Red Blood Cells, Nitric Oxide and Pulmonary Circulation

描述(由申请人提供)： 本项目的长期目标是阐明红细胞(RBC)、血红蛋白(Hb)和一氧化氮(NO)在微血管和大血管水平调节肺血流中的作用，从而深入了解RBC影响肺气体交换的机制。 从这个项目中获得的知识将产生与健康相关的影响，因为它将使人们能够更知情地了解和治疗贫血这一常见的疾病，并最终通过优化输血策略和开发基于血红蛋白的氧气载体来改善患者护理。 Deem博士先前描述了红细胞通过Hb灭活NO来增强缺氧性肺血管收缩的重要性，并描述了在某些条件下贫血增强肺气体交换的作用。目前的项目将在以下具体目标的基础上建立在这些发现的基础上：i.确定以氧化产物亚硝酸盐的形式生物保留的NO，或者NO-Hb的产物亚硝酰(血红素)Hb和S-亚硝基Hb是否可以在肺循环中释放并导致血管扩张。这些产品将在常氧和低氧条件下，在隔离、灌流的大鼠肺模型和麻醉大鼠中研究其对肺动脉压和NO产生的影响。此外，这一目标将探索将Hb包裹在红细胞膜中是否会改变非Hb产品的血管活性特性。利用活体显微镜在分离、灌流的大鼠肺中确定红细胞在确定微血管血流动力学中的作用。这一目的将直接探讨肺微循环的流变学，有助于确定红细胞在决定肺微血管血流动力学中起主动还是被动作用，并为深入了解红细胞改变肺血流分布和气体交换的机制提供依据。

DESCRIPTION (provided by applicant): The long term objectives of this project are to elucidate the role of red blood cells (RBCs), hemoglobin (Hb), and nitric oxide (NO) in modulating pulmonary blood flow at the microvascular and macrovascular levels, and to thereby provide insight into the mechanisms by which RBCs affect pulmonary gas exchange. The knowledge gained from this project will have health-related ramifications, in that it will allow more informed understanding and treatment of anemia, a common accompaniment of illness, and ultimately lead to improvements in patient care through the optimization of transfusion strategies and the development of hemoglobin-based oxygen carriers. Dr. Deem has previously described the importance of RBCs in augmenting hypoxic pulmonary vasoconstriction through inactivation of NO by Hb, and has delineated the enhancement of pulmonary gas exchange by anemia under certain conditions. The current project will build on these findings in the following Specific Aims: I. Determine whether NO that is "biopreserved in the form of the oxidation product nitrite, or the NO-Hb products nitrosyl(heme)Hb and S-nitrosoHb can be released in the pulmonary circulation and result in vasodilation. The effect of these products on pulmonary artery pressure and NO production will be studied during normoxic and hypoxic conditions in an isolated, perfused rat lung model and in anesthetized rats. In addition, this aim will explore whether encapsulation of Hb within the red blood cell membrane alters the vasoactive properties of NO-Hb products. II. Determine the role of RBCs in determining microvascular hemodynamics using intravital microscopy in isolated, perfused rat lungs. This Aim will directly explore the rheology of the pulmonary microcirculation, help determine whether the RBC plays an active or passive role in determining pulmonary microvascular hemodynamics, and provide insights into the mechanisms by which RBCs alter pulmonary blood flow distribution and gas exchange.