Hypertonic Saline and Neutrophil Function

高渗盐水与中性粒细胞功能

基本信息

批准号：
8304664
负责人：
WOLFGANG G JUNGER
金额：
$ 10.14万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304664
关键词：
ATP Hydrolysis Address Adenosine Adenosine Deaminase Inhibitor Adverse effects Affect Alkaline Phosphatase Animal Model Attenuated Cell surface Cells Clinical Clinical effectiveness Country Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Early treatment Effectiveness Enzymes Equilibrium Event Extracellular Space Feedback Funding Hemorrhagic Shock Human Hydrolysis Hypertonic Saline Solution In Vitro Inflammation Institute of Medicine (U.S.)Kinetics Knowledge Liquid substance MAP Kinase Gene MAPK14 gene Mediating Membrane Methods Molecular Monitor Organ Patients Pharmacologic Substance Plasma Prevention Process Receptor Activation Resuscitation Saline Sepsis Shock Signal Transduction Site Testing Therapeutic Agents Time Tissues Trauma Whole Blood Work adenosine deaminase autocrine base combat controlled release dosage ecto-nucleotidase extracellular improved in vivo inhibitor/antagonist interest mouse model neutrophil novel novel strategies prevent protective effect receptor research study response success

项目摘要

Hypertonic saline (HS) resuscitation is a promising new approach in the prevention of tissue damage in trauma patients, because of its capacity to block neutrophil (PMN) activation. We have studied the molecular mechanisms through which HS controls PMN function and have found that HS triggers the release of ATP. ATP can augment PMN responses via P2 receptors. ATP converted to adenosine inhibits PMN activation via P1 receptors. We hypothesize that the balance between ATP and adenosine determines whether HS increases or dampens PMN function. In the following three Specific Aims, we propose to define the components that control this ATP/adenosine balance and determine pharmaceutical approaches to shift it toward adenosine, and thus toward inhibition of PMN function. Specific Aim 1: ATP release and P2 receptor activation: The mechanisms of ATP release will be studied, a novel method for real-time monitoring of ATP release will be established, and P2 receptor subtype expression and colocalization with sites of ATP release and hydrolysis will be assessed. Specific Aim 2) Adenosine formation and P1 receptor activation: The dynamics of expression and colocalization of ecto-enzymes generating and hydrolyzing adenosine, specifically alkaline phosphatase, adenosine deaminase, and of the P1 receptors that are activated by adenosine will be studied. Specific Aim 3) Modulation of the effect ofHS: The effect of ATP released from other cells surrounding PMN will be studied and pharmacological approaches to improve the efficacy of HS resuscitation by modulating adenosine accumulation will be tested with human whole blood and a mouse model of hemorrhagic shock. The proposed experiments will elucidate general principles of HS-induced ATP release and the control of PMN function by extracellular ATP and its products. This knowledge will allow us to better understand how HS resuscitation can regulate PMN function and how the clinical effectiveness of HS can be optimized to attenuate inflammation and PMN-induced organ damage in trauma victims.

高渗盐水（HS）复苏是预防组织损伤的一种有前途的新方法创伤患者，因为它能够阻止中性粒细胞 (PMN) 激活。我们研究了分子 HS 控制 PMN 功能的机制，并发现 HS 触发 ATP 的释放。 ATP 可通过 P2 受体增强 PMN 反应。 ATP 转化为腺苷抑制 PMN 激活 P1受体。我们假设 ATP 和腺苷之间的平衡决定了 HS 是否增强或抑制 PMN 功能。在以下三个具体目标中，我们建议定义控制这种 ATP/腺苷平衡并确定改变其平衡的药物方法的成分腺苷，从而抑制 PMN 功能。具体目标1：ATP释放和P2受体激活：将研究ATP释放的机制，将建立一种实时监测ATP释放的新方法，以及P2受体亚型将评估表达以及与 ATP 释放和水解位点的共定位。具体目标 2) 腺苷形成和 P1 受体激活：表达和激活的动力学产生和水解腺苷的胞外酶的共定位，特别是碱性磷酸酶，将研究腺苷脱氨酶以及腺苷激活的 P1 受体。具体目标 3) HS 作用的调节：周围其他细胞释放的 ATP 的作用将研究 PMN 和药理学方法，以通过以下方式提高 HS 复苏的功效：调节腺苷积累将用人类全血和小鼠模型进行测试失血性休克。拟议的实验将阐明 H2S 诱导的 ATP 释放的一般原理和控制 PMN 通过细胞外 ATP 及其产物发挥作用。这些知识将使我们更好地理解如何 HS 复苏可以调节 PMN 功能以及如何优化 HS 的临床效果减轻创伤受害者的炎症和 PMN 引起的器官损伤。