HYPERTONIC SALINE AND NEUTROPHIL FUNCTION

描述：(逐字摘自申请者摘要)中性粒细胞(PMN)可以 造成创伤后的器官损伤。我们发现生理上相关的水平 高渗盐水(HS)对体外培养的人PMN有抑制作用，提示HS 复苏可以用来预防创伤患者的器官损伤。近期 有报道表明，HS复苏确实可以预防失血 动物模型中的器官损伤。然而，HS不仅能够抑制PMN， 但它也可以在特定情况下增强PMN的功能。因此， 在某些临床情况下，HS可加重组织损伤。考虑 对高渗复苏液的高度兴趣，条件 必须确定HS可以抑制或增强PMN以提供 为创伤患者提供最好的护理。这就是本提案的目标，即 回答以下三个问题： PMN如何检测HS？涉及渗透压的受体的性质 将研究信号及其下游通路。重点将是 被放置在异三聚体G蛋白偶联受体的规则上， 机械感受器和拉伸激活的离子通道。 HS是如何干扰PMN激活的？HS-Signal的机制 将使用超氧化物的形成来研究阻断激活信号 以fMLP刺激的细胞为模型。重点将放在串音上 HS信号与超氧化物激活途径之间的关系 队形。 HS能阻止创伤后中性粒细胞的激活吗？HS对分离的中性粒细胞的影响 创伤患者来源和创伤患者血浆刺激的正常细胞 将通过在体外用临床相关的HS处理细胞来进行研究 剂量。这将显示在哪些条件下可以使用HS进行最佳控制 创伤患者的PMN以及何时不能使用HS以避免可能的阴性 副作用。 该项目将确定细胞外紧张性的机制 调节PMN的功能。这项工作将使创伤患者受益于评估 HS复苏在预防器官损伤中的价值以及HS如何 可以对复苏方法进行改进，以提高其临床价值。

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.