Neutrophil activation and trauma

中性粒细胞激活和创伤

基本信息

批准号：
8774227
负责人：
WOLFGANG G JUNGER
金额：
$ 50.9万
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 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774227
关键词：
ATP Hydrolysis Address Adenosine Adverse effects Affect Autocrine Communication Cell Aging Cell surface Cells Clinical Clinical effectiveness Critical Illness Data Employee Strikes Equilibrium Event Excision Funding Goals Health Host Defense Hydrolysis Immune Inflammation Inflammatory Inflammatory Response Injury Invaded Knowledge Lead Mediator of activation protein Modeling Molecular Motion Multiple Organ Failure Mus Neutrophil Activation Organ Organ failure Outcome Pathway interactions Patients Pattern Play Process Progress Reports Publications Purinoceptor Regulation Research Resuscitation Risk Role Saline Sepsis Sepsis Syndrome Septic Shock Signal Pathway Signal Transduction Surface Syndrome System Tail Tars Testing Therapeutic Tissues Trauma Trauma patient Work autocrine base cell age extracellular improved injured innovation neutrophil novel novel therapeutic intervention novel therapeutics pathogen prevent receptor receptor expression response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Neutrophil activation and trauma - Neutrophils (PMN) cause the systemic inflammatory response (SIRS) and multi-organ failure syndromes (MOFS) that damage host tissues. Approaches to block PMN can reduce SIRS and MOFS, but detailed knowledge of the mechanisms involved in PMN activation is still missing. The purpose of this proposal is to continue our work elucidating these mechanisms. Over the last several years, our research has revealed that hypertonic saline (HS) resuscitation can markedly suppress PMN activation. We identified that ATP release and autocrine signaling via purinergic receptors is the underlying molecular mecha- nism by which HS can suppress but also enhance PMN responses. An unexpected finding of our work has been that ATP release and autocrine purinergic signaling is a much more fundamental mechanism that is re- quired for PMN activation in general. We discovered that PMN require two separate signals for appropriate cell activation: (1) qualitative signals through receptors that recognize specific extracellular danger mediators, and (2) quantitative signals, generated by autocrine purinergic signaling, that regulate subsequent cellular re- sponses. Based on these important findings and our exciting preliminary data, we hypothesize that trauma influences the autocrine signaling system of PMN in several ways, which leads to excessive PMN activation, SIRS, and MOFS. The release of large amounts of ATP from damaged tissues disrupts the autocrine puriner- gic signaling system of PMN. Trauma changes purinergic receptor expression and distort PMN responses, re- sulting in inflammation, SIRS, MOFS, and sepsis. Modulating purinergic signaling can prevent this progression. Specific Aim 1) Autocrine purinergic regulation of PMN: We will deepen our understanding of the autocrine purinergic signaling mechanisms that regulate PMN by studying upstream pathways leading to ATP release, mechanisms of ATP release and conversion of ATP to adenosine, and the roles of all puriner- gic receptors expressed by PMN. Specific Aim 2) Effect of sepsis on purinergic signaling of PMN: We will study how septic shock influences the autocrine purinergic signaling system of PMN for example by changing the expression of purinergic re- ceptors and overloading the autocrine purinergic system of PMN by ATP that is released from injured and in- flamed tissues. Specific Aim 3) Purinergic signaling as a therapeutic target: Finally, we will evaluate the feasibility of tar- geting purinergic signalin to improve outcome after sepsis. We anticipate that the proposed work will lead to entirely novel therapeutic strategies to block PMN activation and reduce SIRS and MOFS in critically ill patients.

描述（由申请人提供）：中性粒细胞活化和创伤 - 中性粒细胞 (PMN) 引起全身炎症反应 (SIRS) 和多器官衰竭综合征 (MOFS)，从而损害宿主组织。阻止 PMN 的方法可以减少 SIRS 和 MOFS，但仍缺乏对 PMN 激活机制的详细了解。该提案的目的是继续我们阐明这些机制的工作。在过去的几年里，我们的研究表明，高渗盐水 (HS) 复苏可以显着抑制 PMN 激活。我们发现 ATP 释放和通过嘌呤能受体的自分泌信号传导是 HS 可以抑制但也增强 PMN 反应的潜在分子机制。我们工作的一个意外发现是，ATP 释放和自分泌嘌呤能信号传导是 PMN 激活一般所需的更为基本的机制。我们发现中性粒细胞需要两种独立的信号来进行适当的细胞激活：（1）通过识别特定细胞外危险介质的受体产生的定性信号，以及（2）由自分泌嘌呤能信号传导产生的定量信号，调节随后的细胞反应。基于这些重要发现和我们令人兴奋的初步数据，我们假设创伤以多种方式影响 PMN 自分泌信号系统，从而导致 PMN 过度激活、SIRS 和 MOFS。受损组织释放大量 ATP 破坏 PMN 的自分泌嘌呤信号系统。创伤改变嘌呤能受体表达并扭曲中性粒细胞反应，导致炎症、SIRS、MOFS 和脓毒症。调节嘌呤能信号可以阻止这种进展。具体目标1）中性粒细胞（PMN）的自分泌嘌呤能调节：通过研究导致ATP释放的上游通路、ATP释放和ATP转化为腺苷的机制以及所有嘌呤体的作用，加深对调节中性粒细胞（PMN）的自分泌嘌呤能信号机制的理解- PMN 表达的 gic 受体。具体目标 2) 脓毒症对 PMN 嘌呤能信号的影响：我们将研究脓毒症如何影响 PMN 自分泌嘌呤能信号系统，例如通过改变嘌呤能受体的表达和 ATP 使 PMN 自分泌嘌呤能系统超载，即从受伤和发炎的组织中释放出来。具体目标 3）嘌呤能信号作为治疗靶点：最后，我们将评估以嘌呤能信号为靶点以改善脓毒症后预后的可行性。我们预计所提出的工作将带来全新的治疗策略，以阻断 PMN 激活并减少危重患者的 SIRS 和 MOFS。