Purinergic signaling in trauma and sepsis

项目总结 脓毒症是一种临床综合征，合并严重感染。它仍然是致病的主要原因。 以及危重病人的死亡率。目前的概念表明，脓毒症的器官衰竭和死亡率是 由宿主防御和免疫系统的不适当调节引起的。这表现为无法 控制细菌的生长和传播，以及过度的炎症，这些过程相互关联和 在很大程度上是由于巨噬细胞功能障碍。危险相关分子模式(湿)S包括 一组不同的分子，它们聚集在细胞外空间，以响应细菌介导的 组织破坏、创伤和烧伤，所有这些都与脓毒症有关。三磷酸腺苷是一种主要的湿气，这是 通过连接蛋白和连接蛋白从细胞内释放到细胞外空间 炎症、感染、休克和败血症。细胞外ATP与P2受体结合并通过P2受体传递信号 调节免疫功能。我们对P2受体缺陷小鼠的初步数据，以及 药理受体和通道配体通过连接蛋白/pAnnexin通道释放ATP 以及随后的P2受体激活对于控制死亡率、细菌杀灭和传播至关重要 以及盲肠结扎和穿孔后的炎症，这是一种临床上相关的多菌败血症模型。 从机制上讲，我们证明了ATP和其中一种P2受体，即P2X4受体，通过 直接增加巨噬细胞对细菌的杀灭。根据这些数据，我们假设ATP 通过巨噬细胞上的P2受体发出信号，控制宿主对脓毒症的反应。要解决这个问题 假设，我们将追求以下具体目标：1.确定支持ATP释放的机制 在脓毒症期间。2.剖析P2X4受体刺激增强脓毒症杀伤作用的机制。 巨噬细胞产生胞外细菌。3.确定单核/巨噬细胞群 脓毒症中P2受体介导的免疫调节靶点。这里的首要目标是勾勒出 P2受体在预防严重感染中的作用，并确定这些受体是否可以 专门针对脓毒症患者的管理。

PROJECT SUMMARY Sepsis is a clinical syndrome, which complicates severe infection. It remains the leading cause of morbidity and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of host defenses and the immune system. This manifests as an inability to control bacterial growth and dissemination, and excessive inflammation, processes that are interrelated and are due, in a large part, to macrophage dysfunction. Danger-associated molecular patterns (DAMP)s comprise a diverse group of molecules that accumulate in the extracellular space in response to bacteria-mediated tissue destruction, trauma, and burns, all of which are associated with sepsis. ATP is a major DAMP, which is released from the intracellular into the extracellular space through connexins and pannexins during inflammation, infection, shock, and sepsis. Extracellular ATP binds to and signals through P2 receptors to modulate immune function. Our preliminary data with mice deficient in P2 receptors, as well as pharmacological receptor and channel ligands establish that ATP release through connexin/pannexin channels and subsequent P2 receptor activation are crucial for the control of mortality, bacterial killing and dissemination and inflammation following cecal ligation and puncture, a clinically relevant model of polymicrobial sepsis. Mechanistically, we show that ATP and one of the P2 receptors, the P2X4 receptor, protects against sepsis by directly increasing the killing of bacteria by macrophages. Based on these data, we hypothesize that ATP governs the host's response to sepsis by signaling through P2 receptors on macrophages. To address this hypothesis, we will pursue the following Specific Aims: 1. Identify the mechanisms that support ATP release during sepsis. 2. Dissect the mechanisms by which P2X4 receptor stimulation augments the killing of sepsis- causing extracellular bacteria by macrophages. 3. Identify the monocyte/macrophage populations that are targets of P2 receptor-mediated immune regulation in sepsis. The overarching goal here is to delineate the role of P2 receptors in protecting against severe infection and to determine whether these receptors can be specifically targeted to manage patients with sepsis.