Ethical Problems of Registered Nurses and Social Workers

在人类疾病的血管内溶血过程中，无细胞血浆血红蛋白与一氧化氮（NO）的反应性增加可能会损害血管舒缩张力和器官灌注。为了验证低水平的脱节或无细胞血浆血红蛋白会严重降低一氧化氮的生物利用度并产生血管舒缩性不稳定的假设，我们在犬模型中实验产生了急性血管内溶血。重要的是，在这个模型中，总的血管内血红蛋白水平是不变的，只有红细胞膜内血红蛋白的区隔化被破坏。使用全因子设计，我们证明了游离水诱导的血管内溶血产生剂量依赖性全身血管收缩和损害肾功能。我们发现这些生理变化是继发于细胞游离血浆氧合血红蛋白对内源性NO的化学计量氧化。在该模型中，吸入80 ppm的NO气体将85-90%的血浆氧合血红蛋白氧化为高铁血红蛋白，从而抑制无细胞血红蛋白对内源性NO的清除。结果，急性溶血引起的血管收缩减弱，对全身输注NO供体的反应性恢复。这些观察结果证实，血管内溶血的急性毒性继发于血浆氧合血红蛋白与内皮来源的NO加速双氧反应，形成生物活性硝酸盐。这些生化和生理研究证明了完整红细胞在一氧化氮稳态中的重要作用，并为人类溶血相关一氧化氮失调综合征的存在提供了机制支持，这种综合征可能导致遗传性、获得性和医源性溶血状态的血管病变。

During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin with nitric oxide (NO). We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma hemoglobin will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular hemoglobin level is unchanged, only the compartmentalization of hemoglobin within the erythrocyte membrane is disrupted. Using a full factorial design, we demonstrate that free water-induced intravascular hemolysis produces dose dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free hemoglobin. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondary to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated nitric oxide dysregulation, which may contribute to the vasculopathy of hereditary, acquired and iatrogenic hemolytic states.