HYPOXIC PULMONARY VASOCANSTRICTION AND RED BLOOD CELLS

描述 （摘自申请人摘要）有证据表明，一氧化氮（NO） 在红细胞（RBC）介导低氧调节中是重要的 肺血管收缩（HPV）。 NO可能直接参与其中 调节，或可通过其与血红蛋白的结合间接起作用 (Hb)形成S-亚硝基血红蛋白（SNO-Hb）。 此外，嘌呤 腺苷和三磷酸腺苷（ATP）可能在调节 RBC测定肺血管张力。 RBC和HPV之间的相互作用是 临床相关，因为贫血和 危重患者的肺部疾病。 具体目标是 项目有：1. 为了确定NO产生的操作的影响， 外源性NO对肺血管张力的影响 在常氧和缺氧时。 2. 为了区分 完整红细胞及其成分Hb单独参与NO代谢和调节 的HPV，并确定潜在的作用，SNO-Hb的调制 肺血管张力 3. 检测肺动脉内皮细胞 在封闭系统中产生NO，并确定缺氧的影响 和RBC对内皮NO产生的影响。 4. 为了阐明红细胞在 嘌呤能调节肺血管张力通过阻断摄取 腺苷，通过阻断嘌呤受体，并通过测定嘌呤能 在常氧和低氧条件下的介质产生。 5. 以确定 嘌呤是否影响肺动脉内皮细胞释放NO 在一个封闭的系统中。 这些目标将使用一个孤立的， 灌注的兔肺模型，在重复的过程中进行HPV的定量 低氧气体挑战在不同的血细胞比容，并与培养的 肺动脉内皮细胞模型。 将使用以下方法测定介体： 化学发光法测定呼出的NO和NO代谢物 光化学发光法测定SNO-Hb， 压力液相色谱法测定灌流液中的嘌呤。

DESCRIPTION (Adapted from applicants' abstract) There is evidence that nitric oxide (NO) is important in red blood cell (RBC)-mediated modulation of hypoxic pulmonary vasoconstriction (HPV). NO may be involved directly in this modulation, or may act indirectly through its combination with hemoglobin (Hb) to form S-nitrosohemoglobin (SNO-Hb). In addition, the purines adenosine and adenosine triphosphate (ATP) may play a role in modulation of pulmonary vascular tone by RBCs. The interactions between RBCs and HPV are clinically relevant because of the common coexistence of anemia and pulmonary disease in critically ill patients. The specific aims of this project are: 1. To determine the effects of manipulation of NO production and metabolism or exogenously administered NO on pulmonary vascular tone during normoxia and hypoxia. 2. To distinguish between the roles played by the intact RBC and its constituent Hb alone in NO metabolism and modulation of HPV, and to determine the potential role of SNO-Hb in modulation of pulmonary vascular tone. 3. To measure pulmonary artery endothelial cell production of NO in a closed system, and to determine the effects of hypoxia and RBCs on endothelial NO production. 4. To elucidate the role of RBCs in purinergic modulation of pulmonary vascular tone by blocking uptake of adenosine by RBCs, by blocking purine receptors, and by assaying purinergic mediator production under normoxic and hypoxic conditions. 5. To determine whether purines affect release of NO by pulmonary artery endothelial cells in a closed system. These aims will be investigated using an isolated, perfused rabbit lung model with quantitiation of HPV done during repeated hypoxic gas challenges at different hematocrits, and with a cultured pulmonary artery endothelial cell model. Mediators will be assayed using chemiluminescence for measurement of expired NO and NO metabolites in perfusate, photolysis chemiluminescence for measurement of SNO-Hb, and high pressure liquid chromatography for measurement of purines in perfusate.