CAPILLARY ENDOTHELIAL CELL SWELLING IN LOW-FLOW ISCHEMIA

低流量缺血时毛细血管内皮细胞肿胀

• 批准号: 3365161
• 负责人: KARL E ARFORS
• 金额: $ 20.12万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3365161
• 关键词: acidity /alkalinity; capillary; cats; edema; hemodynamics; hemorrhagic shock; ion transport; ischemia; microcirculation; reperfusion; sodium channel; vascular endothelium

The emphasis of the proposed research is to examine in-depth capillary endothelial cell swelling in low-flow ischemia at the microcirculatory and whole-organ levels. We have previously shown that this microcirculatory phenomenon evolves in hemorrhagic shock, and the hypothesis is now advanced that it is a universal manifestation of hypoperfused organs. The long-term research objective is to further understand the pathophysiology involved in low-flow ischemia at the vital nutritive capillary level. With reference to capillary endothelial cell swelling in low-flow ischemia, the specific research aims are to: 1. examine the relationship between swelling and perfusion, 2. determine the role of blood pH in swelling, 3. identify the mechanisms for swelling, 4. examine the effects of fluid reperfusion on swelling, and 5. determine the implications of swelling on whole-organ blood flow. To define the extent of endothelial cell swelling in low-flow states, intravital microscopy will be used to visualize capillaries in the rabbit tenuissimus muscle after hemorrhage or proximal arterial occlusion. In hemorrhagic shock, swelling could be due to the diminished capillary perfusion or the induced metabolic acidosis (drop in systemic pH), or a combination of the two. The influence of blood pH will be investigated by maintaining pH after hemorrhage, and alternatively, be decreasing pH with flow unchanged. A causal role of blood pH is supported by the theory that swelling results from intracellular pH regulation through Na+/H+ exchange. To characterize the mechanisms for swelling, the drug amiloride and its analogs will be given prior to an ischemic episode to inhibit transmembrane Na+ pathways. We have found that hypertonic, but not isotonic, saline infusion after shock reverses swollen endothelium beyond expected osmotic shrinkage. Hypertonic mannitol infusion will be tried to explore the possible specific role of the Na+ ion. The impact of conventional blood and iso-osmotic fluids, along with hyperosmotic solutions, will be assessed in those ischemic states in which cell edema is produced. The hemodynamic consequence of cell swelling is that it narrows the capillary lumen, thereby increasing resistance to flow. The effects of narrowed capillaries on whole-organ blood flow during shock and reperfusion will be assessed with a microsphere technique. These proposed studies are intended to give a better understanding of capillary dysfunction in low-flow microcirculatory ischemias germane to clinical medicine, with the ultimate goal of improving therapeutic strategies.

建议的研究重点是深入研究毛细管 微循环低流量缺血时内皮细胞肿胀， 全器官水平。 我们以前已经证明，这种微循环 出血性休克的现象，现在的假设是先进的 这是器官灌注不足的普遍表现。 长期 研究目的是进一步了解参与的病理生理学 在重要的营养毛细血管水平的低流量缺血。 参照 低流量缺血时毛细血管内皮细胞肿胀， 研究目的是：1.研究肿胀和 灌注，2.确定血液pH值在肿胀中的作用，3.识别 膨胀机制，4.检查液体再灌注对 肿胀，和5.确定肿胀对整个器官的影响 血流 确定低流量时内皮细胞肿胀的程度 国家，活体显微镜将用于可视化毛细血管中， 家兔薄肌出血后或近端动脉闭塞。 在失血性休克中，肿胀可能是由于毛细血管减少 灌注或诱导的代谢性酸中毒（全身pH值下降），或 两者的结合。 将通过以下方法研究血液pH值的影响： 出血后维持pH值，或者降低pH值， 流量不变。 血液pH值的因果作用得到以下理论的支持， 溶胀是由通过Na+/H+交换的细胞内pH调节引起的。 为了描述肿胀的机制，药物阿米洛利及其 类似物将在缺血发作之前给予， Na+通道。 我们发现高渗盐水，但不是等渗盐水， 休克后输注逆转肿胀的内皮细胞超过预期的渗透压 收缩 将尝试高渗甘露醇输注以探索 Na+离子可能的特殊作用。 传统血液的影响 和等渗液，沿着高渗溶液，将进行评估 在这些局部缺血状态下，细胞水肿产生。 血流动力学 细胞肿胀的结果是它使毛细血管腔变窄， 从而增加流动阻力。 毛细血管狭窄的影响 将评估休克和再灌注期间全器官血流的影响 用微球技术。 这些研究旨在提供 更好地了解低流量时的毛细血管功能障碍 微循环缺血与临床医学密切相关， 改善治疗策略的目标。