Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve

Wasilczuk, Kelsey M.; Bayer, Kelsey C.; Somann, Jesse P.; Albors, Gabriel O.; Sturgis, Jennifer; Lyle, L. Tiffany; Robinson, J. Paul; Irazoqui, Pedro P.

doi:10.1016/j.ultrasmedbio.2018.09.005

Cited by 20 publications

(17 citation statements)

References 41 publications

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“…The consequences of subdiaphragmatic vagotomy should be investigated to see if it is a clinically viable option to aid in selectivity of therapy. Alternative and less invasive methods could also be used to stimulate the subdiaphragmatic branches, such as focused ultrasound, which was recently used to modulate TNF-α by activating the left cervical vagus nerve [30].…”

Section: Discussionmentioning

confidence: 99%

“…We fabricated custom bi-polar stimulation cuffs (S1 Fig) using platinum-iridium wire and medical-grade silicone tubing, as done previously [29]. The cervical cuffs used in this study have been previously characterized [30]. Our cervical electrodes had a measured impedance of 1.40–1.62 kΩ at 1 kHz.…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed plasma samples using a LEGENDplex Rat Th Cytokine Panel (13-plex) (Biolegend, San Diego, CA), which allowed simultaneous analysis of 13 cytokines: Interleukin (IL)-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α. The cytokine kit was modified for use with 384-well plates and the samples processed, as described previously [30]. Many of our IL-6 samples showed levels far above the upper limits of our established flow-cytometry methods.…”

Section: Methodsmentioning

confidence: 99%

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Characterization of plasma cytokine response to intraperitoneally administered LPS & subdiaphragmatic branch vagus nerve stimulation in rat model

et al. 2019

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Vagus nerve stimulation (VNS) has been on the forefront of inflammatory disorder research and has yielded many promising results. Questions remain, however, about the biological mechanisms of such treatments and the inconsistencies in the methods used in research efforts. Here, we aimed to clarify the inflammatory response to intraperitoneal (IP) injections of lipopolysaccharide (LPS) in rats, while analyzing corresponding effects of electrical stimulation to subdiaphragmatic branches (anterior gastric, accessory celiac, and hepatic) of the left vagus nerve. We accomplished an in-depth characterization of the time-varying cytokine cascade response in the serum of 58 rats to an acute IP LPS challenge over a 330-minute period by utilizing curve-fitting and starting point-alignment methods. We then explored the post-LPS neuromodulation effects of electrically stimulating individually cuffed subdiaphragmatic branches. Through our analysis, we found there to be a consistent order of IP LPS cytokine response (IL-10, TNF-α, GM-CSF, IL-17F, IL-6, IL-22, INF-γ). Apart from IL-10, the IP cytokine cascade was more variable in starting time and occurred later than in previously recorded intravenous (IV) challenges. We also found distinct regulatory effects on multiple cytokine levels by each of the three subdiaphragmatic stimulation subsets. While the timevariability of IP LPS use in rats complicates its utility, we have shown it to be a practical, arguably more physiologically relevant method than IV in rats when our methods are used. More importantly, we have shown that selective subdiaphragmatic neurostimulation can be utilized to selectively induce specific effects on inflammation in the body.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Characterization of plasma cytokine response to intraperitoneally administered LPS & subdiaphragmatic branch vagus nerve stimulation in rat model

et al. 2019

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“…Protection by ultrasound was also demonstrated in a cecal ligation and puncture model of sepsis. Although the mechanism by which ultrasound protects the kidney from AKI needs further investigation, recent findings suggest that the direct target of ultrasound could be the vagus nerve 119 or the spleen, including the splenic nerve. 120,121 Stimulation of neurons in a specific brain region, C1 neurons, can also activate the CAP and protect the kidney against AKI.…”

Section: Neuroimmune Interaction In Regulating Inflammatory Diseasesmentioning

confidence: 99%

Crosstalk between the nervous system and the kidney

Tanaka

Okusa

2020

Kidney International

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Under physiological states, the nervous system and the kidneys communicate with each other to maintain normal body homeostasis. However, pathological states disrupt this interaction as seen in hypertension, and kidney damage can cause impaired renorenal reflex and sodium handling. In acute kidney injury (AKI) and chronic kidney disease (CKD), damaged kidneys can have a detrimental effect on the central nervous system. CKD is an independent risk factor for cerebrovascular disease and cognitive impairment, and many factors, including retention of uremic toxins and phosphate, have been proposed as CKD-specific factors responsible for structural and functional cerebral changes in patients with CKD. However, more studies are needed to determine the precise pathogenesis. Epidemiological studies have shown that AKI is associated with a subsequent risk for developing stroke and dementia. However, recent animal studies have shown that the renal nerve contributes to kidney inflammation and fibrosis, whereas activation of the cholinergic anti-inflammatory pathway, which involves the vagus nerve, the splenic nerve, and immune cells in the spleen, has a significant renoprotective effect. Therefore, elucidating mechanisms of communication between the nervous system and the kidney enables us not only to develop new strategies to ameliorate neurological conditions associated with kidney disease but also to design safe and effective clinical interventions for kidney disease, using the neural and neuroimmune control of kidney injury and disease.

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“…Moreover, bone marrow chimera studies demonstrated that α7nAChRs expressed in hematopoietic cells are essential for the protection by US. Wasilczuk et al (Wasilczuk et al 2018) recently showed that focused ultrasound application to the left cervical vagus nerve in rats significantly reduced plasma TNFα levels after LPS administration, whereas US insonation targeted to the spleen also conferred an anti-inflammatory effect (Cotero et al 2019) (Zachs et al 2019), indicating that the vagus/ splenic nerve and splenocytes can be the direct target of US. Regarding the mechanism by which US can affect the nerve, several possibilities have been proposed including a mechanical or thermal effect on mechanically-activated ion channels or voltage-gated ion channels expressed in the neurons and a cavitational effect leading to ionic flux (Downs et al 2018;Kim et al 2012;Tyler et al 2008) (Wright et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway

Tanaka

Hammond²,

Rosin

2019

Bioelectron Med

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Neuroimmunomodulation through peripheral nerve activation is an important therapeutic approach to various disorders. Central to this approach is the inflammatory reflex pathway in which the cholinergic anti-inflammatory pathway represents the efferent limb. Recent studies provide a framework for understanding this control pathway, however our understanding remains incomplete. Genetically modified mice, using optogenetics and pharmacogenomics, have been invaluable resources that will allow investigators to disentangle neural pathways that provide a unifying mechanism by which vagal nerve stimulation (and other means of stimulating the pathway) leads to an anti-inflammatory and tissue protective effect. In this review we describe disease models that contribute to our understanding of how vagal nerve stimulation attenuates inflammation and organ injury: acute kidney injury, rheumatoid arthritis, and inflammatory gastrointestinal disease. The gut microbiota contributes to health and disease and the potential role of the vagus nerve in affecting the relationship between gut microbiota and the immune system and modifying diseases remains an intriguing opportunity to attenuate local and systemic inflammation that undergird disease processes.

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Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve

Cited by 20 publications

References 41 publications

Characterization of plasma cytokine response to intraperitoneally administered LPS & subdiaphragmatic branch vagus nerve stimulation in rat model

Characterization of plasma cytokine response to intraperitoneally administered LPS & subdiaphragmatic branch vagus nerve stimulation in rat model

Crosstalk between the nervous system and the kidney

Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway

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