Neutrophil A2A receptors in sepsis

总结 脓毒症是严重感染并发的临床综合征。脓毒症仍然是发病的主要原因 和死亡率之间的关系。目前尚无FDA批准的治疗败血症的特定药物。 目前脓毒症的病理生理学概念表明，中性粒细胞功能的不适当调节 导致败血症中的器官衰竭和死亡率。这表现为无法控制细菌生长， 传播、持续性和继发性感染、炎症和终末器官损伤。细胞外腺苷 是一种生物活性信号分子，在脓毒症的代谢应激部位积累。细胞外 腺苷通过结合并激活G蛋白偶联的A2A腺苷而具有有效的免疫抑制作用 受体（AR）在中性粒细胞表面。A2AAR信号转导在细胞内复制了许多表型变化， 脓毒症特征性中性粒细胞，包括趋化性降低、摄取和杀伤能力降低 细菌和延迟凋亡。鉴于脓毒性中性粒细胞改变与 通过A2AAR信号转导，我们假设内源性腺苷参与脓毒症诱导的发病， 通过刺激A2AAR引起的中性粒细胞功能障碍。我们的初步数据使用两种靶向基因缺失 在盲肠结扎和穿孔诱导的脓毒症小鼠中的药理学拮抗作用已经证实， A2AAR导致细菌传播、器官损伤和死亡。我们的人类患者数据 表明血浆腺苷和中性粒细胞A2AAR表达增加，表明A2AAR增加 导致中性粒细胞功能障碍的信号传导。基于这些数据，我们假设内源性腺苷 导致脓毒症诱导的免疫失调、细菌传播、器官损伤和死亡， 中性粒细胞中的A2AAR信号传导。为了解决这个问题，我们提出了两个具体的目标。具体目标1将 描述中性粒细胞中A2AAR信号在促进细菌传播、器官损伤和 CLP诱导的小鼠败血症死亡率。具体目标2将研究A2AAR信号传导对中性粒细胞的贡献。 脓毒症患者的功能障碍。本研究的长期目标是研究靶向A2AAR信号转导 作为脓毒症患者管理的治疗选择。

SUMMARY Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis. Current concepts of the pathophysiology of sepsis suggest that inappropriate regulation of neutrophil functions contribute to organ failure and mortality in sepsis. This manifests as an inability to control bacterial growth and dissemination, persistent and secondary infections, inflammation, and end organ injury. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (ARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased chemotaxis, diminished ability to ingest and kill bacteria and delayed apoptosis. Given this similarity between septic neutrophil alterations and the ones caused by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset of neutrophil dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion and pharmacological antagonism in mice with cecal ligation and puncture-induced sepsis have confirmed that A2AARs contribute to bacterial dissemination, organ injury, and mortality. Our data with human patients demonstrate increased plasma adenosine and neutrophil A2AAR expression indicating increased A2AAR signaling leading to neutrophil dysfunction. Based on these data, we hypothesize that endogenous adenosine contributes to sepsis-induced immune dysregulation, bacterial dissemination, organ injury and mortality through A2AAR signaling in neutrophils. To address this hypothesis, we propose 2 Specific Aims. Specific Aim 1 will delineate the role of A2AAR signaling in neutrophils in contributing to bacterial dissemination, organ injury, and mortality in CLP-induced sepsis in mice. Specific Aim 2 will study the contribution of A2AAR signaling to neutrophil dysfunction in patients with sepsis. The long-term goal of this study is to pharmacologically target A2AAR signaling as a treatment option for the management of patients with sepsis.