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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.

脓毒症是伴随着不受控制的炎症反应的全身性感染；一种可以迅速恶化。早期诊断是生存的关键。心率变异性(HRV)，一种建议的脓毒症的生物标志物，预测其预后，但太不特异而无法做出诊断。通常，HRV是由其功率谱、其在频域中的变化性来量化；“高频”分量反映了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为迷走神经提出了合理的神经机制。耦合。与HRV相比，动态网络分析(DYNA)和动态贝叶斯网络(DyBN) 模型高度特异性和成功地识别了脓毒症的“临界点”，即当一个对照炎症反应变得失控，但它的许多变量很难衡量。最近，我们发现脑干在内毒素血症中发炎。我们假设进步主义炎症是导致HRV、呼吸模式变异性(VPV)和心肺功能丧失的关键因素与脓毒症相关的偶联(CRC)。我们建议在基于代理的和计算建模方法并执行模型驱动的实验，以确定如何进行更改脓毒症的脑干神经生理学研究限制了生理模式的变异性。我们的初步数据显示，内毒素血症大鼠CRC进行性丧失与促炎细胞因子表达有关孤束核(NTS)则位于疑核。此外，与进步一致的结直肠癌局灶性IL-1β在孤束核内微量注射的缺失对动脉脉压的影响呼吸使RSA完好无损。具体目标是：1)建立细胞因子的DyNA和DyBN模型败血症时脑干心肺控制核团的表达外周炎症模式，2)使这些模型适用于有脓毒症风险的危重患者和通过在大鼠身上应用治疗性干预来探索该模型的稳健性，以及3)应用我们的对照为细胞因子对血管内皮细胞功能的影响提出可信和可测试的机制的模型心肺控制电路。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经被成功应用于其他情况(交感-呼吸耦合)或外周组织(细胞因子表达和互动)。集成这些模型将提供跨尺度的机制解释在脓毒症期间观察RSA和CVC的丢失，确定用于治疗干预的关键细胞因子，并将为使用CRC和可变性措施作为补充和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.