A2B receptor stimulation for sepsis

总结 脓毒症是由对感染的压倒性全身炎症反应引起的医学病症。 虽然现在可以用抗生素有效地治疗潜在的感染，但没有有效的治疗方法 以控制由宿主的炎症反应引起的器官损伤。因此，败血症是导致 重症监护病房的死亡原因，是美国第十大死亡原因。细胞外 腺苷是一种生物活性的信号分子，其在脓毒症中的代谢应激部位积累。 细胞外腺苷通过结合和激活G蛋白偶联的A2 B而具有有效的抗炎作用 腺苷受体（AR）的免疫和内皮细胞表面。使用A2 BAR缺陷小鼠和 药理学拮抗剂，我们已经发现A2 BAR保护小鼠免受多微生物败血症诱导的 炎症、器官损伤和死亡率。基于这些结果，我们假设药理学 A2 BAR的刺激通过抑制炎症来保护免于脓毒性死亡和器官损伤。解决 基于这一假设，我们将研究我们开发的两种新型的、有效的和选择性的A2 BAR激动剂P453 和P517，逆转脓毒性死亡率，炎症和器官功能障碍。提案的具体目标 具体目标1。评估P453和P517对小鼠脓毒症死亡率的影响。具体目标2。划定 P453和P517在脓毒症小鼠炎症和器官损伤中的作用。因此，这一建议提出 控制和/或减轻脓毒症引起的器官损伤和死亡的新的治疗应用。

SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent anti-inflammatory effects by binding to and activating G protein-coupled A2B adenosine receptors (ARs) on the surface of immune and endothelial cells. Using A2BAR deficient mice and pharmacological antagonists, we have discovered that A2BARs protect mice against polymicrobial sepsis-induced inflammation, organ damage, and mortality. Based on these results, we hypothesize that pharmacological stimulation of A2BARs protects against septic mortality and organ injury by suppressing inflammation. To address this hypothesis, we will study the efficacy of two novel, potent and selective A2BAR agonists we developed, P453 and P517, in reversing septic mortality, inflammation, and organ dysfunction. The Specific Aims of the proposal are: Specific Aim 1. Assess the effect of P453 and P517 on mortality in murine sepsis. Specific Aim 2. Delineate the effect of P453 and P517 on inflammation and organ injury in murine sepsis. This proposal thus advances new therapeutic applications to control and/or alleviate sepsis-induced organ injury and mortality.