Neutrophil activation and trauma

中性粒细胞激活和创伤

• 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
• 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

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）：中性粒细胞的激活和创伤 - 中性粒细胞（PMN）导致全身性炎症反应（SIRS）和多器官衰竭综合症（MOF）损害宿主组织。阻止PMN的方法可以减少SIRS和MOF，但仍缺少有关PMN激活所涉及的机制的详细知识。该提案的目的是继续我们阐明这些机制的工作。在过去的几年中，我们的研究表明，高渗盐水（HS）复苏可以显着抑制PMN激活。我们确定通过嘌呤能受体释放和自分泌信号传导是基本的分子机制，HS可以抑制，但也可以增强PMN反应。我们工作的一个意外发现是，ATP释放和自分泌嘌呤能信号是一种更基本的机制，通常是PMN激活的。我们发现，PMN需要两个单独的信号才能进行适当的细胞激活：（1）通过识别特定细胞外危险介体的受体定性信号，以及（2）由自分泌嘌呤能信号传导产生的定量信号，这些信号调节后续细胞重复。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的自分泌信号系统，从而导致PMN激活过多，SIRS和MOF。从受损组织中释放大量ATP会破坏PMN的自分泌puiner-gus-gic信号传导系统。创伤会改变嘌呤能受体的表达，并扭曲PMN反应，炎症，SIRS，MOF和败血症。调节嘌呤能信号传导可以防止这种进展。具体目的1）PMN的自分泌嘌呤能调节：我们将通过研究导致ATP释放的上游途径，ATP释放的机制以及将ATP转换为腺苷转化为腺苷的上游途径来加深对PMN调节PMN的理解，以及PMN表达的所有Putiner-GIC受体的作用。具体目的2）败血症对PMN的嘌呤能信号传导的影响：我们将研究败血性休克如何通过改变受伤和染色的组织中释放出ATP的ATP的ATP来影响PMN的自分泌嘌呤能信号传导系统。具体目标3）嘌呤能信号传导是一种治疗靶标：最后，我们将评估焦油嘌呤能信号蛋白的可行性，以改善败血症后的预后。我们预计拟议的工作将导致完全新颖的治疗策略，以阻止重症患者的PMN激活并减少SIRS和MOF。