Neutrophil A2A receptors in sepsis

摘要 脓毒症是一种临床综合征，合并严重感染。脓毒症仍然是发病率的主要原因 以及危重病人的死亡率。目前还没有FDA批准的治疗脓毒症的特效药。 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 导致脓毒症的器官衰竭和死亡。这表现为无法控制细菌生长和 传播、持续性和继发性感染、炎症和最终器官损伤。胞外腺苷 是一种生物活性的信号分子，聚集在脓毒症的代谢应激部位。胞外 腺苷通过结合和激活G蛋白偶联的A2A腺苷而具有强大的免疫抑制作用 中性粒细胞表面的受体(AR)。A2AAR信号重现了许多表型变化 中性粒细胞是败血症的特征，包括趋化性降低，摄取和杀死的能力减弱 细菌和延缓的细胞凋亡。鉴于败血症中性粒细胞改变与引起的 通过A2AAR信号转导，我们推测内源性腺苷参与了脓毒症的发病。 通过刺激A2AARs导致中性粒细胞功能障碍。我们的初步数据使用了两种定向基因缺失 而对盲肠结扎和穿刺性脓毒症小鼠的药理拮抗作用已证实 A2AARs会导致细菌传播、器官损伤和死亡。我们对人类患者的数据 显示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。基于这些数据，我们假设内源性腺苷 通过以下途径导致脓毒症引起的免疫失调、细菌传播、器官损伤和死亡 中性粒细胞中的A2AAR信号。为了解决这一假设，我们提出了两个具体目标。具体目标1将 阐明A2AAR信号在中性粒细胞促进细菌传播、器官损伤和 CLP诱导的小鼠脓毒症的死亡率。特定目标2将研究A2AAR信号对中性粒细胞的作用 脓毒症患者的功能障碍。这项研究的长期目标是以A2AAR信号为药理靶点 作为脓毒症患者治疗的一种选择。

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.