Early Diagnosis and Novel Treatment of Sepsis

脓毒症是一种由感染引起的常见和破坏性的综合征，由 失控的炎症反应。如更新的协商一致定义所强调的 脓毒症今年发表(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控和有害。理论上的 炎症从防御过渡到破坏内稳态的临界点不是 但它确定了脓毒症相关器官衰竭的风险和 死亡率显著增加。因此，提高脓毒症的存活率需要了解 神经免疫相互作用定义了这一转变，开发了识别这一点的指数， 以及测试新的疗法，以使系统重新走向有益的反应。这个 拟议的项目解决了这些重要的知识差距。我们的一般假设是 存在一种破坏性循环，使外周炎症引起脑干炎症 在脓毒症期间，这是免疫失调和器官功能障碍的许可；最终 导致进一步的外周炎症。为了支持这一假设，我们发现 啮齿动物心肺控制核团中脑干炎症的进行性发展 败血症模型；导致感觉反馈效果降低，心率减慢和 呼吸模式的变化，自主神经和呼吸节律的解偶联。抑制 脑干细胞因子的表达逆转了许多这些变化。此外，我们初步的 一项涉及血管加压素依赖型感染性休克患者的临床试验结果证实 心脏搏动动力学预测28天死亡率的准确性高于 疾病严重程度的标准临床评分。这些发现构成了我们具体假设的基础：1) 脑干炎症本身会导致自主神经稳态调节的丧失和 在脓毒症期间传播紊乱的炎症反应；和2)心肺 解偶联和不稳定模式的出现定义了一个转折点 先于并促进器官衰竭发展的宿主免疫反应。我们会 在大肠杆菌败血症的动物模型中测试这些假设。我们还建议进行临床前、试点 迷走神经刺激(VNS)作为炎症反应提示的研究 有益于有害，作为一种新的调节神经炎性疾病的电针疗法 回应。我们计划的实验将为脓毒症的进展和 确定标记物以指导使用VNS来阻止疾病进展和改善预后 在败血症中。

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.