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: 3365162
• 负责人: KARL E ARFORS
• 金额: $ 6.48万
• 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 1993-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3365162
• 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。 低流量缺血时内皮细胞肿胀在微循环和 整个器官的水平。我们之前已经证明，这种微循环 失血性休克中的现象演变，现在提出了这个假说 这是器官灌流不足的普遍表现。长期的 研究的目的是进一步了解涉及的病理生理学。 重要营养血管水平的低流量缺血。有参考价值 对低流量缺血时毛细血管内皮细胞肿胀的特异性 研究的目的是：1.研究肿胀与高血压的关系 血流灌注，2.确定血液pH值在肿胀中的作用，3.确定 肿胀的机制，4.检查液体再灌流对 肿胀，以及5.确定肿胀对整个器官的影响 血液流动。确定低流量时内皮细胞肿胀的程度 国家，活体显微镜将被用来可视化毛细血管在 兔近端动脉闭塞或出血后的狭窄肌。 在失血性休克中，肿胀可能是由于毛细血管减少所致。 灌流或诱导的代谢性酸中毒(全身pH值下降)，或 两者的结合。血液pH值的影响将通过以下方式进行调查 在出血后维持pH，或者，用以下方法降低pH 流量不变。血液pH值的因果作用得到了以下理论的支持 肿胀是通过Na+/H+交换调节细胞内pH而产生的。 为了表征肿胀的机制，药物阿米洛利和它的 将在缺血发作之前给予类似物以抑制跨膜 NA+通路。我们发现高渗盐水，但不是等渗盐水 休克后输液逆转超出预期渗透压的内皮细胞肿胀 缩水。高渗甘露醇输注将尝试探索 可能是Na+离子的特定作用。常规血液的影响 并将评估等渗液以及高渗透溶液。 在那些产生细胞水肿的缺血状态中。血液动力学 细胞肿胀的后果是使毛细血管管腔变窄， 从而增加了流动阻力。毛细血管变窄的影响 对休克和再灌流期间的全器官血流进行评估 使用微球技术。这些拟议的研究旨在给出 对低流量状态下毛细血管功能障碍的进一步认识 微循环缺血与临床医学密切相关，具有终极 改进治疗策略的目标。