Hypertonic Saline and Neutrophil Function

高渗盐水与中性粒细胞功能

• 批准号: 7590327
• 负责人: WOLFGANG G JUNGER
• 金额: $ 29.71万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590327
• 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; 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

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 havestudied the molecular mechanisms through which HS controls PMNfunction and havefound that HStriggers the release ofATP. ATP can augment PMNresponses via P2 receptors. ATP convertedto adenosine inhibits PMNactivation via P1 receptors. We hypothesize that the balance between ATP and adenosine determines whether HS increases or dampens PMNfunction. Inthe following three Specific Aims, we proposeto define the components that control this ATP/adenosine balance and determine pharmaceutical approaches to shift it toward adenosine, and thus towardinhibition of PMNfunction. Specific Aim 1:ATPrelease and P2receptor activation: Themechanisms of ATP release will bestudied, a novel method for real-time monitoring of ATP release will be established, and P2 receptorsubtype expression and colocalization with sites of ATP release and hydrolysis will be assessed. Specific Aim 2)Adenosine formation and P1receptor activation:Thedynamics of expressionand colocalization of ecto-enzymesgenerating 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:Theeffect of ATP released from other cells surrounding PMNwill be studied and pharmacological approachesto improvethe efficacy of HS resuscitation by modulating adenosine accumulation will be tested with humanwhole blood and a mousemodel of hemorrhagic shock. The proposed experiments will elucidate general principles of HS-induced ATP release and the control of PMNfunction by extracellular ATP and its products. This knowledge will allow us to better understand how HS resuscitation can regulate PMNfunction and howthe clinical effectivenessof HScan be optimized to attenuate inflammation and PMN-induced organ damage in trauma victims.

高渗盐水（HS）复苏是预防组织损害的一种有希望的新方法 创伤患者，由于其阻断嗜中性粒细胞（PMN）激活的能力。我们对分子进行了 HS控制PMNFUNCTICT并具有hStrigging hS释放的机制。 ATP可以通过P2受体增强PMNRESRESOBS。 ATP转化为腺苷通过 P1受体。我们假设ATP和腺苷之间的平衡决定了HS是否 增加或衰减PMN功能。在以下三个特定目标中，我们建议定义 控制此ATP/腺苷平衡并确定将其转移的药物的组件 朝向腺苷，从而抑制PMNFunction。 具体目标1：ATPREALE和P2RECEPTOR激活：ATP释放的主体机制将质疑， 将建立一种实时监测ATP释放的新方法，并将P2受体tubtype 将评估与ATP释放和水解部位的表达和共定位。 具体目标2）腺苷的形成和P1受体激活：表达和表达的动力学 异位 - 酶的共定位和水解腺苷，特别是碱性磷酸酶的共定位 将研究腺苷脱氨酶以及被腺苷激活的P1受体的。 特定目的3）调节hs的效果：从周围其他细胞释放的ATP的影响 对PMNWill进行研究，并通过药理学方法提高了HS复苏的功效 调节腺苷积累将通过人类全血和菌群测试 出血性休克。 提出的实验将阐明HS诱导的ATP释放的一般原则，并控制 细胞外ATP及其产品的PMNFUNCTION。这些知识将使我们能够更好地了解 HS复苏可以调节PMN功能，以及如何优化HSCAN的临床有效性 衰减创伤受害者的炎症和PMN引起的器官损伤。