Adenosine in trauma and sepsis

腺苷在创伤和脓毒症中的作用

• 批准号: 7429510
• 负责人: George HASKO
• 金额: $ 27.21万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429510
• 关键词: Adenosine; Adenosine A3 Receptor; Animals; Apoptosis; Azathioprine; Binding; Cell Surface Receptors; Cells; Cessation of life; Complex; Disease; Enzymes; Functional disorder; Funding; Generations; 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; Mediator of activation protein; Metabolic Pathway; Metabolic stress; Mus; Organ; Pathway interactions; Physiological; Production; Puncture procedure; Purine Nucleosides; Purinergic P1 Receptors; Regulatory Pathway; Relative (related person); Reporting; Role; Sepsis; Signal Pathway; Signaling Molecule; Site; Stimulus; Stress; System; Testing; Therapeutic immunosuppression; Trauma; Work; base; cytokine; extracellular; immunoregulation; insight; macrophage; mortality; novel; prevent; receptor; receptor expression; septic

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.

嘌呤核苷腺苷是一种具有生物活性的细胞外信号分子， 与创伤和败血症相关的代谢应激部位。腺苷可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。期间 在前一个资助期，我们测试了高浓度的内源性腺苷 有助于免疫抑制，促进细菌生长，并使动物死亡率恶化， 腹腔内多种微生物败血症。由于A2A受体通常具有免疫抑制作用，我们将重点放在 我们对这些受体在介导腺苷免疫抑制作用中的作用的研究， 败血症我们已经发现用内源性腺苷刺激A2A受体有助于 经受脓毒性损伤的小鼠的死亡率。这降低了A2A受体引起的小鼠存活率 刺激与A2A受体刺激增加细菌负荷的能力密切相关， 增加免疫细胞凋亡和增加炎性细胞因子的产生。虽然我们的研究 测试A2A受体的作用验证了腺苷具有潜在致死性的假设。 免疫抑制和感染促进作用后，败血症，进一步的工作进行期间， 先前的周期表明腺苷在脓毒症的病理生理学中具有更复杂的作用。从而 为了更好地了解腺苷受体系统在脓毒症中的复杂调节途径，我们建议 以下高度集成的具体目的：目的1：阐明全球腺苷缺乏症的影响， 调节脓毒症期间的免疫应答。目标2：阐明以下方面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 脓毒症免疫的不同腺苷受体可能导致新的药理学鉴定 改善脓毒症病程和预防脓毒症死亡的方法。目标3：阐明 受体和细胞内信号通路介导的调节作用，腺苷对 革兰氏阴性和革兰氏阳性细胞刺激巨噬细胞后细胞因子的转录和分泌 细菌