Restoration and Function of S-Nitrosothiol in Stored Blood

项目总结 输血的治疗效益假定血液携氧能力与 和氧气输送。然而，研究表明，储存的血液失去了给组织充氧的能力。这个 输血后可能出现的后遗症(肾损伤、心肌梗死、死亡)与这个想法是一致的。 这些储存的血液可能会加剧而不是纠正贫血引起的缺氧。 我们发现，库血中的一氧化氮/S亚硫醇(NO/SnO)水平明显降低。 生物活性包括减少的S-硝基形式的血红蛋白(SNO-HB)，一个主要的介体 血流和外周氧气输送。SNO的这种下降为残障人士提供了一个机械基础 储存红细胞(RBC)的血管扩张活性及其对为什么输血如此之少的解释 血量过多可能会损害组织的灌注量。我们在这一新发现的基础上证明了 恢复SNO-Hb水平(肾氨酸化)纠正储存引起的红细胞供氧不足 以及多种临床前输血范例中输血引起的器官功能障碍，我们已经开始 评估输血对人体组织氧合影响的临床研究。我们还开发了 已经在接受临床测试的一流肾硝化剂。 我们的定位是提供急需的数据，关于输血对组织氧合的影响 并通过以下目标促进肾硝化疗法对氧气输送的益处： 1.促进对红细胞利用基于SNO的信号的分子机制的了解 调节新鲜和储存血液中的组织氧合。 2.研制一种体外肾硝化装置。 3.确定输注去重氮红细胞的生理反应是否优于 临床前创伤模型中未处理的库血。 4.在有无创伤的人体中进行自体标准流量(即无创伤)输血研究 肾硝化反应描述输血的生理效应和增加/恢复输血的益处 SNO-Hb水平对组织氧合的影响。 总而言之，我们的研究将为输血对组织氧合的影响提供亟需的见解， 阐明与输血相关的不良缺血事件的机制基础，并加速 开发治疗方法(补充SNO-Hb)。氧气输送能力的恢复 应导致输血以达到其临床目的：血管扩张 改善贫血患者终末器官氧输送的微循环。在某种程度上，世界上 储存的红细胞缺乏SNO-Hb，肾亚硝酸化可能具有重要的治疗前景。

PROJECT SUMMARY The therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacity and oxygen delivery. However, studies have shown that stored blood loses its ability to oxygenate tissues. The sequelae that can occur after transfusion (renal injury, myocardial infarction, death) are consistent with the idea that banked blood may exacerbate rather than correct anemia-induced hypoxia. We have discovered that banked blood has markedly diminished levels of nitric oxide/S-nitrosothiol (NO/SNO) bioactivity including reduced amounts of the S-nitrosylated form of hemoglobin (SNO-Hb), a major mediator of blood flow and peripheral oxygen delivery. This decline in SNO provides a mechanistic basis for the impaired vasodilatory activity of stored red blood cells (RBCs) and an explanation for why transfusion of even small amounts of blood may impair tissue perfusion. We have built on this novel finding by demonstrating that restoration of SNO-Hb levels (renitrosylation) corrects storage-induced deficiencies in RBC oxygen delivery and transfusion-induced organ dysfunction in multiple preclinical transfusion paradigms, and we have initiated clinical studies to assess the effects of transfusion on human tissue oxygenation. We have also developed first-in-class renitrosylating agents that are already undergoing clinical testing. We are positioned to provide critically needed data on the effects of transfusion on tissue oxygenation in humans and to advance the benefits of renitrosylation therapy on oxygen delivery through the following aims: 1. To advance understanding of the molecular mechanisms by which RBCs deploy SNO-based signals to regulate tissue oxygenation in fresh and stored blood. 2. To develop a device for ex vivo renitrosylation. 3. To determine if the physiologic responses to transfusion with renitrosylated RBCs are superior to untreated banked blood in a preclinical trauma model. 4. To conduct an autologous standard flow (i.e. non-trauma) transfusion study in humans with and without renitrosylation to delineate the physiologic effects of transfusion and the benefits of increased/restored SNO-Hb levels on tissue oxygenation. Collectively, our studies will provide much-needed insight into the effects of transfusion on tissue oxygenation, shed light on the mechanistic basis of adverse ischemic events associated with transfusion, and accelerate development of therapeutic approaches (repletion of SNO-Hb). Restoration of the oxygen delivery capabilities of banked blood should result in blood transfusion achieving its clinical purpose: vasodilation in the microcirculation to improve end-organ oxygen delivery in the anemic patient. To the extent that the world's supplies of banked RBCs are deficient in SNO-Hb, renitrosylation may hold significant therapeutic promise.