Adenosine in trauma and sepsis

腺苷在创伤和脓毒症中的作用

基本信息

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
项目类别：
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

项目摘要

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，形成于与创伤和败血症相关的代谢应激部位。腺苷可以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。期间在之前的资助期间，我们测试了高浓度内源性腺苷的假设有助于免疫抑制，促进细菌生长，并加重患有此类疾病的动物的死亡率腹内多种微生物败血症。由于 A2A 受体通常具有免疫抑制作用，因此我们重点关注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。我们发现内源性腺苷刺激 A2A 受体有助于遭受败血性损伤的小鼠的死亡率。 A2A 受体导致小鼠存活率下降刺激与 A2A 受体刺激增加细菌负担的能力密切相关，增强免疫细胞凋亡，并增加炎症细胞因子的产生。虽然我们的学业测试 A2A 受体的作用验证了腺苷具有潜在致命性的假设脓毒症后的免疫抑制和感染促进作用，在该研究期间进行的进一步工作之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脓毒症中腺苷受体系统的复杂调节途径，我们建议以下高度综合的具体目标：目标 1：阐明全球腺苷缺乏症对调节脓毒症期间的免疫反应。目标 2：阐明其作用和相对重要性 A1、A2B 和 A3 腺苷受体在败血症期间调节免疫。关于控制的新知识不同腺苷受体对脓毒症免疫的研究可能导致新药理学的鉴定改善败血症病程和预防死亡的方法。目标 3：阐明介导腺苷调节作用的受体和细胞内信号通路革兰氏阴性和革兰氏阳性刺激的巨噬细胞转录和分泌细胞因子细菌。