Role of purinergic signaling in pediatric multi-organ failure

导致非常严重或多器官功能障碍的感染被称为严重脓毒症，是导致死亡的主要原因 小儿由于宿主反应受损，器官功能障碍恶化， 在病原体被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。要在这一领域取得进展，就需要更好地理解为什么 重症儿童的免疫反应受损。我们以前的工作表明，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，这会损害PMNs清除 细菌和促进PMN介导的组织损伤，导致儿科重症监护患者的MODS。 目的1：全身ATP对儿科患者MODS的作用：首先，我们将评估ATP和 脓毒症伴不同程度MODS患儿血浆腺苷水平。接下来我们就 研究这些水平如何影响PMN保护患者的功能和恶化MODS的功能。 目的2：小儿中性粒细胞的嘌呤能系统是否与MODS有关？接下来，我们将研究 儿童中性粒细胞与成人不同，其嘌呤能信号机制调节保护性 有害的PMN功能。 目的3：脓毒症相关MODS的可能治疗靶点：最后，我们将研究嘌呤能 信号传导可以被靶向以改善PMN的保护功能，并使对PMN的附带损伤最小化。 宿主器官 我们希望发现血浆ATP水平和嘌呤能信号的先天差异损害了 儿童，使他们容易受到感染。儿童常见的病原体产生溶细胞素， 增加全身ATP水平和PMN失调，阻止抗微生物宿主防御和促进 附带组织损伤和MODS阻断ATP释放或清除全身ATP是有希望的 治疗策略，以恢复中性粒细胞功能，减少感染期间严重MODS的风险。

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.