Adenosine in trauma and sepsis

嘌呤核苷腺苷是一种生物活性的细胞外信号分子，在 代谢应激的部位与创伤和脓毒症相关。腺苷可以与四种细胞中的一种或多种结合 表面受体(A1、A2A、A2B和A3)，通过这些受体发挥不同的免疫调节作用。在.期间 在之前的资助期，我们测试了高浓度内源性腺苷 有助于免疫抑制，促进细菌生长，并恶化动物的死亡率 腹内多菌败血症。因为A2A型受体通常具有免疫抑制作用，所以我们关注 这些受体在介导腺苷免疫抑制作用中的作用 败血症。我们已经发现，内源性腺苷刺激A2A受体有助于 小鼠遭受败血症侮辱后的死亡率。这降低了由A2a受体引起的小鼠的存活率 刺激与A2a受体刺激增加细菌负荷的能力密切相关， 促进免疫细胞凋亡，增加炎性细胞因子的产生。虽然我们的研究 测试A2a受体的作用证实了腺苷具有潜在致命性的假设 脓毒症后的免疫抑制和感染促进作用，在 以前的循环表明，腺苷在脓毒症的病理生理学中扮演着更复杂的角色。因此，要 更好地理解脓毒症中腺苷受体系统的复杂调控途径，我们建议 以下高度整合的特定目标：目标1：阐明全球腺苷缺乏对 调节脓毒症时的免疫反应。目标2：阐明以下各项的作用和相对重要性 A1、A2B和A3腺苷受体在脓毒症免疫调节中的作用关于控制的新知识 不同的腺苷受体对脓毒症免疫的研究可能导致新的药理作用的鉴定 改善脓毒症病程和预防死亡的途径。目标3：阐明 腺苷调节血管内皮细胞生长的受体和细胞内信号通路 革兰氏阴性和革兰氏阳性刺激巨噬细胞转录和分泌细胞因子 细菌。

The purine nucleoside adenosine is a biologically active extracellular signaling molecule that is formed at sites of metabolic stress associated 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. During the previous funding period, we tested the hypothesis that high concentrations of endogenous adenosine contribute to immunosuppression, promote bacterial growth, and worsen mortality in animals with intraabdominal polymicrobial sepsis. Because A2A receptors are generally immunosuppressive, we focused our investigations on the role of these receptors in mediating the immunosuppressive effects of adenosine in sepsis. 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 stimulation to increase bacterial burden, to augment immune cell apoptosis, and to increase production of inflammatory cytokines. Although our studies testing the role of A2A receptors validate the hypothesis that adenosine has potentially lethal immunosuppressive and infection-promoting effects following sepsis, further work performed during the previous cycle suggests that adenosine has a more complex role in the pathophysiology of 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 effect of global adenosine deficiency in regulating immune responsiveness during sepsis. Aim 2: Elucidate the role and the relative importance of A1, A2B and A3 adenosine receptors in regulating immunity during sepsis. 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. Aim 3: 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.