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。 从该项目中获得的知识将产生与健康相关的影响，因为它将允许更明智地理解和治疗贫血，疾病的常见伴随物，并最终通过优化输血策略和开发血红蛋白为基础的氧载体来改善患者护理。 博士Deem先前已经描述了红细胞通过Hb使NO失活而在增强缺氧性肺血管收缩中的重要性，并且描述了在某些条件下贫血对肺气体交换的增强。目前的项目将以这些调查结果为基础，实现以下具体目标：确定以氧化产物亚硝酸盐或NO-Hb产物亚硝酰（血红素）Hb和S-亚硝基Hb形式被生物保存的NO是否可以在肺循环中释放并导致血管舒张。将在离体灌注大鼠肺模型和麻醉大鼠中研究常氧和缺氧条件下这些产品对肺动脉压和NO产生的影响。此外，这一目标将探讨是否封装血红蛋白内的红细胞膜改变血管活性的NO-Hb产品的属性。二.在离体灌注大鼠肺中，使用活体显微镜确定RBC在确定微血管血流动力学中的作用。该目的将直接探索肺微循环的流变学，帮助确定红细胞是否在决定肺微血管血流动力学中起主动或被动作用，并提供对红细胞改变肺血流分布和气体交换的机制的见解。

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.