NO on End Organ Injury in Model of acute Hemolysis

本研究探讨了吸入一氧化氮（NO）在减轻犬血管内溶血引起的血管效应和器官损伤方面的治疗价值。溶血，红细胞的体内破坏，导致无细胞血红蛋白（无细胞血红蛋白或无基质血红蛋白）流入循环。当大量存在时，无细胞血红蛋白清除NO。NO是由血管内皮产生的内源性血管扩张剂。在溶血过程中，血管内皮细胞产生NO和血红蛋白清除NO之间的平衡部分决定了NO的生物利用度。无细胞血红蛋白快速清除NO破坏了这种平衡。这种NO稳态的破坏允许发生无抵抗的血管收缩，这可能导致终末器官损伤。我们已经开发了NO消耗方法，其最终表明血红蛋白水平升高在体内消耗NO。通过将这些方法应用于犬溶血模型，我们希望确定吸入NO的给药是否会减弱溶血的全身效应。本研究将验证我们的假设，即吸入NO将结合无细胞血红蛋白，从而减轻急性溶血过程中发生的终末器官损伤。如果这项研究证明NO治疗急性溶血有有益作用，那么它将作为未来人体临床试验的基础。 已完成产生溶血的模型开发。在主要研究之后，正在制定适当的镇静方案。

This study examines the therapeutic value of inhaled nitric oxide (NO) in attenuating the vascular effects and organ damage resulting from intravascular hemolysis in a canine model. Hemolysis, the in vivo destruction of red blood cells, causes a flux of cell-free hemoglobin (cell-free hemoglobin or stroma-free hemoglobin) into the circulation. Cell-free hemoglobin, when present in large quantities, scavenges NO. NO is an endogenous vasodilator produced by the vascular endothelium. The balance between the production of NO by the vascular endothelium and scavenging of NO by hemoglobin during hemolysis partially determines NO bioavailability. Rapid NO scavenging by cell-free hemoglobin disrupts this balance. This disruption in NO homeostasis permits unopposed vasoconstriction to occur, which can lead to end organ injury. We have developed NO consumption methodologies that conclusively show that elevated levels of hemoglobin consume NO in vivo. By applying these methodologies to a canine model of hemolysis, we hope to determine whether the administration of inhaled NO will attenuate the systemic effects of hemolysis. This study will test our hypothesis that inhaled NO will bind cell-free hemoglobin and therefore attenuate the end organ damage incurred during acute hemolysis. If this study proves that there is a beneficial effect of NO therapy in acute hemolysis, then it will serve as the basis for future human clinical trials. The model development for producing hemolysis has been completed. An appropriate sedation protocol is being developed followed by the main study.