Role of purinergic signaling in pediatric multi-organ failure

导致严重或多器官功能障碍的感染称为严重败血症，是导致死亡的主要原因。 在孩子们身上。由于宿主反应受损，甚至可以进展，导致器官功能障碍恶化 在病原体清除后。大多数改善败血症患者预后的治疗方法都有 结果令人失望。这一领域的进展需要更好地理解为什么 危重儿童的免疫反应受损。我们之前的工作揭示了内源性ATP 释放和自分泌嘌呤能信号机制调节中性粒细胞(PMN)功能 外源性三磷酸腺苷和腺苷干扰了中性粒细胞的正常功能。基于这项工作，我们假设 感染和组织损伤使血浆中的三磷酸腺苷水平升高，从而削弱了中性粒细胞清除 细菌并促进中性粒细胞介导的组织损伤，导致儿科重症监护患者出现多器官功能障碍综合征。 目的1：全身性三磷酸腺苷在儿科患者多器官功能障碍综合征中的作用：首先，我们将评估三磷酸腺苷和 小儿败血症合并不同程度MODS患者的血浆腺苷水平。接下来，我们将 研究这些水平如何影响保护患者的PMN功能和加重MODS的功能。 目的2：儿科中性粒细胞的嘌呤能系统是否参与了MODS？接下来，我们将研究如何 儿童的中性粒细胞在调节保护性的嘌呤能信号机制方面不同于成人。 和有害的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 可以针对信号转导来改善PMN的保护功能，并将附带损害降至最低 寄主器官。 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中性粒细胞。 儿童，使他们容易受到感染。儿童中常见的病原体产生细胞溶血素，进一步 增加全身性ATP水平和PMN失调，防止抗菌宿主防御和促进 附带组织损伤和多器官功能障碍综合征。阻断三磷酸腺苷的释放或清除全身性三磷酸腺苷是有希望的 恢复PMN功能和降低感染期间严重MODS风险的治疗策略。

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.