Thrombin Mediates Vagal Apoptosis and Dysfunction in Inflammatory Bowel Disease

Fritze, Danielle; Zhang, Weizhen; Li, Ji Yao; Chai, Biaoxin; Mulholland, Michael W.

doi:10.1007/s11605-014-2565-6

Cited by 8 publications

(7 citation statements)

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“…Rectal administration of TNBS resulted in the development of clinical symptoms of colitis, which manifested as a decrease in food intake and a decrease in body weight, similar to what has been observed in previous studies [33, 34, 39]. On the experimental day 0, the body weight was 352 ± 24 g and did not differ significantly between the groups (one-way ANOVA, F = 0.512, p = 0.61).…”

Section: Resultssupporting

confidence: 85%

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Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

et al. 2016

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PurposeUlcerative colitis (UC) is a chronic inflammatory disease of the colon that affects an increasing number of patients. High comorbidity is observed between UC and other diseases in which inflammation may be involved, including brain diseases such as cognitive impairment, mental disorders, anxiety, and depression. To investigate the increased occurrence of these brain diseases in patients with UC, non-invasive methods for monitoring peripheral and central inflammation could be applied. Therefore, the goal of this study is to assess the feasibility of monitoring gut and brain inflammation in a rat model of chemically induced colitis by positron emission tomography (PET) with [11C]PBR28, a tracer targeting the translocator protein (TSPO), which is upregulated when microglia and macrophages are activated.ProceduresColitis was induced in rats by intra-rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Rats with colitis and healthy control animals were subjected to [11C]PBR28 PET of the abdomen followed by ex vivo biodistribution in order to assess whether inflammation in the gut could be detected. Another group of rats with colitis underwent repetitive [11C]PBR28 PET imaging of the brain to investigate the development of neuroinflammation.ResultsEleven days after TNBS injection, ex vivo biodistribution studies demonstrated increased [11C]PBR28 uptake in the inflamed cecum and colon of rats with colitis as compared to healthy controls, whereas PET imaging did not show any difference between groups at any time. Similarly, repetitive PET imaging of the brain did not reveal any neuroinflammation induced by the TNBS administration in the colon. In contrast, significantly increased [11C]PBR28 uptake in cerebellum could be detected in ex vivo biodistribution studies on day 11.ConclusionInflammation in both the gut and the brain of rats with chemically induced colitis was observed by ex vivo biodistribution. However, these effects could not be detected by [11C]PBR28 PET imaging in our colitis model, which is likely due to spill-over effects and insufficient resolution of the PET camera.

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Section: Resultssupporting

confidence: 85%

“…The rat model of TNBS-induced colitis was employed according to a previously described method [32, 34]. Briefly, on experimental day 0, rats were anesthetized with isoflurane (5 % induction and 3 % maintenance) mixed with oxygen.…”

Section: Methodsmentioning

confidence: 99%

Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

et al. 2016

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“…Colitis induced in an experimental model was markedly decreased in PAR1 knockout mice or in mice exposed to the PAR1 antagonist RW-56110 compared with control and expression of PAR1 was upregulated in intestinal biopsies from patients with colitis [89]. Administration of FR171113 decreased intestinal vagal apoptosis observed following experimentally induced colitis [90]. PAR1 functions in the immune response to viral infection and PAR1 knockout is protective in mouse models of influenza and coxsackievirus-induced myocarditis [91,92].…”

Section: Indications For Par1 Modulationmentioning

confidence: 99%

Targeting PAR1: Now What?

Flaumenhaft

Ceunynck

2017

Trends in Pharmacological Sciences

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Protease-activated receptors (PARs) are a ubiquitously expressed class of GPCRs that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. This review will critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

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“…Since cortisol is an efferent agent in anti-inflammatory neural reflexes like the CAP (Bonaz et al, 2021 ), its reduced production may alter the CAP development itself. Indeed, low cortisol levels could fail in regulating postnatal inflammation, e.g., necrotizing enterocolitis (NEC), which could induce cell death in the vagal brainstem centers (Fritze et al, 2014 ).…”

Section: The Fetal Ans Development: the Search Of “Critical Windows”mentioning

confidence: 99%

A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows

Cerritelli¹,

Frasch²,

Antonelli³

et al. 2021

Front. Neurosci.

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The autonomic nervous system (ANS) is one of the main biological systems that regulates the body's physiology. Autonomic nervous system regulatory capacity begins before birth as the sympathetic and parasympathetic activity contributes significantly to the fetus' development. In particular, several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal, and postnatal life: from the regulation of inflammation through the anti-inflammatory cholinergic pathway, which may affect the functioning of each organ, to the production of hormones involved in bioenergetic metabolism. In addition, the vagus nerve has been recognized as the primary afferent pathway capable of transmitting information to the brain from every organ of the body. Therefore, this hypothesis paper aims to review the development of ANS during fetal and perinatal life, focusing particularly on the vagus nerve, to identify possible “critical windows” that could impact its maturation. These “critical windows” could help clinicians know when to monitor fetuses to effectively assess the developmental status of both ANS and specifically the vagus nerve. In addition, this paper will focus on which factors—i.e., fetal characteristics and behaviors, maternal lifestyle and pathologies, placental health and dysfunction, labor, incubator conditions, and drug exposure—may have an impact on the development of the vagus during the above-mentioned “critical window” and how. This analysis could help clinicians and stakeholders define precise guidelines for improving the management of fetuses and newborns, particularly to reduce the potential adverse environmental impacts on ANS development that may lead to persistent long-term consequences. Since the development of ANS and the vagus influence have been shown to be reflected in cardiac variability, this paper will rely in particular on studies using fetal heart rate variability (fHRV) to monitor the continued growth and health of both animal and human fetuses. In fact, fHRV is a non-invasive marker whose changes have been associated with ANS development, vagal modulation, systemic and neurological inflammatory reactions, and even fetal distress during labor.

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Thrombin Mediates Vagal Apoptosis and Dysfunction in Inflammatory Bowel Disease

Abstract: IBD is associated with DMV microglial activation and production of prothrombin. Thrombin in the DMV causes vagal neuron apoptosis and decreased sensitivity to neurotransmitters.

Cited by 8 publications

References 44 publications

Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

Targeting PAR1: Now What?

A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows

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