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）在外周微循环灌注控制中的作用。 氧气（O2）供应与需求的精确匹配需要组织O2需求的传感器和O2供应的改变的影响器以满足那些需求。 我们早期的研究表明，当O2供应受限时，RBC O2含量在维持组织O2供应方面比其P02更重要。 由于直接受O2含量影响的O2运输途径的唯一部分是RBC内的血红蛋白，因此我们认为RBC参与感测O2需求和响应于局部O2需要而调节血流。 如果移动的RBC本身能够感测O2、需要和调节血管口径，则无论何时何地需要都将增加血流和O2输送，从而消除了对整个脉管系统中的感测部位的不同网络的需要。 ATP响应于低P02从RBC释放，并且当管腔内施加到小动脉和小静脉中时诱导传导的血管扩张剂反应。 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和通过释放ATP进行血管扩张反应的启动器，ATP使氧气供应与需求适当匹配。四种方法将用于评估这一假设：（1）利用离体仓鼠牵开肌微动脉和微静脉，我们将确定位于这些血管上的嘌呤能受体的性质; 2）由于我们已经表明，乳酸盐升高会损害RBC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，这些研究将提供对在疟疾、败血症和其它病理条件下观察到的组织O2供应紊乱的深入了解;（3）利用牵开肌在体实验，进一步证实低P02、RBC诱导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。 这些研究结果将结合到一个生理模型的血流分布的调节，以满足组织的需要，并可能提供洞察外周氧合损伤经常观察到的病理条件。

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.