NO on End Organ Injury in Model of acute Hemolysis

NO对急性溶血模型终末器官损伤的影响

• 批准号: 6825415
• 负责人: Steven Solomon
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6825415
• 关键词: acute disease /disorder; dogs; free radical scavengers; hemoglobin; hemolysis; homeostasis; inhalation drug administration; nitric oxide; organ; pathologic process; protein binding; vascular endothelium

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.

本研究探讨吸入一氧化氮(NO)对减轻犬血管内溶血引起的血管效应和器官损伤的治疗价值。溶血是红细胞在体内的破坏，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，无细胞血红蛋白能清除NO。NO是血管内皮细胞产生的一种内源性血管扩张剂。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。无细胞血红蛋白对NO的快速清除破坏了这种平衡。这种体内平衡的破坏使非抵抗性血管收缩发生，这可能导致终末性器官损伤。我们没有开发出任何消耗方法，最终表明体内高水平的血红蛋白不消耗任何物质。通过将这些方法应用于犬的溶血模型，我们希望确定吸入NO是否会减弱溶血的全身影响。这项研究将检验我们的假设，即吸入NO会结合无细胞的血红蛋白，从而减轻急性溶血过程中造成的终末器官损害。如果这项研究证明NO疗法对急性溶血有有益效果，那么它将作为未来人类临床试验的基础。 已经完成了产生溶血的模型开发。在主要研究之后，正在开发适当的镇静方案。