Modeling Brainstem Inflammation's Role in Systemic Dysfunction during Sepsis

模拟脑干炎症在脓毒症期间全身功能障碍中的作用

基本信息

批准号：
10002328
负责人：
THOMAS E DICK
金额：
$ 61.32万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002328
关键词：
Affect Bayesian Modeling Bilateral Biological Biological Markers Bioperiodicity Blood Brain Stem Breathing Cause of Death Cell Nucleus Clinical Coagulation Process Computer Models Coupling Critical Illness Data Data Analyses Dependence Diagnosis Early Diagnosis Early identification Endotoxemia Escherichia coli Fibrin Frequencies Functional disorder Goals Heart Rate Homeostasis Human Implant Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intensive Care Units Interleukin-1 beta Life Link Measures Medical Microinjections Modeling Multiple Organ Failure Nerve Neural Network Simulation Neurons Neurophysiology - biologic function Observational Study Organ Pathologic Pathway Analysis Patients Pattern Peripheral Physiological Pontine structure Pressoreceptors Prognostic Marker Public Health Pulse Pressure Rattus Regulation Research Personnel Respiration Risk Role Sepsis Septic Shock Septicemia Severity of illness Sinus Arrhythmia Systemic Inflammatory Response Syndrome Systemic infection Testing Therapeutic Intervention Time Tissues Translating Visceral analytical tool base cytokine experimental study gram-negative sepsis heart rate variability indexing mortality risk network dysfunction neural network neuroinflammation neuromechanism neurophysiology neuroregulation nucleus ambiguus outcome forecast prevent prospective relating to nervous system respiratory sensory feedback septic septic patients therapeutic cytokines therapeutic target

项目摘要

Sepsis is systemic infection accompanied by an uncontrolled inflammatory response; a condition that can deteriorate rapidly. Early diagnosis is critical for survival. Heart rate variability (HRV), a proposed biomarker for sepsis, predicts its prognosis but is too nonspecific to make a diagnosis. Often HRV is quantified by its power spectra, its variability in the frequency domain; the `high-frequency' component reflects respiratory modulation of vagal nerve activity. Computational deterministic models of the brainstem cardiorespiratory control networks have proposed plausible neural mechanisms for the vago-respiratory coupling. In contrast to HRV, Dynamic Network Analysis (DyNA) and Dynamic Bayesian Network (DyBN) models are highly specific and successful in identifying a `tipping point' in sepsis, i.e. when a controlled inflammatory response becomes uncontrolled but its many variables are hard to measure. Recently, we identified that the brainstem becomes inflamed in endotoxemia. We hypothesize that progressive inflammation is a critical factor in losing HRV, ventilatory pattern variability (VPV), and cardiorespiratory coupling (CRC) associated with sepsis. We propose to build on the strengths of agent-based and computational modeling approaches and perform model-driven experiments to determine how alterations of brainstem neurophysiology in sepsis limit physiologic pattern variability. Our preliminary data show that endotoxemic rats lose CRC progressively in association with proinflammatory cytokines expression first in the nucleus tractus solitarius (nTS) then in the nucleus Ambiguus. Further, consistent with a progressive loss of CRC focal IL-1β microinjections in the nTS uncouples the arterial pulse pressure's influence on respiration leaving RSA intact. The Specific Aims are: 1) to develop DyNa and DyBN models of cytokine expression in brainstem cardiorespiratory control nuclei during septicemia to determine if central and peripheral inflammation patterns, 2) to adapt these models to critically-ill humans at risk for sepsis and probe the robustness of the model by applying therapeutic interventions in rats, and 3) to apply our control model to propose plausible and testable mechanisms for the effects of cytokines on the function of cardiorespiratory control circuitry. Our computational model of the neural control of cardiorespiratory coupling as well as the models defining the interactions among cytokines in tissue inflammation have been applied successfully to other conditions (sympatho-respiratory coupling) or to peripheral tissues (cytokine expression and interaction). Integrating these models will provide cross-scale mechanistic explanations for the loss of RSA and CVC observed during sepsis, identify critical cytokines for therapeutic intervention, and will establish a scientific rationale for using CRC and variability measures as complementary and sensitive biomarkers of sepsis.

