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)在控制外周微循环血流中的作用。氧气(02)供应与需求的精确匹配需要组织O2需求的传感器和O2供应变化的影响来满足这些需求。我们早期的研究表明，在维持组织的02供应方面，RBC 02的含量比当02供应有限时的P02更重要。由于02转运途径中唯一直接受O2含量影响的部分是RBC内的血红蛋白，我们认为RBC参与了感知O2需求和调节血流以响应局部O2需求。组织中特定时间点RBC的O2含量与组织的氧气利用水平直接相关。如果移动RBC本身能够感知O2、需要和调节血管口径，则血流量和O2的输送将随时随地增加，从而消除了对遍及血管系统的不同传感部位网络的需要。低P02使红细胞释放三磷酸腺苷，当将三磷酸腺苷作用于小动脉和小静脉时，可诱导一种传导的血管扩张反应。这些结果导致我们提出这样的假设：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来启动传导的血管扩张反应，从而使氧气供应与需求适当匹配。将使用四种方法来评估这一假设：1)利用分离的仓鼠牵引肌小动脉和小静脉，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，乳酸升高会损害红细胞释放ATP的能力，我们将确定这种缺陷是否对血管控制有影响，研究将为观察到的II疟疾、败血症和其他病理条件下组织02供应的紊乱提供洞察力；3)使用原位牵引肌，我们将在体内确认低P02、RBC诱导的ATP释放和血管扩张之间的关系；4)我们将确定Hb 02饱和度的降低如何激活ATP释放的信号转导途径。这些发现将被结合到一个生理模型中，用于调节血流分布以满足组织需求，并可能为在病理条件下经常观察到的外周氧合损伤提供洞察力。

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.