The timing and degree of fetal systemic and cerebral inflammatory responses correlate with a subset of heart rate variability measures: Evidence of cholinergic anti-inflammatory pathway activation in sepsis

Neuroinflammation in utero may contribute to brain injury resulting in life long neurological disabilities. The pivotal role of the efferent cholinergic anti-inflammatory pathway (CAP) in controlling inflammation has been described in adults, but its importance in the fetus is unknown. Moreover, it is unknown whether CAP may also exert anti-inflammatory effects on the brain via CAP's afferent component of the vagus nerve. Based on multiple clinical studies in adults and our own work in fetal autonomic nervous system, we gauged the degree of CAP activity in vivo using heart rate variability measures reflecting fluctuations in vagus nerve activity. Measuring microglial activation in the ovine fetal brain near-term, we show in vivo that afferent fetal CAP may translate increased vagal cholinergic signaling into suppression of cerebral inflammation in response to near-term hypoxic acidemia as might occur during labour. Our findings suggest a new control mechanism of fetal neuroinflammation via the vagus nerve, providing novel possibilities for its non-invasive monitoring in utero and for targeted treatment.

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Personalized mathematical model of endotoxin-induced inflammatory responses in young men and associated changes in heart rate variability

Mathematical Modelling of Natural Phenomena ◽

10.1051/mmnp/2018031 ◽

2018 ◽

Vol 13 (5) ◽

pp. 42 ◽

Cited By ~ 2

Author(s):

R. Brady ◽

D.O. Frank-Ito ◽

H.T. Tran ◽

S. Janum ◽

K. Møller ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Tnf Alpha ◽

Non Invasive ◽

Estimated Parameters ◽

Subject Specific ◽

The Subject ◽

Necrosis Factor

The objective of this study was to develop a personalized inflammatory model and estimate subject-specific parameters that could be related to changes in heart rate variability (HRV), a measure that can be obtained non-invasively in real time. An inflammatory model was developed and calibrated to measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), interleukin-8 (IL-8) and interleukin-10 (IL-10) over 8 hours in 20 subjects administered a low dose of lipopolysaccharide. For this model, we estimated 11 subject-specific parameters for all 20 subjects. Estimated parameters were correlated with changes in HRV, computed from ECG measurements using a built-in HRV module available in Labchart. Results revealed that patients could be separated into two groups expressing normal and abnormal responses to endotoxin. Abnormal responders exhibited increased HRV, most likely as a result of increased vagal firing. The observed correlation between the inflammatory response and HRV brings us a step further towards understanding if HRV predictions can be used as a marker for inflammation. Analyzing HRV parameters provides an easy, non-invasively obtained measure that can be used to assess the state of the subject, potentially translating to identifying a non-invasive marker that can be used to detect the onset of sepsis.

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Heart Rate Variability Predicts Cell Death and Inflammatory Responses to Global Cerebral Ischemia

Frontiers in Physiology ◽

10.3389/fphys.2012.00131 ◽

2012 ◽

Vol 3 ◽

Cited By ~ 13

Author(s):

Greg J. Norman ◽

Kate Karelina ◽

Gary G. Berntson ◽

John S. Morris ◽

Ning Zhang ◽

...

Keyword(s):

Heart Rate ◽

Cell Death ◽

Heart Rate Variability ◽

Cerebral Ischemia ◽

Inflammatory Responses ◽

Global Cerebral Ischemia

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The Cholinergic Anti-Inflammatory Pathway as a Conceptual Framework to Treat Inflammation-Mediated Renal Injury

Kidney & Blood Pressure Research ◽

10.1159/000500920 ◽

2019 ◽

Vol 44 (4) ◽

pp. 435-448 ◽

Cited By ~ 4

Author(s):

Jonas Jarczyk ◽

Benito A. Yard ◽

Simone Hoeger

Keyword(s):

Vagus Nerve ◽

Inflammatory Responses ◽

Current Knowledge ◽

Kidney Injury ◽

Organ Injury ◽

Inflammatory Pathway ◽

Inflammatory Conditions ◽

Promising Strategy ◽

Anti Inflammatory ◽

The Brain

Background: The cholinergic anti-inflammatory pathway, positioned at the interface of the nervous and immune systems, is the efferent limb of the “inflammatory reflex” which mainly signals through the vagus nerve. As such, the brain can modulate peripheral inflammatory responses by the activation of vagal efferent fibers. Importantly, immune cells in the spleen express most cholinergic system components such as acetylcholine (ACh), choline acetyltransferase, acetylcholinesterase, and both muscarinic and nicotinic ACh receptors, making communication between both systems possible. In general, this communication down-regulates the inflammation, achieved through different mechanisms and depending on the cells involved. Summary: With the awareness that the cholinergic anti-inflammatory pathway serves to prevent or limit inflammation in peripheral organs, vagus nerve stimulation has become a promising strategy in the treatment of several inflammatory conditions. Both pharmacological and non-pharmacological methods have been used in many studies to limit organ injury as a consequence of inflammation. Key Messages: In this review, we will highlight our current knowledge of the cholinergic anti-inflammatory pathway, with emphasis on its potential clinical use in the treatment of inflammation-triggered kidney injury.

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Transcutaneous Auricular Vagus Nerve Stimulation Protects Endotoxemic Rat from Lipopolysaccharide-Induced Inflammation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/627023 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 33

Author(s):

Yu Xue Zhao ◽

Wei He ◽

Xiang Hong Jing ◽

Jun Ling Liu ◽

Pei Jing Rong ◽

...

Keyword(s):

Vagus Nerve ◽

Proinflammatory Cytokines ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Nf Kappa B ◽

Necrosis Factor Alpha ◽

Inflammatory Pathway ◽

Anti Inflammatory

Background. Transcutaneous auricular vagus nerve stimulation (ta-VNS) could evoke parasympathetic activities via activating the brainstem autonomic nuclei, similar to the effects that are produced after vagus nerve stimulation (VNS). VNS modulates immune function through activating the cholinergic anti-inflammatory pathway.Methods. VNS, ta-VNS, or transcutaneous electrical acupoint stimulation (TEAS) on ST36 was performed to modulate the inflammatory response. The concentration of serum proinflammatory cytokines and tissue NF-kappa B p65 (NF-κB p65) were detected in endotoxaemia affected anesthetized rats.Results. Similar to the effect of VNS, ta-VNS suppressed the serum proinflammatory cytokines levels, such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as well as NF-kappa B p65 expressions of lung tissues. ST36 stimulation also decreases LPS-induced high TNF-αlevel and NF-κB signal, but it did not restrain proinflammatory cytokine IL-1βand IL-6. Neither ta-VNS nor ST36 stimulation could suppress LPS-induced TNF-αand NF-κB after vagotomy or withα7nAChR antagonist injection.Conclusions. The present paper demonstrated that ta-VNS could be utilized to suppress LPS-induced inflammatory responses viaα7nAChR-mediated cholinergic anti-inflammatory pathway.

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