services, Seattle and King County Public Health, Seattle, WA.
Crit Care Med. 2015 Jul;43(7):1361-7. doi: 10.1097/CCM.0000000000000971.
Since blood selenium levels decrease after ischemia and reperfusion injury, and low blood selenium correlates with negative outcome, we designed and performed experiments to determine how selenium distribution is affected by ischemia reperfusion injury. Furthermore, we tested whether different chemical forms of selenium would affect outcome after ischemia and reperfusion injury. We also examined the metabolic effects of selenide administration.
Laboratory investigation.
Animal research laboratory.
Adult male C57BL/6 mice.
To determine selenium localization, we administered tracer doses of radioactive selenium 75 in the form of selenite or selenide and measured blood and tissue selenium levels after ischemia and reperfusion injury. Anesthetized mice were subjected to myocardial ischemia reperfusion injury (coronary artery occlusion for 60 min followed by 5 min of reperfusion after occlusion was removed) or hindlimb ischemia reperfusion injury (left leg tourniquet for 90 min followed by 5 min reperfusion after tourniquet removal). To determine whether exogenous selenium administration could reduce ischemia reperfusion injury, we synthesized and administered sodium hydroselenide and sodium selenite solutions (0.05-2.4 mg/kg). Solutions were administered at the end of coronary artery occlusion but before reperfusion. In order to determine the metabolic effects of selenide administration, we exposed mice to hydrogen selenide gas (0-5 ppm) mixed into air (20.95% oxygen) for up to 3 hours.
In targeting assays, we measured blood and tissue selenium levels. We observed that blood selenium decreases after myocardial ischemia reperfusion and displays an inverse correlation with injury severity; selenium accumulation in heart correlates directly with injury severity. We also measured whether oxidized selenium, selenite, and reduced selenium, selenide, would target to injured heart tissue in myocardial ischemia reperfusion and injured leg muscle in a hindlimb model of ischemia reperfusion. Only selenide targets to injured tissue. We also measured damage after myocardial ischemia reperfusion injury using morphometry, neutrophil accumulation, blood cardiac troponin levels, and echocardiography and observed in all assays that selenide reduced damage to the heart; selenite was not effective. And finally, to assay metabolism, we measured oxygen consumption, carbon dioxide production, and body core temperature before, during, and after hydrogen selenide administration. All measurements indicate that selenide decreases metabolism.
Selenide targets to reperfusing tissue and reduces reperfusion injury perhaps by affecting oxygen metabolism.
由于血液中的硒水平在缺血再灌注损伤后会降低，而低血硒与不良预后相关，因此我们设计并进行了实验，以确定硒的分布如何受到缺血再灌注损伤的影响。此外，我们还测试了不同化学形式的硒是否会影响缺血再灌注损伤后的结果。我们还研究了亚硒化物给药的代谢作用。
实验室研究。
动物研究实验室。
成年雄性 C57BL/6 小鼠。
为了确定硒的定位，我们以亚硒酸盐或硒化物的形式给予放射性硒 75 的示踪剂量，并在缺血再灌注损伤后测量血液和组织中的硒水平。麻醉后的小鼠经历心肌缺血再灌注损伤（冠状动脉闭塞 60 分钟，然后闭塞解除后再灌注 5 分钟）或后肢缺血再灌注损伤（左小腿止血带 90 分钟，然后止血带解除后再灌注 5 分钟）。为了确定外源性硒的给药是否可以减少缺血再灌注损伤，我们合成并给予了亚硒酸钠和亚硒酸钠溶液（0.05-2.4mg/kg）。溶液在冠状动脉闭塞结束时给予，但在再灌注之前。为了确定亚硒化物给药的代谢作用，我们将小鼠暴露于氢气硒气体（0-5ppm）混合到空气中（20.95%氧气）长达 3 小时。
在靶向测定中，我们测量了血液和组织中的硒水平。我们观察到，血液中的硒在心肌缺血再灌注后减少，并与损伤严重程度呈负相关；心脏中的硒积累与损伤严重程度直接相关。我们还测量了在心肌缺血再灌注和后肢缺血再灌注模型中，氧化硒、亚硒酸盐和还原硒、硒化物是否会靶向损伤的心肌组织和损伤的腿部肌肉。只有硒化物靶向损伤组织。我们还使用形态计量学、中性粒细胞积累、血液心肌肌钙蛋白水平和超声心动图测量心肌缺血再灌注损伤后的损伤，并在所有检测中观察到，亚硒化物减少了心脏损伤；亚硒酸钠无效。最后，为了检测代谢，我们在给予亚硒化物之前、期间和之后测量了耗氧量、二氧化碳产生量和体核温度。所有测量结果表明，亚硒化物降低了新陈代谢。
硒化物靶向再灌注组织，并通过影响氧代谢来减少再灌注损伤。
