HYPERTONIC SALINE AND NEUTROPHIL FUNCTION

高渗盐水和中性粒细胞功能

• 批准号: 6628852
• 负责人: WOLFGANG G JUNGER
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628852
• 关键词: G protein; NAD(P)H dehydrogenase; biological signal transduction; chemoattractants; cyclic AMP; enzyme activity; human tissue; leukocyte activation /transformation; mechanoreceptors; mitogen activated protein kinase; neutrophil; peptides; phosphatidylinositol 3 kinase; physiologic stressor; protein kinase A; protein kinase C; pulmonary stretch receptors; receptor coupling; saline; superoxides; tissue /cell culture; trauma

DESCRIPTION: (Verbatim from the applicant's abstract) Neutrophils (PMNs) can cause organ damage after trauma. We found that physiologically relevant levels of hypertonic saline (HS) can inhibit human PMNs in vitro, suggesting that HS resuscitation could be used to prevent organ damage in trauma patients. Recent reports have shown that HS resuscitation can indeed prevent hemorrhage-induced organ damage in animal models. However, HS is not only able to inhibit PMNs, but it can also augment PMN functions under specific circumstances. Therefore, HS could aggravate tissue damage in certain clinical situations. Considering the heightened interest in hypertonic resuscitation fluids, the conditions under which HS can inhibit or augment PMNs must be determined to provide the best care for trauma patients. This is the goal of the present proposal, which addresses the following three questions: How do PMNs detect HS? The nature of the receptors involved in osmotic signaling and their downstream pathways will be studied. Emphasis will be placed on the rules of heterotrimeric G protein-coupled receptors, mechanoreceptors, and stretch-activated ion channels. How does HS interfere with PMN activation? The mechanism whereby HS-signals block activation signaling will be studied using superoxide formation of fMLP-stimulated cells as a model. Emphasis will be placed on the cross-talk between HS-signaling and the activation pathway leading to superoxide formation. Can HS prevent PMN activation after trauma? The effect of HS on PMNs isolated from trauma patients and on normal cells stimulated with trauma patient plasma will be studied by treating the cells in vitro with clinically relevant HS doses. This will show under which conditions HS can be used to best control PMNs in trauma patients and when HS must not be used to avoid possible negative side effects. This project will identify the mechanisms whereby extracellular tonicity regulates PMN functions. This work will benefit trauma patients by assessing the value of HS resuscitation to prevent organ damage and by suggesting how HS resuscitation could be modified to improve its clinical value.

描述：（逐字引用申请人摘要）中性粒细胞（PMN）可以 会导致外伤后的器官损伤我们发现生理相关水平 高渗盐水（HS）对体外培养的人中性粒细胞有抑制作用，提示HS 复苏可用于防止创伤患者的器官损伤。最近 有报道表明，HS复苏确实可以防止创伤引起的 动物模型中的器官损伤。然而，HS不仅能够抑制PMNs， 但它也可以在特定情况下增强PMN功能。因此，我们认为， 在某些临床情况下，HS可加重组织损伤。考虑 对高渗复苏液的兴趣增加， 在什么条件下HS可以抑制或增加PMNs必须确定，以提供 为创伤患者提供最佳护理。这是本提案的目标， 处理以下三个问题： PMNs如何检测HS？渗透调节受体的性质 信号传导及其下游通路将被研究。重点将 根据异源三聚体G蛋白偶联受体的规则， 机械感受器和牵张激活离子通道。 HS如何干扰PMN激活？HS信号的机制 阻断激活信号传导将使用超氧化物形成来研究， fMLP刺激的细胞作为模型。重点将放在相声上 HS信号传导和导致超氧化物的活化途径之间的关系 阵 HS能预防创伤后PMN活化吗？HS对中性粒细胞的影响 来自创伤患者和用创伤患者血浆刺激的正常细胞 将通过在体外用临床相关HS处理细胞来研究 剂量这将显示在哪些条件下HS可以用于最佳控制 创伤患者中的中性粒细胞和HS时不得使用，以避免可能的阴性 副作用. 本项目将确定细胞外张力的机制， 调节PMN功能。这项工作将有利于创伤患者评估 HS复苏对预防器官损伤的价值以及建议HS如何 复苏法可加以改进以提高其临床价值。