Maximizing transfusion efficacy through nitric oxide enhancement strategies

项目摘要 该项目旨在提高输血(BTS)的效率，从而减少血液的使用 在BTS中，通过抵消由于向血液中添加红细胞(RBC)而导致的血流阻力的增加 循环，增加血液粘度，从而减少氧气输送(DO2)。可行性一直是 由初步研究和BT研究证实，血液粘度增加会增加切应力 血管内皮细胞通过刺激一氧化氮(NO)的产生而引起血管扩张。 我们对有限的现有临床BT数据的分析研究，以及我们对实验数据的更广泛研究 动物模型显示，BTS的有益效果可以通过增加血流量显著改善 导致与乘积心输出量(CO)乘以携氧量成正比的DO2增加 容量(CaO2)：DO2=CO x CaO2。我们的研究还表明，BTS期间血流增加是由于血管扩张所致 与提高循环NO的生物利用度有关。最重要的是，对现有临床数据的分析 表明BTS的氧气输送与红细胞压积(Hct)的增加不成正比， 结果显示，多达1/3的输注红细胞对增加氧气输送没有贡献。 我们建议通过增加血液粘度来避免血液流动障碍。 血流量通过三种不同途径的NO介导的血管扩张：1)增加BT后的血浆粘度 通过粘性淀粉为基础的血浆膨胀剂HEXTEND®，已批准临床使用，但未用于 治疗贫血。我们的宏观和微血管实验研究表明，这是一种非常有效的方法。 用于增加可在很短时间内应用于临床的血流量；2)静脉注射 经过良好测试的携带和释放NO的硅烷纳米颗粒(NO-NPS)具有可调节的NO类型(NO， SNO、亚硝酸盐)和释放率，特别适用于在以下条件下立即治疗贫血 限制生物利用度的内皮功能障碍；以及，3)以NO为基础的药理学方法 已经被批准用于其他治疗的血管扩张剂被重新用于增加贫血的血流量 静脉注射纳米粒或口服给药。 我们建议通过以下方法来验证我们的假设：1)分析体内替换氧气输送对微血管的影响 通过增加流量与增加CaO2；2)确定基于NO的BTS支持是否改善了治疗 通过限制所需输血量，以及，3)确定口服与口服的相对疗效 静脉注射无强化策略。 该项目的积极成果将使治疗急性贫血的费用更低、更有效、更多 实用，更安全。

Project Summary The project seeks to improve the efficacy of blood transfusions (BTs), and thereby reduce the use of blood in BTs, by counteracting the increase in blood flow resistance caused by adding red blood cells (RBCs) to the circulation which increases blood viscosity thereby reducing oxygen delivery (DO2). Feasibility has been established from preliminary studies and BT studies, that show increased blood viscosity increases shear stress on the vascular endothelium which in turn causes vasodilation by stimulating the production of nitric oxide (NO). Our analytical studies of limited existing clinical BT data, and our more extensive studies on experimental animal models, show that beneficial effects due to BTs can be significantly improved by increased blood flow causing an increase of DO2 which is proportional to the product cardiac output (CO) times oxygen carrying capacity (CaO2): DO2 = CO x CaO2. Our studies also show that flow increases during BTs are due to vasodilation related to increased bioavailability of circulating NO. Most significantly, an analysis of existing clinical data indicates that O2 delivery by BTs falls short of being directly proportional to the increase of hematocrit (Hct), revealing that as much as 1/3 of the transfused RBCs do not contribute to increasing O2 delivery. We propose to circumvent the hindrance to blood flow due to increased blood viscosity by BTs by increasing blood flow via NO mediated vasodilation by three different approaches: 1) Increasing plasma viscosity after BT by means of the viscogenic starch-based plasma expander Hextend®, approved for clinical use but not for treating anemia. Our macro and microvascular experimental studies show that this is a highly effective approach for increasing flow that could become clinically applicable in the very short term; 2) Intravenous introduction of well tested biocompatible NO carrying and releasing silane nanoparticles (NO-nps) with tunable NO type (NO, SNO, nitrite) and rates of release, particularly suitable for the immediate treatment of anemia in conditions of endothelial dysfunction that limit bioavailability; and, 3) A pharmacological approach where existing NO based vasodilators, already approved for use for other treatments are re-purposed for increasing flow in anemia via either intravenous nanoparticle or oral administration. We propose validating our hypothesis by: 1) Analyzing in vivo microvascular effects of replacing O2 delivery by increased flow vs. increased CaO2; 2) Determining whether an NO based support of BTs improves treating anemia by limiting the amount of needed transfused blood, and, 3) Determining the relative efficacy of oral versus intravenous NO enhancement strategies. A positive outcome for this project will make the treatment of acute anemia less costly, more effective, more practical, and safer.