Role of purinergic signaling in pediatric multi-organ failure

嘌呤能信号在儿童多器官衰竭中的作用

• 批准号: 10829152
• 负责人: WOLFGANG G JUNGER
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10829152
• 关键词: Role; purinergic; signaling; pediatric; multi

Infection leading to very severe or multiple organ dysfunction is called severe sepsis, a leading cause of death in children. Worsening organ dysfunction develops due to an impaired host response that can progress even after clearance of the pathogen. Most therapeutic approaches to improve outcome in septic patients have resulted in disappointment. Progress in this field requires a better understanding of the reasons why the immune response in critically ill children is impaired. Our previous work has revealed that endogenous ATP release and autocrine purinergic signaling mechanisms regulate neutrophil (PMN) functions and that exogenous ATP and adenosine disrupt normal PMN functions. Based on this work, we hypothesize that infections and tissue damage elevate plasma ATP levels, which impairs the ability of PMNs to eliminate bacteria and promotes PMN-mediated tissue damage that causes MODS in pediatric critical care patients. Aim 1: Contribution of systemic ATP to MODS in pediatric patients: First, we will assess ATP and adenosine levels in the plasma of pediatric patients with sepsis with varying degrees of MODS. Next, we will study how these levels influence PMN functions that protect patients and functions that worsening MODS. Aim 2: Does the purinergic system of pediatric PMNs contribute to MODS? Next, we will study how the PMNs of children differ from adults with regard to the purinergic signaling mechanisms that regulate protective and harmful PMN functions. Aim 3: Possible therapeutic targets for sepsis-related MODS: Finally, we will study how purinergic signaling can be targeted to improve the protective functions of PMNs and to minimize collateral damage to host organs. We expect to find that innate differences in plasma ATP levels and purinergic signaling impair PMNs of children, making them susceptible to infections. Common pathogens in children produce cytolysins that further increase systemic ATP levels and PMN dysregulation, preventing antimicrobial host defenses and promoting collateral tissue damage and MODS. Blocking ATP release or removal of systemic ATP are promising therapeutic strategies to restore PMN function and reduce the risks of severe MODS during infection.

导致非常严重或多器官功能障碍的感染称为严重脓毒症，是死亡的主要原因 在儿童中。由于宿主反应受损而导致器官功能障碍恶化，甚至可能进一步恶化 病原体清除后。大多数改善脓毒症患者预后的治疗方法 结果令人失望。这一领域的进展需要更好地理解其原因 危重儿童的免疫反应受损。我们之前的工作表明，内源性 ATP 释放和自分泌嘌呤能信号机制调节中性粒细胞 (PMN) 功能 外源性 ATP 和腺苷会破坏正常的 PMN 功能。基于这项工作，我们假设 感染和组织损伤会升高血浆 ATP 水平，从而损害 PMN 消除病毒的能力 细菌并促进 PMN 介导的组织损伤，从而导致儿科重症监护患者的 MODS。 目标 1：全身 ATP 对儿科患者 MODS 的贡献：首先，我们将评估 ATP 和 患有不同程度 MODS 的脓毒症儿科患者血浆中的腺苷水平。接下来，我们将 研究这些水平如何影响 PMN 保护患者的功能以及使 MODS 恶化的功能。 目标 2：儿童中性粒细胞的嘌呤能系统是否会导致 MODS？接下来我们将研究如何 儿童中性粒细胞在调节保护性的嘌呤能信号机制方面与成人不同。 和有害的 PMN 功能。 目标 3：脓毒症相关 MODS 的可能治疗靶点：最后，我们将研究嘌呤能如何 信号传导可以有针对性地改善中性粒细胞的保护功能，并最大限度地减少对中性粒细胞的附带损害 宿主器官。 我们期望发现血浆 ATP 水平和嘌呤能信号的先天差异会损害 PMN 儿童，使他们容易受到感染。儿童常见病原体产生的溶细胞素进一步 增加全身 ATP 水平和 PMN 失调，防止抗菌宿主防御并促进 附带组织损伤和MODS。阻断 ATP 释放或去除全身 ATP 是有希望的 恢复 PMN 功能并降低感染期间发生严重 MODS 风险的治疗策略。