Adenosine and Oxygen Modulate Antimicrobial Defenses

腺苷和氧调节抗菌防御

• 批准号: 8085386
• 负责人: Daniel G. Remick
• 金额: $ 31.84万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085386
• 关键词: Abdomen; Acute; Adenosine; Adenosine A2B Receptor; Adverse effects; Animal Model; Antibiotics; Bacteria; Bacterial Infections; Biological Markers; Cell physiology; Cells; Cessation of life; Chronic Phase; Code; Coupled; Data; Disease; Documentation; Environment; Failure; Goals; Greater sac of peritoneum; Human; Hypoxia; Immune; Immune response; Immunity; Immunoassay; Immunosuppression; Inflammation; Inflammation Mediators; Inflammatory Response; Knockout Mice; Knowledge; Ligation; Liquid substance; Lung; Mediating; Methodology; Methods; Modality; Modeling; Morbidity - disease rate; Mus; Outcome; Oxygen; Pathway interactions; Patients; Peritoneum; Pharmaceutical Preparations; Phase; Pneumonia; Production; Pseudomonas; Publishing; Puncture procedure; Purinergic P1 Receptors; Reagent; Resuscitation; Role; Sepsis; Specificity; Supplementation; Surgical incisions; Time; Tissues; Trauma; antimicrobial; cell killing; chemokine; clinically relevant; cytokine; effective therapy; extracellular; improved; insight; knockout gene; mortality; mouse model; novel; novel strategies; oxygen toxicity; prevent; receptor; research study; response; septic; treatment strategy

DESCRIPTION (provided by applicant): Therapies to reduce the mortality of sepsis still need to be developed due to the high morbidity and mortality of the disease. We have strong preliminary data indicating that local tissue hypoxia coupled with an increase in extracellular adenosine suppresses the ability of cells to eradicate bacteria. Failure to appropriately control bacteria results in excessive and prolonged inflammation. This proposal will evaluate 2 different modalities to treat sepsis by 1) blocking specific adenosine receptors and 2) providing supplemental oxygen. To increase the applicability of the findings, 4 different murine sepsis models will be studied. The first model is the acute phase of sepsis present in the first four days after cecal ligation and puncture (CLP) and the second model is the chronic phase of sepsis where deaths occur after day five. The third sepsis model evaluates the treatment modalities in a model of trauma (abdominal incision) plus Pseudomonas pneumonia. The fourth will use the recently developed humanized mouse model of sepsis induced by CLP. Our first specific aim will closely study the role of adenosine in sepsis by treating septic mice with specific A2A and A2B receptor antagonists. We will confirm the specificity of these findings using A2A and A2B receptor knockout mice. A novel approach of using biomarkers to direct blockade of the adenosine receptors will also be employed. The second aim will verify that local hypoxia occurs during sepsis and provide supplemental oxygen to improve outcome. The third aim will combine adenosine receptor blockade with supplemental oxygen to determine the potential synergistic interactions of the treatments. The fourth specific aim will closely examine the cellular mechanisms of how these treatment strategies improve outcome by determining the augmented pathways that result in improved bacterial clearance. If successful, this application offers both new treatment strategies for sepsis, and the mechanistic knowledge to understand why they are effective. PUBLIC HEALTH RELEVANCE: The project will try and find new ways to treat severe bacterial infections. We believe that providing a small amount of oxygen and blocking receptors on cells will help these cells kill the bacteria.

描述（由申请人提供）：由于脓毒症的高发病率和死亡率，仍需要开发降低脓毒症死亡率的疗法。我们有强有力的初步数据表明，局部组织缺氧加上细胞外腺苷的增加抑制了细胞消灭细菌的能力。未能适当控制细菌会导致过度和长期的炎症。本提案将通过1）阻断特异性腺苷受体和2）提供补充氧气来评价2种不同的脓毒症治疗方式。为了增加研究结果的适用性，将研究4种不同的鼠脓毒症模型。第一个模型是盲肠结扎和穿孔（CLP）后前四天出现的脓毒症急性期，第二个模型是脓毒症慢性期，其中在第五天后发生死亡。第三个脓毒症模型评价了创伤（腹部切口）加假单胞菌肺炎模型中的治疗方式。第四部分将使用最近开发的CLP诱导的脓毒症的人源化小鼠模型。我们的第一个具体目标是通过用特异性A2A和A2B受体拮抗剂治疗脓毒症小鼠来密切研究腺苷在脓毒症中的作用。我们将使用A2A和A2B受体敲除小鼠证实这些发现的特异性。还将采用使用生物标志物直接阻断腺苷受体的新方法。第二个目标是证实败血症期间发生局部缺氧，并提供补充氧气以改善结局。第三个目标将结合联合收割机腺苷受体阻断与补充氧气，以确定治疗的潜在协同相互作用。第四个具体目标将通过确定导致细菌清除改善的增强途径，密切研究这些治疗策略如何改善结果的细胞机制。如果成功，该应用将为败血症提供新的治疗策略，并提供了解其有效原因的机制知识。 公共卫生相关性：该项目将尝试寻找治疗严重细菌感染的新方法。我们认为，提供少量氧气并阻断细胞上的受体将有助于这些细胞杀死细菌。