The Erythrocyte: a Regulator of Microvascular Perfusion

描述（由申请人提供）：本项目的目标是证实红细胞（RBC）在控制外周血微循环灌注中的作用。氧气供应与需求的精确匹配需要组织需求的传感器和氧气供应变化的感受器来满足这些需求。我们早期的研究表明，当02供应受限时，RBC 02含量在维持组织02供应方面比P02含量更重要。由于02转运途径中唯一直接受02含量影响的部分是红细胞内的血红蛋白，我们认为RBC参与感知02需求和调节血流以响应局部02需求。红细胞在组织中某一特定点的02含量与组织的氧气使用水平直接相关。如果移动红细胞本身能够感知02，需要并调节血管口径，无论何时何地，只要有需要，血流量和02的输送就会增加，从而消除了对整个血管系统中不同传感点网络的需求。ATP从红细胞中释放，以响应低P02，当腔内应用于小动脉和小静脉诱导传导血管舒张反应。这些结果使我们提出了这样的假设：红细胞除了作为氧气的主要载体外，还是组织氧气需求的传感器，并通过释放ATP来实现氧气供应与需求的适当匹配，从而引发血管扩张反应。将采用四种方法来评估这一假设：1)使用分离的仓鼠牵张肌小动脉和小静脉，我们将确定位于这些血管上的嘌呤能受体的性质；2)由于我们已经证明升高的乳酸会损害红细胞释放ATP的能力，我们将确定这种缺陷是否对血管控制有影响，这些研究将为在疟疾、败血症和其他病理条件下观察到的组织02供应紊乱提供见解；3)利用原位牵开肌，在体内验证低P02、红细胞诱导的ATP释放与血管舒张的关系；4)我们将确定血红蛋白02饱和度的降低如何激活ATP释放的信号转导途径。这些发现将结合成一个生理模型来调节血流分布以满足组织需要，并可能为病理条件下观察到的外周氧合损伤提供见解。

DESCRIPTION (provided by applicant): The goal of this project is to substantiate a role for the red blood cell (RBC) in the control of perfusion of the peripheral microcirculation. The precise matching of oxygen (02) supply to demand requires a sensor of tissue 02 need and affector of alterations in 02 supply to meet those needs. Our earlier studies indicated RBC 02 content is more important in maintaining tissue 02 supply than is its P02 when 02 supply is limiting. Since the only portion of the 02 transport pathway directly influenced by 02 content is the hemoglobin within the RBC we suggest that the RBC is involved in both sensing 02 demand and regulating blood flow in response to local 02 need.The 02 content of the RBC at a particular point in the tissue is directly linked to the level of oxygen use by the tissue. If the mobile RBC itself were able to sense 02, need and modulate vascular calibre, blood flow and 02 delivery would be increased wherever and whenever the need might arise thereby eliminating the need for diverse network of sensing sites throughout the vasculature. ATP is released from RBCs in response to low P02 and when applied intraluminally into arterioles and venules induces a conducted vasodilator response. These results led us to formulate the hypothesis that: the red blood cell, in addition to serving as the primary carriei of oxygen, is a sensor of tissue oxygen requirements and initiator of a conducted vasodilator response via its release of ATP which enables the appropriate matching of oxygen supply with demand.Four approaches will be used to evaluate this hypothesis: 1) Using isolated hamster retractor muscle arteriole and venules, we will ascertain the nature of the purinergic receptors located on these vessels; 2) Since we have shown that elevated lactate impairs the ability of the RBC to release ATP, we will determine if this deficit has an impact on vascular control, studies which will provide insight into derangements in tissue 02 supply observed ii malaria, sepsis and other pathological conditions; 3) Using the retractor muscle in situ, we will confirm the relationship among low P02, RBC-induced ATP release and vasodilation in vivo; 4) We will determine how decreases in hemoglobin 02 saturation activate the signal transduction pathway for ATP release. These findings will be combined into a physiological model for the regulation of blood flow distribution to meet tissue needs and may provide insight into the impairment in peripheral oxygenation observed frequently in pathological conditions.