Adenosine in trauma and sepsis

腺苷在创伤和脓毒症中的作用

• 批准号: 7370902
• 负责人: George HASKO
• 金额: $ 27.46万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370902
• 关键词: Adenosine; Adenosine A3 Receptor; Animals; Apoptosis; Binding; Cell Surface Receptors; Cell physiology; Cells; Cessation of life; Complex; Disease; Functional disorder; Funding; GTP-Binding Proteins; Genetic; Genetic Transcription; Gram-Positive Bacteria; Growth; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Injury; Investigation; Ischemia; Knowledge; Laboratories; Lead; Ligation; Mediating; Metabolic stress; Mitogen-Activated Protein Kinases; Mus; Organ; Pathway interactions; Patients; Pattern recognition receptor; Physiological; Process; Production; Puncture procedure; Purine Nucleosides; Purinergic P1 Receptors; Receptor Activation; Regulatory Pathway; Relative (related person); Reporting; Role; Sepsis; Signal Pathway; Signaling Molecule; Site; Stimulus; System; Testing; Therapeutic immunosuppression; Trauma; Work; base; cytokine; extracellular; immune function; immunoregulation; insight; macrophage; mortality; novel; prevent; receptor; receptor expression; receptor function; response to injury; septic; transcription factor

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.

描述（由申请人提供）：嘌呤核苷腺苷是一种具有生物活性的细胞外信号分子，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。我们发现内源性腺苷刺激 A2A 受体会导致遭受败血症的小鼠死亡。 A2A 受体刺激引起的小鼠存活率下降与 A2A 受体激活增加细菌负荷、增强免疫细胞凋亡和增加炎症细胞因子产生的能力密切相关。进一步的研究表明，腺苷在脓毒症的病理生理学中具有更复杂的作用。具体来说，根据激活的受体，腺苷可以差异性地调节免疫功能。例如，内源性腺苷激活 A2B 受体会减少脓毒症小鼠炎症细胞因子的产生。因此，为了更好地理解脓毒症中腺苷受体系统的复杂调节途径，我们提出以下高度整合的具体目标： 目标 1：阐明 A1、A2A、A2B 和 A3 腺苷受体在脓毒症期间调节免疫中的作用和相对重要性。目标 2：阐明介导腺苷对革兰氏阴性和革兰氏阳性细菌刺激的巨噬细胞转录和分泌细胞因子的调节作用的受体和细胞内信号通路。关于不同腺苷受体控制脓毒症免疫的新知识可能会导致确定改善脓毒症病程和预防死亡的新药理学方法。相关性：通过阐明脓毒症期间腺苷受体如何调节免疫和器官功能，我们可以利用这些信息开发针对腺苷受体的新药理学方法来治疗脓毒症患者。