Adenosine in trauma and sepsis

描述（由申请人提供）：嘌呤核苷腺苷是一种生物活性细胞外信号分子，在与创伤和脓毒症相关的代谢应激部位形成。腺苷可以与四种细胞表面受体（A1，A2A，A2B和A3）中的一种或多种结合，通过这些受体发挥不同的免疫调节作用。我们已经发现，内源性腺苷刺激A2A受体有助于感染性损伤小鼠的死亡率。由A2A受体刺激引起的小鼠存活率降低与A2A受体活化增加细菌负荷、增强免疫细胞凋亡和增加炎性细胞因子产生的能力密切相关。进一步的研究表明，腺苷在败血症的病理生理学中具有更复杂的作用。具体而言，取决于哪些受体被激活，腺苷差异调节免疫功能。例如，内源性腺苷对A2B受体的激活减少了患有脓毒症的小鼠中炎性细胞因子的产生。因此，为了更好地了解腺苷受体系统在脓毒症中的复杂调节途径，我们提出了以下高度集成的具体目标：目标1：阐明A1，A2A，A2B和A3腺苷受体在脓毒症期间调节免疫的作用和相对重要性。目标二：阐明介导腺苷对革兰氏阴性菌和革兰氏阳性菌刺激的巨噬细胞的细胞因子转录和分泌的调节作用的受体和细胞内信号传导途径。关于不同腺苷受体控制脓毒症免疫的新知识可能会导致发现改善病程和预防脓毒症死亡的新型药理学方法。相关性：通过阐明腺苷受体在脓毒症期间如何调节免疫和器官功能，我们可以利用这些信息开发靶向腺苷受体的新药理学方法来治疗脓毒症患者。

DESCRIPTION (provided by applicant): The purine nucleoside adenosine is a biologically active extracellular signaling molecule that is formed at sites of metabolic stress associated with trauma and sepsis. Adenosine can bind to one or more of four cell surface receptors (A1, A2A, A2B, and A3) through which it exerts varying immunomodulatory effects. We have discovered that stimulation of A2A receptors with endogenous adenosine contributes to the mortality of mice subjected to a septic insult. This decreased survival of mice caused by A2A receptor stimulation was tightly associated with a capacity of A2A receptor activation to increase bacterial burden, to augment immune cell apoptosis, and to increase production of inflammatory cytokines. Further work performed suggests that adenosine has a more complex role in the pathophysiology of sepsis. Specifically, depending on which receptors are activated, adenosine differentially modulates immune function. For example, activation of A2B receptors by endogenous adenosine decreases the production of inflammatory cytokines in mice suffering from sepsis. Thus to better understand the complex regulatory pathways of the adenosine receptor system in sepsis, we propose the following highly integrated Specific Aims: Aim 1: Elucidate the role and relative importance of A1, A2A, A2B and A3 adenosine receptors in regulating immunity during sepsis. Aim 2: Elucidate the receptors and intracellular signaling pathways that mediate the modulatory effects of adenosine on the transcription and secretion of cytokines by macrophages stimulated with Gram-negative and Gram-positive bacteria. New knowledge about the control of septic immunity by distinct adenosine receptors could lead to the identification of novel pharmacological approaches for ameliorating the course of disease and preventing death in sepsis. RELEVANCE: By elucidating how adenosine receptors modulate immune and organ function during sepsis, we can utilize this information to develop new pharmacologic approaches targeting adenosine receptors to treat patients suffering from sepsis.