脓毒症是一种全身性感染，伴有不受控制的炎症反应。快速恶化的心率变异性 (HRV) 是至关重要的。 HRV 是脓毒症的生物标志物，可预测其预后，但特异性太低，无法做出诊断。通过其功率谱及其在频域中的变化来量化；迷走神经活动的呼吸调节。脑干的计算确定性模型。心肺控制网络提出了迷走呼吸的合理神经机制与 HRV 不同的是，动态网络分析 (DyNA) 和动态贝叶斯网络 (DyBN)。模型在识别脓毒症的“临界点”方面具有高度特异性并成功，即当受控的炎症反应变得不受控制，但其许多变量最近很难测量。确定脑干在内毒素血症中发炎，我们对进行性进行了扰乱。炎症是导致 HRV、通气模式变异性 (VPV) 和心肺功能丧失的关键因素我们建议利用基于代理和脓毒症的耦合（CRC）。计算建模方法并执行模型驱动的实验以确定如何改变我们的初步数据表明，脓毒症中脑干神经生理学的研究限制了生理模式的变异性。内毒素血症大鼠逐渐丧失 CRC，首先与促炎细胞因子表达相关孤束核（nTS）然后是模糊核，进一步与进行性一致。 nTS 中 CRC 局灶性 IL-1β 显微注射的缺失消除了动脉脉压对呼吸作用使 RSA 保持完整。具体目标是：1) 开发细胞因子的 DyNa 和 DyBN 模型。败血症期间脑干心肺控制核中的表达以确定是否中枢和外周炎症模式，2）使这些模型适应有败血症风险的危重患者和通过对大鼠应用治疗干预措施来探讨模型的稳健性，以及 3）应用我们的控制模型提出细胞因子对细胞功能影响的合理且可测试的机制心肺控制电路。我们的心肺神经控制的计算模型。耦合以及定义组织炎症中细胞因子之间相互作用的模型已被成功应用于其他条件（交感呼吸耦合）或外周组织（细胞因子表达和相互作用）。整合这些模型将为以下问题提供跨尺度的机制解释：败血症期间观察到的 RSA 和 CVC 丢失，确定治疗干预的关键细胞因子，并将建立使用 CRC 和变异性测量作为补充和补充的科学原理脓毒症的敏感生物标志物。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years.

DOI：
10.1113/jp281953
发表时间：
2022-05
期刊：
JOURNAL OF PHYSIOLOGY-LONDON
影响因子：
5.5
作者：
Paton, Julian F. R.;Machado, Benedito H.;Moraes, Davi J. A.;Zoccal, Daniel B.;Abdala, Ana P.;Smith, Jeffrey C.;Antunes, Vagner R.;Murphy, David;Dutschmann, Mathias;Dhingra, Rishi R.;McAllen, Robin;Pickering, Anthony E.;Wilson, Richard J. A.;Day, Trevor A.;Barioni, Nicole O.;Allen, Andrew M.;Menuet, Clement;Donnelly, Joseph;Felippe, Igor;St-John, Walter M.
通讯作者：
St-John, Walter M.

Pre- and post-inspiratory neurons change their firing properties in female rats exposed to chronic intermittent hypoxia.

暴露于慢性间歇性缺氧的雌性大鼠中，吸气前和吸气后神经元的放电特性发生变化。

DOI：
10.1016/j.neuroscience.2019.03.043
发表时间：
2019
期刊：
Neuroscience
影响因子：
3.3
作者：
Souza,GeorgeMPR;Barnett,WilliamH;Amorim,MateusR;Lima-Silveira,Ludmila;Moraes,DaviJA;Molkov,YaroslavI;Machado,BeneditoH
通讯作者：
Machado,BeneditoH

Chemoreception and neuroplasticity in respiratory circuits.

DOI：
10.1016/j.expneurol.2016.05.036
发表时间：
2017-01
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Barnett, William H.;Abdala, Ana P.;Paton, Julian F. R.;Rybak, Ilya A.;Zoccal, Daniel B.;Molkov, Yaroslav I.
通讯作者：
Molkov, Yaroslav I.

Inhibitory control of active expiration by the Bötzinger complex in rats.