Early Diagnosis and Novel Treatment of Sepsis

脓毒症的早期诊断和新疗法

• 批准号: 9898317
• 负责人: Frank Joseph Jacono
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898317
• 关键词: Address; Adult Respiratory Distress Syndrome; Affect; Animal Model; Animal Testing; Anti-Inflammatory Agents; Antibiotics; Appearance; Back; Biological Models; Brain Stem; Cardiac; Cardiovascular system; Cell Nucleus; Cessation of life; Clinical; Clinical Trials; Coagulation Process; Consensus; Coupling; Data; Disease; Disease Progression; Early Diagnosis; Early identification; Escherichia coli; Fibrin; Functional disorder; Heart Rate; Homeostasis; Human; Immune; Immune response; Incidence; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Knowledge; Maps; Mediating; Microinjections; Military Personnel; Morbidity - disease rate; Nerve; Neuroimmune; Organ; Organ failure; Outcome Measure; Pathway interactions; Patients; Pattern; Peripheral; Peritoneal; Pharmaceutical Preparations; Physiological; Pilot Projects; Pre-Clinical Model; Prevention; Production; Publishing; Rattus; Reflex action; Regulation; Respiration; Risk; Rodent Model; Sepsis; Septic Shock; Severities; Severity of illness; Standardization; Synapses; Syndrome; System; Systemic infection; Testing; Therapeutic; Time; Update; Vasoconstrictor Agents; Veterans; Work; base; care costs; cytokine; experimental study; high risk; immunoregulation; implantation; improved; improved outcome; indexing; inflammatory marker; lung injury; mortality; neuroinflammation; neuroregulation; novel; novel therapeutics; organ growth; pre-clinical; respiratory; response; sensory feedback; systemic inflammatory response; translational study

Sepsis is a common and devastating syndrome induced by infection and results from an uncontrolled inflammatory response. As highlighted in the updated consensus definition for sepsis published this year (JAMA 23; 315:801), the initial inflammatory response to infection is beneficial; but this protective response can become dysregulated and harmful. The theoretical tipping-point at which inflammation transitions from defending to destroying homeostasis is not predictable, but it identifies the point at which the risks for sepsis-related organ failure and mortality increase significantly. Consequently, improving sepsis survival requires understanding the neuro-immune interactions that define this transition, developing indices to identify this point, and testing novel therapeutics to tip the system back towards a beneficial response. The proposed project addresses each of these important knowledge gaps. Our general hypothesis is that a destructive loop exists such that peripheral inflammation evokes brainstem inflammation during sepsis, which is permissive for immune dysregulation and organ dysfunction; ultimately leading to further peripheral inflammation. In support of this hypothesis, we discovered that brainstem inflammation develops progressively in cardiorespiratory control nuclei in a rodent model of sepsis; leading to decreased efficacy of sensory feedback, reduced heart rate and ventilatory pattern variabilities, and uncoupling of autonomic and respiratory rhythms. Inhibiting brainstem cytokine expression reversed many of these changes. Furthermore, our preliminary results from a clinical trial involving patients with vasopressor-dependent septic shock identified that cardiac beat-to-beat dynamics predicted 28-day mortality with higher accuracy than standard clinical severity of illness scores. These findings underlie our specific hypotheses: 1) brainstem inflammation itself causes the loss of regulation of autonomic homeostasis and propagates the disordered inflammatory response during sepsis; and 2) cardiorespiratory uncoupling and the appearance of unstable patterns define a tipping point to a dysregulated host immune response that precedes and promotes the development of organ failure. We will test these hypotheses in an animal model of E. coli sepsis. We also propose a pre-clinical, pilot study of vagal nerve stimulation (VNS), applied as the inflammatory response tips from beneficial to harmful, as a novel `electroceutical' therapy to modulate the neuro-inflammatory response. Our planned experiments will establish a novel pathway for sepsis progression and identify markers to guide the use of VNS to oppose disease progression and improve outcomes in sepsis.

脓毒症是由感染引起的一种常见的毁灭性综合征， 不受控制的炎症反应。正如更新的共识定义所强调的那样， 脓毒症（JAMA 23; 315：801），感染的初始炎症反应是 有益的;但这种保护性反应可能会变得失调和有害。理论 炎症从防御转变为破坏体内平衡的临界点， 可预测，但它确定了脓毒症相关器官衰竭的风险， 死亡率大幅上升。因此，提高脓毒症生存率需要了解 定义这种转变的神经免疫相互作用，开发指标来识别这一点， 并测试新的治疗方法，使系统回到有益的反应。的 拟议的项目解决了这些重要的知识差距。我们的假设是 存在一个破坏性的环，使得外周炎症引起脑干炎症， 在败血症期间，这是允许免疫失调和器官功能障碍的;最终 导致进一步的外周炎症。为了支持这一假设，我们发现， 脑干炎症在啮齿类动物的心肺控制核团中进行性发展 脓毒症模型;导致感觉反馈的功效降低，心率降低， 呼吸模式的变异性，以及自主神经和呼吸节律的解耦。抑制 脑干细胞因子表达逆转了许多这些变化。此外，我们的初步 一项涉及血管加压素依赖性脓毒性休克患者的临床试验结果表明， 心脏搏动动力学预测28天死亡率的准确性高于 标准临床疾病严重程度评分。这些发现支持了我们的特定假设：1） 脑干炎症本身导致自主稳态调节的丧失， 传播脓毒症期间的紊乱的炎症反应;和2）心肺 脱钩和不稳定模式的出现定义了一个临界点， 先于并促进器官衰竭发展的宿主免疫反应。我们将 在E.大肠杆菌败血症。我们还提出了一个临床前，试点 迷走神经刺激（VNS）的研究，作为炎症反应提示， 有益于有害的，作为一种新的“电"疗法，以调节神经炎症 反应我们计划的实验将建立脓毒症进展的新途径， 识别标志物以指导VNS的使用，以对抗疾病进展并改善结局 败血症