The Erythrocyte: a Regulator of Microvascular Perfusion

红细胞：微血管灌注的调节器

• 批准号: 6605041
• 负责人: MARY L ELLSWORTH
• 金额: $ 18.38万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605041
• 关键词: adenosine triphosphate; biological signal transduction; capillary; cell morphology; chloride channels; erythrocytes; hamsters; hemoglobin; laboratory rabbit; microcirculation; oxygen tension; oxygen transport; vasomotion

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.

描述（由申请人提供）：该项目的目的是证实红细胞（RBC）在控制外围微循环灌注中的作用。 氧气（02）供需的精确匹配需要组织02的传感器和02供应中的改变和改变的伴侣，以满足这些需求。 我们较早的研究表明，RBC 02在维持组织02供应方面比02供应限制时更重要。 由于直接受02含量影响的02传输途径的唯一部分是RBC内的血红蛋白，因此我们建议RBC参与感应02需求和调节血液流动，以响应局部02的需求。在组织中特定点的RBC的02含量直接链接到组织使用的氧气水平。 如果移动RBC本身能够感知02，需要和调节血管口径，血流和02输送将在任何地方增加，每当可能出现需求时，就消除了整个脉管系统中对感应地点的多样化网络的需求。 ATP响应低P02而从RBC中释放出来，当静脉内应用于小动脉中时，静脉会诱导导致的血管扩张剂反应。 这些结果使我们提出了以下假设：除作为氧气的主要carriei外，红细胞除了是组织氧的需求的传感器和导致的血管舒张剂反应的传感器，通过释放ATP的释放，可以使氧气供应与需求相匹配，以评估该假说的习惯：1）。确定位于这些血管上的嘌呤能受体的性质； 2）由于我们已经表明乳酸升高会损害RBC释放ATP的能力，因此我们将确定这种赤字是否对血管控制有影响，研究将洞悉组织02供应的疾病02供应观察到的II疟疾，败血症和其他病理条件； 3）使用缩回肌原位，我们将确认低P02，RBC诱导的ATP释放和体内血管舒张的关系； 4）我们将确定血红蛋白02饱和度的减少如何激活ATP释放的信号转导途径。 这些发现将合并为一个生理模型，以调节血液流量分布以满足组织需求，并可以深入了解在病理条件下频繁观察到的外周氧合的损害。